Stress B Plus

Calcium (Calcium Carbonate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stress B Plus (Calcium (Calcium Carbonate)) reviews

1 INDICATIONS AND USAGE

Stress B Plus (Calcium (Calcium Carbonate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Stress B Plus (Calcium (Calcium Carbonate)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Stress B Plus (Calcium (Calcium Carbonate)) acetate capsule.

- Capsule: 667 mg Stress B Plus (Calcium (Calcium Carbonate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Stress B Plus ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Stress B Plus (Calcium (Calcium Carbonate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Stress B Plus (Calcium (Calcium Carbonate)), including Stress B Plus (Calcium (Calcium Carbonate)) acetate. Avoid the use of Stress B Plus (Calcium (Calcium Carbonate)) supplements, including Stress B Plus (Calcium (Calcium Carbonate)) based nonprescription antacids, concurrently with Stress B Plus (Calcium (Calcium Carbonate)) acetate.

An overdose of Stress B Plus (Calcium (Calcium Carbonate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Stress B Plus (Calcium (Calcium Carbonate)) levels twice weekly. Should hypercalcemia develop, reduce the Stress B Plus (Calcium (Calcium Carbonate)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Stress B Plus (Calcium (Calcium Carbonate)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Stress B Plus (Calcium (Calcium Carbonate)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Stress B Plus (Calcium (Calcium Carbonate)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Stress B Plus (Calcium (Calcium Carbonate)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Stress B Plus (Calcium (Calcium Carbonate)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Stress B Plus (Calcium (Calcium Carbonate)) acetate has been generally well tolerated.

Stress B Plus (Calcium (Calcium Carbonate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Stress B Plus (Calcium (Calcium Carbonate)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Preferred Term	Total adverse reactions reported for Stress B Plus (Calcium (Calcium Carbonate)) acetate N=167 N (%)	3 month, open label study of Stress B Plus (Calcium (Calcium Carbonate)) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Stress B Plus (Calcium (Calcium Carbonate)) acetate N=69
			Stress B Plus (Calcium (Calcium Carbonate)) acetate N (%)	Placebo N (%)
Nausea	6 (3.6)	6 (6.1)	0 (0)	0 (0)
Vomiting	4 (2.4)	4 (4.1)	0 (0)	0 (0)
Hypercalcemia	21 (12.6)	16 (16.3)	5 (7.2)	0 (0)

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Stress B Plus (Calcium (Calcium Carbonate)) concentration could reduce the incidence and severity of Stress B Plus (Calcium (Calcium Carbonate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Stress B Plus (Calcium (Calcium Carbonate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Stress B Plus ) acetate is characterized by the potential of Stress B Plus (Calcium (Calcium Carbonate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Stress B Plus (Calcium (Calcium Carbonate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Stress B Plus (Calcium (Calcium Carbonate)) acetate and most concomitant drugs. When administering an oral medication with Stress B Plus (Calcium (Calcium Carbonate)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Stress B Plus (Calcium (Calcium Carbonate)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Stress B Plus (Calcium (Calcium Carbonate)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Stress B Plus (Calcium (Calcium Carbonate)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Stress B Plus (Calcium (Calcium Carbonate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Stress B Plus ) acetate capsules contains Stress B Plus (Calcium (Calcium Carbonate)) acetate. Animal reproduction studies have not been conducted with Stress B Plus (Calcium (Calcium Carbonate)) acetate, and there are no adequate and well controlled studies of Stress B Plus (Calcium (Calcium Carbonate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Stress B Plus (Calcium (Calcium Carbonate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Stress B Plus (Calcium (Calcium Carbonate)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Stress B Plus (Calcium (Calcium Carbonate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Stress B Plus (Calcium (Calcium Carbonate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Stress B Plus (Calcium (Calcium Carbonate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Stress B Plus ) Acetate Capsules contains Stress B Plus (Calcium (Calcium Carbonate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Stress B Plus (Calcium (Calcium Carbonate)) acetate is not expected to harm an infant, provided maternal serum Stress B Plus (Calcium (Calcium Carbonate)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Stress B Plus (Calcium (Calcium Carbonate)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Stress B Plus (Calcium (Calcium Carbonate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Stress B Plus (Calcium (Calcium Carbonate)) acetate acts as a phosphate binder. Its chemical name is Stress B Plus (Calcium (Calcium Carbonate)) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Stress B Plus (Calcium (Calcium Carbonate)) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Stress B Plus (Calcium (Calcium Carbonate)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Stress B Plus (Calcium (Calcium Carbonate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Stress B Plus ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Stress B Plus (Calcium (Calcium Carbonate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Stress B Plus (Calcium (Calcium Carbonate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Stress B Plus (Calcium (Calcium Carbonate)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Stress B Plus (Calcium (Calcium Carbonate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Stress B Plus (Calcium (Calcium Carbonate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Stress B Plus (Calcium (Calcium Carbonate)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Stress B Plus (Calcium (Calcium Carbonate)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Stress B Plus (Calcium (Calcium Carbonate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Stress B Plus (Calcium (Calcium Carbonate)) levels are also presented.

* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE.
Parameter	Pre-Study	Week 4*	Week 8	Week 12	p-value†
Phosphorus (mg/dL)‡	7.4 ± 0.17	5.9 ± 0.16	5.6 ± 0.17	5.2 ± 0.17	≤0.01
Stress B Plus (Calcium (Calcium Carbonate)) (mg/dL)‡	8.9 ± 0.09	9.5 ± 0.10	9.7 ± 0.10	9.7 ± 0.10	≤0.01

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Stress B Plus (Calcium (Calcium Carbonate)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Stress B Plus (Calcium (Calcium Carbonate)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Stress B Plus (Calcium (Calcium Carbonate)) acetate is shown in the Table 3.

* ANOVA of Stress B Plus (Calcium (Calcium Carbonate)) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Stress B Plus (Calcium (Calcium Carbonate)) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Stress B Plus (Calcium (Calcium Carbonate)) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with Stress B Plus (Calcium (Calcium Carbonate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Stress B Plus (Calcium (Calcium Carbonate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Stress B Plus (Calcium (Calcium Carbonate)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Stress B Plus (Calcium (Calcium Carbonate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Stress B Plus (Calcium (Calcium Carbonate)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Stress B Plus (Calcium (Calcium Carbonate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Citrate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stress B Plus (Calcium (Calcium Citrate)) reviews

1 INDICATIONS AND USAGE

Stress B Plus (Calcium (Calcium Citrate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Stress B Plus (Calcium (Calcium Citrate)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Stress B Plus (Calcium (Calcium Citrate)) acetate capsule.

- Capsule: 667 mg Stress B Plus (Calcium (Calcium Citrate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Stress B Plus ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Stress B Plus (Calcium (Calcium Citrate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Stress B Plus (Calcium (Calcium Citrate)), including Stress B Plus (Calcium (Calcium Citrate)) acetate. Avoid the use of Stress B Plus (Calcium (Calcium Citrate)) supplements, including Stress B Plus (Calcium (Calcium Citrate)) based nonprescription antacids, concurrently with Stress B Plus (Calcium (Calcium Citrate)) acetate.

An overdose of Stress B Plus (Calcium (Calcium Citrate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Stress B Plus (Calcium (Calcium Citrate)) levels twice weekly. Should hypercalcemia develop, reduce the Stress B Plus (Calcium (Calcium Citrate)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Stress B Plus (Calcium (Calcium Citrate)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Stress B Plus (Calcium (Calcium Citrate)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Stress B Plus (Calcium (Calcium Citrate)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Stress B Plus (Calcium (Calcium Citrate)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Stress B Plus (Calcium (Calcium Citrate)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Stress B Plus (Calcium (Calcium Citrate)) acetate has been generally well tolerated.

Stress B Plus (Calcium (Calcium Citrate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Stress B Plus (Calcium (Calcium Citrate)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Preferred Term	Total adverse reactions reported for Stress B Plus (Calcium (Calcium Citrate)) acetate N=167 N (%)	3 month, open label study of Stress B Plus (Calcium (Calcium Citrate)) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Stress B Plus (Calcium (Calcium Citrate)) acetate N=69
			Stress B Plus (Calcium (Calcium Citrate)) acetate N (%)	Placebo N (%)
Nausea	6 (3.6)	6 (6.1)	0 (0)	0 (0)
Vomiting	4 (2.4)	4 (4.1)	0 (0)	0 (0)
Hypercalcemia	21 (12.6)	16 (16.3)	5 (7.2)	0 (0)

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Stress B Plus (Calcium (Calcium Citrate)) concentration could reduce the incidence and severity of Stress B Plus (Calcium (Calcium Citrate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Stress B Plus (Calcium (Calcium Citrate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Stress B Plus ) acetate is characterized by the potential of Stress B Plus (Calcium (Calcium Citrate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Stress B Plus (Calcium (Calcium Citrate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Stress B Plus (Calcium (Calcium Citrate)) acetate and most concomitant drugs. When administering an oral medication with Stress B Plus (Calcium (Calcium Citrate)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Stress B Plus (Calcium (Calcium Citrate)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Stress B Plus (Calcium (Calcium Citrate)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Stress B Plus (Calcium (Calcium Citrate)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Stress B Plus (Calcium (Calcium Citrate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Stress B Plus ) acetate capsules contains Stress B Plus (Calcium (Calcium Citrate)) acetate. Animal reproduction studies have not been conducted with Stress B Plus (Calcium (Calcium Citrate)) acetate, and there are no adequate and well controlled studies of Stress B Plus (Calcium (Calcium Citrate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Stress B Plus (Calcium (Calcium Citrate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Stress B Plus (Calcium (Calcium Citrate)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Stress B Plus (Calcium (Calcium Citrate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Stress B Plus (Calcium (Calcium Citrate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Stress B Plus (Calcium (Calcium Citrate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Stress B Plus ) Acetate Capsules contains Stress B Plus (Calcium (Calcium Citrate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Stress B Plus (Calcium (Calcium Citrate)) acetate is not expected to harm an infant, provided maternal serum Stress B Plus (Calcium (Calcium Citrate)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Stress B Plus (Calcium (Calcium Citrate)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Stress B Plus (Calcium (Calcium Citrate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Stress B Plus (Calcium (Calcium Citrate)) acetate acts as a phosphate binder. Its chemical name is Stress B Plus (Calcium (Calcium Citrate)) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Stress B Plus (Calcium (Calcium Citrate)) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Stress B Plus (Calcium (Calcium Citrate)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Stress B Plus (Calcium (Calcium Citrate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Stress B Plus ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Stress B Plus (Calcium (Calcium Citrate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Stress B Plus (Calcium (Calcium Citrate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Stress B Plus (Calcium (Calcium Citrate)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Stress B Plus (Calcium (Calcium Citrate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Stress B Plus (Calcium (Calcium Citrate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Stress B Plus (Calcium (Calcium Citrate)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Stress B Plus (Calcium (Calcium Citrate)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Stress B Plus (Calcium (Calcium Citrate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Stress B Plus (Calcium (Calcium Citrate)) levels are also presented.

* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE.
Parameter	Pre-Study	Week 4*	Week 8	Week 12	p-value†
Phosphorus (mg/dL)‡	7.4 ± 0.17	5.9 ± 0.16	5.6 ± 0.17	5.2 ± 0.17	≤0.01
Stress B Plus (Calcium (Calcium Citrate)) (mg/dL)‡	8.9 ± 0.09	9.5 ± 0.10	9.7 ± 0.10	9.7 ± 0.10	≤0.01

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Stress B Plus (Calcium (Calcium Citrate)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Stress B Plus (Calcium (Calcium Citrate)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Stress B Plus (Calcium (Calcium Citrate)) acetate is shown in the Table 3.

* ANOVA of Stress B Plus (Calcium (Calcium Citrate)) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Stress B Plus (Calcium (Calcium Citrate)) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Stress B Plus (Calcium (Calcium Citrate)) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with Stress B Plus (Calcium (Calcium Citrate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Stress B Plus (Calcium (Calcium Citrate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Stress B Plus (Calcium (Calcium Citrate)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Stress B Plus (Calcium (Calcium Citrate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Stress B Plus (Calcium (Calcium Citrate)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Stress B Plus (Calcium (Calcium Citrate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Gluconate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stress B Plus (Calcium (Calcium Gluconate)) reviews

1 INDICATIONS AND USAGE

Stress B Plus (Calcium (Calcium Gluconate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Stress B Plus (Calcium (Calcium Gluconate)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Stress B Plus (Calcium (Calcium Gluconate)) acetate capsule.

- Capsule: 667 mg Stress B Plus (Calcium (Calcium Gluconate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Stress B Plus ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Stress B Plus (Calcium (Calcium Gluconate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Stress B Plus (Calcium (Calcium Gluconate)), including Stress B Plus (Calcium (Calcium Gluconate)) acetate. Avoid the use of Stress B Plus (Calcium (Calcium Gluconate)) supplements, including Stress B Plus (Calcium (Calcium Gluconate)) based nonprescription antacids, concurrently with Stress B Plus (Calcium (Calcium Gluconate)) acetate.

An overdose of Stress B Plus (Calcium (Calcium Gluconate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Stress B Plus (Calcium (Calcium Gluconate)) levels twice weekly. Should hypercalcemia develop, reduce the Stress B Plus (Calcium (Calcium Gluconate)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Stress B Plus (Calcium (Calcium Gluconate)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Stress B Plus (Calcium (Calcium Gluconate)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Stress B Plus (Calcium (Calcium Gluconate)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Stress B Plus (Calcium (Calcium Gluconate)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Stress B Plus (Calcium (Calcium Gluconate)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Stress B Plus (Calcium (Calcium Gluconate)) acetate has been generally well tolerated.

Stress B Plus (Calcium (Calcium Gluconate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Stress B Plus (Calcium (Calcium Gluconate)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Preferred Term	Total adverse reactions reported for Stress B Plus (Calcium (Calcium Gluconate)) acetate N=167 N (%)	3 month, open label study of Stress B Plus (Calcium (Calcium Gluconate)) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Stress B Plus (Calcium (Calcium Gluconate)) acetate N=69
			Stress B Plus (Calcium (Calcium Gluconate)) acetate N (%)	Placebo N (%)
Nausea	6 (3.6)	6 (6.1)	0 (0)	0 (0)
Vomiting	4 (2.4)	4 (4.1)	0 (0)	0 (0)
Hypercalcemia	21 (12.6)	16 (16.3)	5 (7.2)	0 (0)

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Stress B Plus (Calcium (Calcium Gluconate)) concentration could reduce the incidence and severity of Stress B Plus (Calcium (Calcium Gluconate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Stress B Plus (Calcium (Calcium Gluconate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Stress B Plus ) acetate is characterized by the potential of Stress B Plus (Calcium (Calcium Gluconate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Stress B Plus (Calcium (Calcium Gluconate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Stress B Plus (Calcium (Calcium Gluconate)) acetate and most concomitant drugs. When administering an oral medication with Stress B Plus (Calcium (Calcium Gluconate)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Stress B Plus (Calcium (Calcium Gluconate)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Stress B Plus (Calcium (Calcium Gluconate)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Stress B Plus (Calcium (Calcium Gluconate)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Stress B Plus (Calcium (Calcium Gluconate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Stress B Plus ) acetate capsules contains Stress B Plus (Calcium (Calcium Gluconate)) acetate. Animal reproduction studies have not been conducted with Stress B Plus (Calcium (Calcium Gluconate)) acetate, and there are no adequate and well controlled studies of Stress B Plus (Calcium (Calcium Gluconate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Stress B Plus (Calcium (Calcium Gluconate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Stress B Plus (Calcium (Calcium Gluconate)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Stress B Plus (Calcium (Calcium Gluconate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Stress B Plus (Calcium (Calcium Gluconate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Stress B Plus (Calcium (Calcium Gluconate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Stress B Plus ) Acetate Capsules contains Stress B Plus (Calcium (Calcium Gluconate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Stress B Plus (Calcium (Calcium Gluconate)) acetate is not expected to harm an infant, provided maternal serum Stress B Plus (Calcium (Calcium Gluconate)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Stress B Plus (Calcium (Calcium Gluconate)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Stress B Plus (Calcium (Calcium Gluconate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Stress B Plus (Calcium (Calcium Gluconate)) acetate acts as a phosphate binder. Its chemical name is Stress B Plus (Calcium (Calcium Gluconate)) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Stress B Plus (Calcium (Calcium Gluconate)) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Stress B Plus (Calcium (Calcium Gluconate)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Stress B Plus (Calcium (Calcium Gluconate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Stress B Plus ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Stress B Plus (Calcium (Calcium Gluconate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Stress B Plus (Calcium (Calcium Gluconate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Stress B Plus (Calcium (Calcium Gluconate)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Stress B Plus (Calcium (Calcium Gluconate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Stress B Plus (Calcium (Calcium Gluconate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Stress B Plus (Calcium (Calcium Gluconate)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Stress B Plus (Calcium (Calcium Gluconate)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Stress B Plus (Calcium (Calcium Gluconate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Stress B Plus (Calcium (Calcium Gluconate)) levels are also presented.

* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE.
Parameter	Pre-Study	Week 4*	Week 8	Week 12	p-value†
Phosphorus (mg/dL)‡	7.4 ± 0.17	5.9 ± 0.16	5.6 ± 0.17	5.2 ± 0.17	≤0.01
Stress B Plus (Calcium (Calcium Gluconate)) (mg/dL)‡	8.9 ± 0.09	9.5 ± 0.10	9.7 ± 0.10	9.7 ± 0.10	≤0.01

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Stress B Plus (Calcium (Calcium Gluconate)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Stress B Plus (Calcium (Calcium Gluconate)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Stress B Plus (Calcium (Calcium Gluconate)) acetate is shown in the Table 3.

* ANOVA of Stress B Plus (Calcium (Calcium Gluconate)) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Stress B Plus (Calcium (Calcium Gluconate)) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Stress B Plus (Calcium (Calcium Gluconate)) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with Stress B Plus (Calcium (Calcium Gluconate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Stress B Plus (Calcium (Calcium Gluconate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Stress B Plus (Calcium (Calcium Gluconate)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Stress B Plus (Calcium (Calcium Gluconate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Stress B Plus (Calcium (Calcium Gluconate)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Stress B Plus (Calcium (Calcium Gluconate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium HVP Chelate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stress B Plus (Calcium (Calcium HVP Chelate)) reviews

1 INDICATIONS AND USAGE

Stress B Plus (Calcium (Calcium HVP Chelate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Stress B Plus (Calcium (Calcium HVP Chelate)) acetate capsule.

- Capsule: 667 mg Stress B Plus (Calcium (Calcium HVP Chelate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Stress B Plus ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Stress B Plus (Calcium (Calcium HVP Chelate)), including Stress B Plus (Calcium (Calcium HVP Chelate)) acetate. Avoid the use of Stress B Plus (Calcium (Calcium HVP Chelate)) supplements, including Stress B Plus (Calcium (Calcium HVP Chelate)) based nonprescription antacids, concurrently with Stress B Plus (Calcium (Calcium HVP Chelate)) acetate.

An overdose of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Stress B Plus (Calcium (Calcium HVP Chelate)) levels twice weekly. Should hypercalcemia develop, reduce the Stress B Plus (Calcium (Calcium HVP Chelate)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Stress B Plus (Calcium (Calcium HVP Chelate)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Stress B Plus (Calcium (Calcium HVP Chelate)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Stress B Plus (Calcium (Calcium HVP Chelate)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Stress B Plus (Calcium (Calcium HVP Chelate)) acetate has been generally well tolerated.

Stress B Plus (Calcium (Calcium HVP Chelate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Preferred Term	Total adverse reactions reported for Stress B Plus (Calcium (Calcium HVP Chelate)) acetate N=167 N (%)	3 month, open label study of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Stress B Plus (Calcium (Calcium HVP Chelate)) acetate N=69
			Stress B Plus (Calcium (Calcium HVP Chelate)) acetate N (%)	Placebo N (%)
Nausea	6 (3.6)	6 (6.1)	0 (0)	0 (0)
Vomiting	4 (2.4)	4 (4.1)	0 (0)	0 (0)
Hypercalcemia	21 (12.6)	16 (16.3)	5 (7.2)	0 (0)

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Stress B Plus (Calcium (Calcium HVP Chelate)) concentration could reduce the incidence and severity of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Stress B Plus ) acetate is characterized by the potential of Stress B Plus (Calcium (Calcium HVP Chelate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Stress B Plus (Calcium (Calcium HVP Chelate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Stress B Plus (Calcium (Calcium HVP Chelate)) acetate and most concomitant drugs. When administering an oral medication with Stress B Plus (Calcium (Calcium HVP Chelate)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Stress B Plus (Calcium (Calcium HVP Chelate)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Stress B Plus (Calcium (Calcium HVP Chelate)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Stress B Plus (Calcium (Calcium HVP Chelate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Stress B Plus ) acetate capsules contains Stress B Plus (Calcium (Calcium HVP Chelate)) acetate. Animal reproduction studies have not been conducted with Stress B Plus (Calcium (Calcium HVP Chelate)) acetate, and there are no adequate and well controlled studies of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Stress B Plus (Calcium (Calcium HVP Chelate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Stress B Plus (Calcium (Calcium HVP Chelate)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Stress B Plus (Calcium (Calcium HVP Chelate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Stress B Plus (Calcium (Calcium HVP Chelate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Stress B Plus ) Acetate Capsules contains Stress B Plus (Calcium (Calcium HVP Chelate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Stress B Plus (Calcium (Calcium HVP Chelate)) acetate is not expected to harm an infant, provided maternal serum Stress B Plus (Calcium (Calcium HVP Chelate)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Stress B Plus (Calcium (Calcium HVP Chelate)) acetate acts as a phosphate binder. Its chemical name is Stress B Plus (Calcium (Calcium HVP Chelate)) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Stress B Plus (Calcium (Calcium HVP Chelate)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Stress B Plus (Calcium (Calcium HVP Chelate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Stress B Plus ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Stress B Plus (Calcium (Calcium HVP Chelate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Stress B Plus (Calcium (Calcium HVP Chelate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Stress B Plus (Calcium (Calcium HVP Chelate)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Stress B Plus (Calcium (Calcium HVP Chelate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Stress B Plus (Calcium (Calcium HVP Chelate)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Stress B Plus (Calcium (Calcium HVP Chelate)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Stress B Plus (Calcium (Calcium HVP Chelate)) levels are also presented.

* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE.
Parameter	Pre-Study	Week 4*	Week 8	Week 12	p-value†
Phosphorus (mg/dL)‡	7.4 ± 0.17	5.9 ± 0.16	5.6 ± 0.17	5.2 ± 0.17	≤0.01
Stress B Plus (Calcium (Calcium HVP Chelate)) (mg/dL)‡	8.9 ± 0.09	9.5 ± 0.10	9.7 ± 0.10	9.7 ± 0.10	≤0.01

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Stress B Plus (Calcium (Calcium HVP Chelate)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Stress B Plus (Calcium (Calcium HVP Chelate)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate is shown in the Table 3.

* ANOVA of Stress B Plus (Calcium (Calcium HVP Chelate)) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Stress B Plus (Calcium (Calcium HVP Chelate)) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Stress B Plus (Calcium (Calcium HVP Chelate)) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with Stress B Plus (Calcium (Calcium HVP Chelate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Stress B Plus (Calcium (Calcium HVP Chelate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Stress B Plus (Calcium (Calcium HVP Chelate)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Stress B Plus (Calcium (Calcium HVP Chelate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Stress B Plus (Calcium (Calcium HVP Chelate)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Stress B Plus (Calcium (Calcium HVP Chelate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Oyster Shells):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stress B Plus (Calcium (Oyster Shells)) reviews

1 INDICATIONS AND USAGE

Stress B Plus (Calcium (Oyster Shells)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Stress B Plus (Calcium (Oyster Shells)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Stress B Plus (Calcium (Oyster Shells)) acetate capsule.

- Capsule: 667 mg Stress B Plus (Calcium (Oyster Shells)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Stress B Plus ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Stress B Plus (Calcium (Oyster Shells)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Stress B Plus (Calcium (Oyster Shells)), including Stress B Plus (Calcium (Oyster Shells)) acetate. Avoid the use of Stress B Plus (Calcium (Oyster Shells)) supplements, including Stress B Plus (Calcium (Oyster Shells)) based nonprescription antacids, concurrently with Stress B Plus (Calcium (Oyster Shells)) acetate.

An overdose of Stress B Plus (Calcium (Oyster Shells)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Stress B Plus (Calcium (Oyster Shells)) levels twice weekly. Should hypercalcemia develop, reduce the Stress B Plus (Calcium (Oyster Shells)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Stress B Plus (Calcium (Oyster Shells)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Stress B Plus (Calcium (Oyster Shells)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Stress B Plus (Calcium (Oyster Shells)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Stress B Plus (Calcium (Oyster Shells)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Stress B Plus (Calcium (Oyster Shells)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Stress B Plus (Calcium (Oyster Shells)) acetate has been generally well tolerated.

Stress B Plus (Calcium (Oyster Shells)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Stress B Plus (Calcium (Oyster Shells)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Preferred Term	Total adverse reactions reported for Stress B Plus (Calcium (Oyster Shells)) acetate N=167 N (%)	3 month, open label study of Stress B Plus (Calcium (Oyster Shells)) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Stress B Plus (Calcium (Oyster Shells)) acetate N=69
			Stress B Plus (Calcium (Oyster Shells)) acetate N (%)	Placebo N (%)
Nausea	6 (3.6)	6 (6.1)	0 (0)	0 (0)
Vomiting	4 (2.4)	4 (4.1)	0 (0)	0 (0)
Hypercalcemia	21 (12.6)	16 (16.3)	5 (7.2)	0 (0)

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Stress B Plus (Calcium (Oyster Shells)) concentration could reduce the incidence and severity of Stress B Plus (Calcium (Oyster Shells)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Stress B Plus (Calcium (Oyster Shells)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Stress B Plus ) acetate is characterized by the potential of Stress B Plus (Calcium (Oyster Shells)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Stress B Plus (Calcium (Oyster Shells)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Stress B Plus (Calcium (Oyster Shells)) acetate and most concomitant drugs. When administering an oral medication with Stress B Plus (Calcium (Oyster Shells)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Stress B Plus (Calcium (Oyster Shells)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Stress B Plus (Calcium (Oyster Shells)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Stress B Plus (Calcium (Oyster Shells)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Stress B Plus (Calcium (Oyster Shells)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Stress B Plus ) acetate capsules contains Stress B Plus (Calcium (Oyster Shells)) acetate. Animal reproduction studies have not been conducted with Stress B Plus (Calcium (Oyster Shells)) acetate, and there are no adequate and well controlled studies of Stress B Plus (Calcium (Oyster Shells)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Stress B Plus (Calcium (Oyster Shells)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Stress B Plus (Calcium (Oyster Shells)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Stress B Plus (Calcium (Oyster Shells)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Stress B Plus (Calcium (Oyster Shells)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Stress B Plus (Calcium (Oyster Shells)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Stress B Plus ) Acetate Capsules contains Stress B Plus (Calcium (Oyster Shells)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Stress B Plus (Calcium (Oyster Shells)) acetate is not expected to harm an infant, provided maternal serum Stress B Plus (Calcium (Oyster Shells)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Stress B Plus (Calcium (Oyster Shells)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Stress B Plus (Calcium (Oyster Shells)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Stress B Plus (Calcium (Oyster Shells)) acetate acts as a phosphate binder. Its chemical name is Stress B Plus (Calcium (Oyster Shells)) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Stress B Plus (Calcium (Oyster Shells)) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Stress B Plus (Calcium (Oyster Shells)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Stress B Plus (Calcium (Oyster Shells)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Stress B Plus ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Stress B Plus (Calcium (Oyster Shells)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Stress B Plus (Calcium (Oyster Shells)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Stress B Plus (Calcium (Oyster Shells)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Stress B Plus (Calcium (Oyster Shells)) acetate.

14 CLINICAL STUDIES

Effectiveness of Stress B Plus (Calcium (Oyster Shells)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Stress B Plus (Calcium (Oyster Shells)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Stress B Plus (Calcium (Oyster Shells)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Stress B Plus (Calcium (Oyster Shells)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Stress B Plus (Calcium (Oyster Shells)) levels are also presented.

* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE.
Parameter	Pre-Study	Week 4*	Week 8	Week 12	p-value†
Phosphorus (mg/dL)‡	7.4 ± 0.17	5.9 ± 0.16	5.6 ± 0.17	5.2 ± 0.17	≤0.01
Stress B Plus (Calcium (Oyster Shells)) (mg/dL)‡	8.9 ± 0.09	9.5 ± 0.10	9.7 ± 0.10	9.7 ± 0.10	≤0.01

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Stress B Plus (Calcium (Oyster Shells)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Stress B Plus (Calcium (Oyster Shells)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Stress B Plus (Calcium (Oyster Shells)) acetate is shown in the Table 3.

* ANOVA of Stress B Plus (Calcium (Oyster Shells)) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Stress B Plus (Calcium (Oyster Shells)) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Stress B Plus (Calcium (Oyster Shells)) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with Stress B Plus (Calcium (Oyster Shells)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Stress B Plus (Calcium (Oyster Shells)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Stress B Plus (Calcium (Oyster Shells)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Stress B Plus (Calcium (Oyster Shells)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Stress B Plus (Calcium (Oyster Shells)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Stress B Plus (Calcium (Oyster Shells)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Choline Bitartrate:

• Stress B Plus (Choline Bitartrate) reviews

A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism.

Indication: For nutritional supplementation, also for treating dietary shortage or imbalance

This compound is needed for good nerve conduction throughout the CNS (central nervous system) as it is a precursor to acetylcholine (ACh). Stress B Plus (Choline Bitartrate) is also needed for gallbladder regulation, liver function and lecithin (a key lipid) formation. Stress B Plus (Choline Bitartrate) also aids in fat and cholesterol metabolism and prevents excessive fat build up in the liver. Stress B Plus (Choline Bitartrate) has been used to mitigate the effects of Parkinsonism and tardive dyskinesia. Stress B Plus (Choline Bitartrate) deficiencies may result in excessive build-up of fat in the liver, high blood pressure, gastric ulcers, kidney and liver dysfunction and stunted growth.

Copper (Copper Citrate):

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Stress B Plus (Copper (Copper Citrate)) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Stress B Plus (Copper (Copper Citrate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Stress B Plus (Copper (Copper Citrate))^®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Stress B Plus (Copper (Copper Citrate))^® onto hair since contact with Stress B Plus (Copper (Copper Citrate))^® may cause some hair loss. Do not contaminate feed.

NOTE: Stress B Plus (Copper (Copper Citrate))^® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Stress B Plus (Copper (Copper Citrate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,^® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Copper (Copper Fumarate):

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Stress B Plus (Copper (Copper Fumarate)) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Stress B Plus (Copper (Copper Fumarate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Stress B Plus (Copper (Copper Fumarate))^®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Stress B Plus (Copper (Copper Fumarate))^® onto hair since contact with Stress B Plus (Copper (Copper Fumarate))^® may cause some hair loss. Do not contaminate feed.

NOTE: Stress B Plus (Copper (Copper Fumarate))^® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Stress B Plus (Copper (Copper Fumarate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,^® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Copper (Copper Gluconate):

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Stress B Plus (Copper (Copper Gluconate)) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Stress B Plus (Copper (Copper Gluconate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Stress B Plus (Copper (Copper Gluconate))^®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Stress B Plus (Copper (Copper Gluconate))^® onto hair since contact with Stress B Plus (Copper (Copper Gluconate))^® may cause some hair loss. Do not contaminate feed.

NOTE: Stress B Plus (Copper (Copper Gluconate))^® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Stress B Plus (Copper (Copper Gluconate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,^® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Copper (Copper Malate):

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Stress B Plus (Copper (Copper Malate)) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Stress B Plus (Copper (Copper Malate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Stress B Plus (Copper (Copper Malate))^®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Stress B Plus (Copper (Copper Malate))^® onto hair since contact with Stress B Plus (Copper (Copper Malate))^® may cause some hair loss. Do not contaminate feed.

NOTE: Stress B Plus (Copper (Copper Malate))^® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Stress B Plus (Copper (Copper Malate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,^® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Copper (Copper Succinate):

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Stress B Plus (Copper (Copper Succinate)) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Stress B Plus (Copper (Copper Succinate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Stress B Plus (Copper (Copper Succinate))^®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Stress B Plus (Copper (Copper Succinate))^® onto hair since contact with Stress B Plus (Copper (Copper Succinate))^® may cause some hair loss. Do not contaminate feed.

NOTE: Stress B Plus (Copper (Copper Succinate))^® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Stress B Plus (Copper (Copper Succinate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,^® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Folic Acid:

• Indications and usage
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage
• Stress B Plus (Folic Acid) reviews

INDICATIONS AND USAGE

Stress B Plus (Folic Acid)^® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.

CONTRAINDICATIONS

This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Hemochromatosis and hemosiderosis are contraindications to iron therapy.

WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.

PRECAUTIONS

Stress B Plus (Folic Acid) acid when administered as a single agent in doses above 0.1 mg daily may obscure pernicious anemia in that hematological remission can occur while neurological manifestations remain progressive. While prescribing this nutritional supplement for pregnant women, nursing mothers, or for women prior to conception, their medical condition and other drugs, herbs, and/or supplements consumption should be considered.

ADVERSE REACTIONS

Allergic sensitization has been reported following both oral and parenteral administration of Stress B Plus (Folic Acid) acid.

DOSAGE AND ADMINISTRATION

One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.

HOW SUPPLIED

Stress B Plus (Folic Acid)^® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)

KEEP OUT OF REACH OF CHILDREN.

STORAGE

Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container to protect from light and moisture.

To report SUSPECTED ADVERSE REACTIONS contact Meda Pharmaceuticals Inc. at 1-888-349-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch

Distributed by:

Meda Pharmaceuticals Inc.

Somerset New Jersey 08873-4120

© 2014 Meda Pharmaceuticals Inc.

U.S. Patent Nos. 7,585,527 and 8,080,520

Proferrin® is a registered trademark of Colorado BioLabs, Inc., Cozad, NE.

Stress B Plus (Folic Acid) and the BIFERA logo are registered trademarks and the Stress B Plus (Folic Acid) logo is a trademark of Alaven Pharmaceutical LLC, used under license by Meda Pharmaceuticals Inc.

MEDA PHARMACEUTICALS mark and logo are trademarks of Meda AB.

IN-6885-02 Rev 6/2014

Inositol:

• Stress B Plus (Inositol) reviews

Niacin is used with a proper diet and exercise program to help lower "bad" cholesterol and fats ( LDL, triglycerides ) and raise "good" cholesterol (HDL) in the blood. It is generally used after non-drug treatments have not been fully successful at lowering cholesterol. Niacin is also known as vitamin B-3 ( nicotinic acid ), one of the B-complex vitamins. It may be used with or without other medications. Lowering "bad" cholesterol/triglycerides and raising "good" cholesterol helps prevent strokes and heart attacks. Lowering fats may also help reduce the risk of pancreas problems ( pancreatitis ) in people at risk. In addition to eating a proper diet (such as a low-cholesterol/low-fat diet), other lifestyle changes that may help this medication work better include exercising, losing weight if overweight, and stopping smoking. Consult your doctor for more details.

Iodine (Kelp):

• Iodine tincture 7%
• Iodine tincture 7%
• Stress B Plus (Iodine (Kelp)) reviews

Stress B Plus ) Tincture 7%

Directions:

Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Stress B Plus (Iodine (Kelp)) with a swab.

If necessary, clip hair around the area being treated and clean with soap and water.

Apply Stress B Plus (Iodine (Kelp)) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.

Do not apply under bandage.

Irritation may occur if used on tender skin areas. If redness, irritation, or swelling persists or increases, discontinue use and consult a veterinarian.

Storage:

Store at 2-30 degrees C (36-86 degrees F).

Keep container away from heat and out of sunlight. Rinse empty container thoroughly and discard.

DANGER - Poison

Caution:

If swallowed, give starch paste, milk, bread, egg white, or

activated charcoal. A 5% solutions of sodium thiosulfate

(Photographic (“hypc”) may be administered orally at a

rate of 10 ml per kilogram of body weight.

Eye irritant: Use only as directed. Avoid contact with eyes. In case of contact, flush eyes immediately with tepid water for at least 15 minutes. Consult a physician.

Avoid contamination of food.

Not for use on burns, deep cuts, or body cavities.

Stress B Plus ) Tincture 7%

image description

Iodine (Potassium Iodide):

• Iodine tincture 7%
• Iodine tincture 7%
• Stress B Plus (Iodine (Potassium Iodide)) reviews

Stress B Plus ) Tincture 7%

Directions:

Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Stress B Plus (Iodine (Potassium Iodide)) with a swab.

If necessary, clip hair around the area being treated and clean with soap and water.

Apply Stress B Plus (Iodine (Potassium Iodide)) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.

Do not apply under bandage.

Irritation may occur if used on tender skin areas. If redness, irritation, or swelling persists or increases, discontinue use and consult a veterinarian.

Storage:

Store at 2-30 degrees C (36-86 degrees F).

Keep container away from heat and out of sunlight. Rinse empty container thoroughly and discard.

DANGER - Poison

Caution:

If swallowed, give starch paste, milk, bread, egg white, or

activated charcoal. A 5% solutions of sodium thiosulfate

(Photographic (“hypc”) may be administered orally at a

rate of 10 ml per kilogram of body weight.

Eye irritant: Use only as directed. Avoid contact with eyes. In case of contact, flush eyes immediately with tepid water for at least 15 minutes. Consult a physician.

Avoid contamination of food.

Not for use on burns, deep cuts, or body cavities.

Stress B Plus ) Tincture 7%

image description

Iron (Ferrous Citrate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stress B Plus (Iron (Ferrous Citrate)) reviews

1 INDICATIONS AND USAGE

Stress B Plus (Iron (Ferrous Citrate)) is indicated for the treatment of Stress B Plus (Iron (Ferrous Citrate)) deficiency anemia in patients with chronic kidney disease (CKD).

Stress B Plus (Iron (Ferrous Citrate)) is an Stress B Plus (Iron (Ferrous Citrate)) replacement product indicated for the treatment of Stress B Plus (Iron (Ferrous Citrate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Stress B Plus ) must only be administered intravenously either by slow injection or by infusion. The dosage of Stress B Plus (Iron (Ferrous Citrate)) is expressed in mg of elemental Stress B Plus (Iron (Ferrous Citrate)). Each mL contains 20 mg of elemental Stress B Plus (Iron (Ferrous Citrate)).

Population		Dose
Adult patients	Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1)	100 mg slow intravenous injection or infusion
	Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2)	200 mg slow intravenous injection or infusion
	Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3)	300 mg or 400 mg intravenous infusion
Pediatric patients	HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5)	0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Stress B Plus (Iron (Ferrous Citrate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Stress B Plus (Iron (Ferrous Citrate)) should be administered early during the dialysis session. The usual total treatment course of Stress B Plus (Iron (Ferrous Citrate)) is 1000 mg. Stress B Plus (Iron (Ferrous Citrate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Citrate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Stress B Plus (Iron (Ferrous Citrate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Stress B Plus (Iron (Ferrous Citrate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Stress B Plus (Iron (Ferrous Citrate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Citrate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Stress B Plus (Iron (Ferrous Citrate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Stress B Plus (Iron (Ferrous Citrate)) in a maximum of 250 mL of 0.9% NaCl. Stress B Plus (Iron (Ferrous Citrate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Citrate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Stress B Plus (Iron (Ferrous Citrate)) maintenance treatment

The dosing for Stress B Plus (Iron (Ferrous Citrate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Stress B Plus (Iron (Ferrous Citrate)) maintenance treatment: Administer Stress B Plus (Iron (Ferrous Citrate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Stress B Plus (Iron (Ferrous Citrate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Stress B Plus (Iron (Ferrous Citrate)) maintenance treatment

The dosing for Stress B Plus (Iron (Ferrous Citrate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Stress B Plus (Iron (Ferrous Citrate)) maintenance treatment: Administer Stress B Plus (Iron (Ferrous Citrate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Stress B Plus (Iron (Ferrous Citrate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Stress B Plus (Iron (Ferrous Citrate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Stress B Plus (Iron (Ferrous Citrate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Stress B Plus (Iron (Ferrous Citrate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Stress B Plus (Iron (Ferrous Citrate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Stress B Plus (Iron (Ferrous Citrate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Stress B Plus (Iron (Ferrous Citrate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Stress B Plus (Iron (Ferrous Citrate))

• Known hypersensitivity to Stress B Plus (Iron (Ferrous Citrate)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Stress B Plus ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Stress B Plus (Iron (Ferrous Citrate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Stress B Plus (Iron (Ferrous Citrate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Stress B Plus (Iron (Ferrous Citrate)). (5.2)
• Stress B Plus (Iron (Ferrous Citrate)) Overload: Regularly monitor hematologic responses during Stress B Plus (Iron (Ferrous Citrate)) therapy. Do not administer Stress B Plus (Iron (Ferrous Citrate)) to patients with Stress B Plus (Iron (Ferrous Citrate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Stress B Plus (Iron (Ferrous Citrate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Stress B Plus (Iron (Ferrous Citrate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Stress B Plus (Iron (Ferrous Citrate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Stress B Plus (Iron (Ferrous Citrate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Stress B Plus (Iron (Ferrous Citrate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Stress B Plus ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Stress B Plus (Iron (Ferrous Citrate)). Hypotension following administration of Stress B Plus (Iron (Ferrous Citrate)) may be related to the rate of administration and/or total dose administered .

5.3 Stress B Plus (Iron (Ferrous Citrate)) Overload

Excessive therapy with parenteral Stress B Plus (Iron (Ferrous Citrate)) can lead to excess storage of Stress B Plus (Iron (Ferrous Citrate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Stress B Plus (Iron (Ferrous Citrate)) require periodic monitoring of hematologic and Stress B Plus (Iron (Ferrous Citrate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Stress B Plus (Iron (Ferrous Citrate)) to patients with evidence of Stress B Plus (Iron (Ferrous Citrate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Stress B Plus (Iron (Ferrous Citrate)) sucrose; do not perform serum Stress B Plus (Iron (Ferrous Citrate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Stress B Plus ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Stress B Plus (Iron (Ferrous Citrate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Stress B Plus ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Stress B Plus (Iron (Ferrous Citrate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

* EPO=Erythropoietin
Adverse Reactions (Preferred Term)	HDD-CKD	NDD-CKD		PDD-CKD
	Stress B Plus (Iron (Ferrous Citrate))	Stress B Plus (Iron (Ferrous Citrate))	Oral Stress B Plus (Iron (Ferrous Citrate))	Stress B Plus (Iron (Ferrous Citrate))	EPO* Only
	(N=231)	(N=139)	(N=139)	(N=75)	(N=46)
	%	%	%	%	%
Subjects with any adverse reaction	78.8	76.3	73.4	72.0	65.2
Ear and Labyrinth Disorders
Ear Pain	0	2.2	0.7	0	0
Eye Disorders
Conjunctivitis	0.4	0	0	2.7	0
Gastrointestinal Disorders
Abdominal pain	3.5	1.4	2.9	4.0	6.5
Diarrhea	5.2	7.2	10.1	8.0	4.3
Dysgeusia	0.9	7.9	0	0	0
Nausea	14.7	8.6	12.2	5.3	4.3
Vomiting	9.1	5.0	8.6	8.0	2.2
General Disorders and
Administration Site Conditions
Asthenia	2.2	0.7	2.2	2.7	0
Chest pain	6.1	1.4	0	2.7	0
Feeling abnormal	3.0	0	0	0	0
Infusion site pain or burning	0	5.8	0	0	0
Injection site extravasation	0	2.2	0	0	0
Peripheral edema	2.6	7.2	5.0	5.3	10.9
Pyrexia	3.0	0.7	0.7	1.3	0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis	2.6	2.2	4.3	16.0	4.3
Injury, Poisoning and Procedural
Complications
Graft complication	9.5	1.4	0	0	0
Metabolism and Nutrition Disorders
Fluid overload	3.0	1.4	0.7	1.3	0
Gout	0	2.9	1.4	0	0
Hyperglycemia	0	2.9	0	0	2.2
Hypoglycemia	0.4	0.7	0.7	4.0	0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia	3.5	1.4	2.2	4.0	4.3
Back pain	2.2	2.2	3.6	1.3	4.3
Muscle cramp	29.4	0.7	0.7	2.7	0
Myalgia	0	3.6	0	1.3	0
Pain in extremity	5.6	4.3	0	2.7	6.5
Nervous System Disorders
Dizziness	6.5	6.5	1.4	1.3	4.3
Headache	12.6	2.9	0.7	4.0	0
Respiratory, Thoracic and
Mediastinal Disorders
Cough	3.0	2.2	0.7	1.3	0
Dyspnea	3.5	5.8	1.4	1.3	2.2
Nasal congestion	0	1.4	2.2	1.3	0
Skin and Subcutaneous
Tissue Disorders
Pruritus	3.9	2.2	4.3	2.7	0
Vascular Disorders
Hypertension	6.5	6.5	4.3	8.0	6.5
Hypotension	39.4	2.2	0.7	2.7	2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Stress B Plus (Iron (Ferrous Citrate)) therapy and were reported to be intolerant (defined as precluding further use of that Stress B Plus (Iron (Ferrous Citrate)) product). When these patients were treated with Stress B Plus (Iron (Ferrous Citrate)) there were no occurrences of adverse reactions that precluded further use of Stress B Plus (Iron (Ferrous Citrate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Stress B Plus (Iron (Ferrous Citrate)) maintenance treatment with Stress B Plus (Iron (Ferrous Citrate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Stress B Plus (Iron (Ferrous Citrate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Stress B Plus (Iron (Ferrous Citrate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Stress B Plus (Iron (Ferrous Citrate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Stress B Plus (Iron (Ferrous Citrate)) 0.5 mg/kg group, 10 (21%) patients in the Stress B Plus (Iron (Ferrous Citrate)) 1.0 mg/kg group, and 10 (21%) patients in the Stress B Plus (Iron (Ferrous Citrate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Stress B Plus (Iron (Ferrous Citrate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Stress B Plus (Iron (Ferrous Citrate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Stress B Plus (Iron (Ferrous Citrate)) injection. Reactions have occurred following the first dose or subsequent doses of Stress B Plus (Iron (Ferrous Citrate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Stress B Plus (Iron (Ferrous Citrate)) have not been studied. However, Stress B Plus (Iron (Ferrous Citrate)) may reduce the absorption of concomitantly administered oral Stress B Plus (Iron (Ferrous Citrate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Stress B Plus ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Stress B Plus (Iron (Ferrous Citrate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Stress B Plus (Iron (Ferrous Citrate)) sucrose. Because animal reproductive studies are not always predictive of human response, Stress B Plus (Iron (Ferrous Citrate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Stress B Plus (Iron (Ferrous Citrate)) sucrose is excreted in human milk. Stress B Plus (Iron (Ferrous Citrate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Stress B Plus (Iron (Ferrous Citrate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Stress B Plus ) for Stress B Plus (Iron (Ferrous Citrate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Stress B Plus (Iron (Ferrous Citrate)) for Stress B Plus (Iron (Ferrous Citrate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Stress B Plus (Iron (Ferrous Citrate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Stress B Plus (Iron (Ferrous Citrate)) has not been studied in patients younger than 2 years of age.

In a country where Stress B Plus (Iron (Ferrous Citrate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Stress B Plus (Iron (Ferrous Citrate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Stress B Plus (Iron (Ferrous Citrate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Stress B Plus (Iron (Ferrous Citrate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Stress B Plus (Iron (Ferrous Citrate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Stress B Plus (Iron (Ferrous Citrate)) in humans. Excessive dosages of Stress B Plus (Iron (Ferrous Citrate)) may lead to accumulation of Stress B Plus (Iron (Ferrous Citrate)) in storage sites potentially leading to hemosiderosis. Do not administer Stress B Plus (Iron (Ferrous Citrate)) to patients with Stress B Plus (Iron (Ferrous Citrate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Stress B Plus (Iron (Ferrous Citrate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Stress B Plus (Iron (Ferrous Citrate)) (iron sucrose injection, USP), an Stress B Plus (Iron (Ferrous Citrate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Stress B Plus (Iron (Ferrous Citrate)) (III)-hydroxide in sucrose for intravenous use. Stress B Plus (Iron (Ferrous Citrate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Stress B Plus (Iron (Ferrous Citrate)) polymerization and m is the number of sucrose molecules associated with the Stress B Plus (Iron (Ferrous Citrate)) (III)-hydroxide.

Each mL contains 20 mg elemental Stress B Plus (Iron (Ferrous Citrate)) as Stress B Plus (Iron (Ferrous Citrate)) sucrose in water for injection. Stress B Plus (Iron (Ferrous Citrate)) is available in 10 mL single-use vials (200 mg elemental Stress B Plus (Iron (Ferrous Citrate)) per 10 mL), 5 mL single-use vials (100 mg elemental Stress B Plus (Iron (Ferrous Citrate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Stress B Plus (Iron (Ferrous Citrate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Stress B Plus ) is an aqueous complex of poly-nuclear Stress B Plus (Iron (Ferrous Citrate)) (III)-hydroxide in sucrose. Following intravenous administration, Stress B Plus (Iron (Ferrous Citrate)) is dissociated into Stress B Plus (Iron (Ferrous Citrate)) and sucrose and the Stress B Plus (Iron (Ferrous Citrate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Stress B Plus (Iron (Ferrous Citrate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Stress B Plus (Iron (Ferrous Citrate)) is dissociated into Stress B Plus (Iron (Ferrous Citrate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Stress B Plus (Iron (Ferrous Citrate)) sucrose containing 100 mg of Stress B Plus (Iron (Ferrous Citrate)), three times weekly for three weeks, significant increases in serum Stress B Plus (Iron (Ferrous Citrate)) and serum ferritin and significant decreases in total Stress B Plus (Iron (Ferrous Citrate)) binding capacity occurred four weeks from the initiation of Stress B Plus (Iron (Ferrous Citrate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Stress B Plus ), its Stress B Plus (Iron (Ferrous Citrate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Stress B Plus (Iron (Ferrous Citrate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Stress B Plus (Iron (Ferrous Citrate)) containing 100 mg of Stress B Plus (Iron (Ferrous Citrate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Stress B Plus (Iron (Ferrous Citrate)) deficiency showed that a significant amount of the administered Stress B Plus (Iron (Ferrous Citrate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Stress B Plus (Iron (Ferrous Citrate)) trapping compartment.

Following intravenous administration of Stress B Plus (Iron (Ferrous Citrate)), Stress B Plus (Iron (Ferrous Citrate)) sucrose is dissociated into Stress B Plus (Iron (Ferrous Citrate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Stress B Plus (Iron (Ferrous Citrate)) containing 1,510 mg of sucrose and 100 mg of Stress B Plus (Iron (Ferrous Citrate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Stress B Plus (Iron (Ferrous Citrate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Stress B Plus (Iron (Ferrous Citrate)) sucrose containing 500 to 700 mg of Stress B Plus (Iron (Ferrous Citrate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Stress B Plus (Iron (Ferrous Citrate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Stress B Plus (Iron (Ferrous Citrate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Stress B Plus (Iron (Ferrous Citrate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Stress B Plus (Iron (Ferrous Citrate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Stress B Plus (Iron (Ferrous Citrate)), the half-life of total serum Stress B Plus (Iron (Ferrous Citrate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Stress B Plus (Iron (Ferrous Citrate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Stress B Plus (Iron (Ferrous Citrate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Stress B Plus (Iron (Ferrous Citrate)) sucrose.

Stress B Plus (Iron (Ferrous Citrate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Stress B Plus (Iron (Ferrous Citrate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Stress B Plus (Iron (Ferrous Citrate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Stress B Plus (Iron (Ferrous Citrate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Stress B Plus ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Stress B Plus (Iron (Ferrous Citrate)) treatment and 24 in the historical control group) with Stress B Plus (Iron (Ferrous Citrate)) deficiency anemia. Eligibility criteria for Stress B Plus (Iron (Ferrous Citrate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Stress B Plus (Iron (Ferrous Citrate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Stress B Plus (Iron (Ferrous Citrate)), who were off intravenous Stress B Plus (Iron (Ferrous Citrate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Stress B Plus (Iron (Ferrous Citrate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.
Efficacy parameters	End of treatment		2 week follow-up		5 week follow-up
	Stress B Plus (Iron (Ferrous Citrate)) (n=69	Historical Control (n=18)	Stress B Plus (Iron (Ferrous Citrate)) (n=73)	Historical Control (n=18)	Stress B Plus (Iron (Ferrous Citrate)) (n=71)	Historical Control (n=15)
Hemoglobin (g/dL)	1.0 ± 0.12**	0.0 ± 0.21	1.3 ± 0.14**	-0.6 ± 0.24	1.2 ± 0.17*	-0.1 ± 0.23
Hematocrit (%)	3.1 ± 0.37**	-0.3 ± 0.65	3.6 ± 0.44**	-1.2 ± 0.76	3.3 ± 0.54	0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Stress B Plus (Iron (Ferrous Citrate)) in 23 patients with Stress B Plus (Iron (Ferrous Citrate)) deficiency and HDD-CKD who had been discontinued from Stress B Plus (Iron (Ferrous Citrate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Stress B Plus (Iron (Ferrous Citrate)). Exclusion criteria were similar to those in studies A and B. Stress B Plus (Iron (Ferrous Citrate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Stress B Plus (Iron (Ferrous Citrate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Stress B Plus (Iron (Ferrous Citrate)) versus Stress B Plus (Iron (Ferrous Citrate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Stress B Plus (Iron (Ferrous Citrate)) (325 mg ferrous sulfate three times daily for 56 days); or Stress B Plus (Iron (Ferrous Citrate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Stress B Plus (Iron (Ferrous Citrate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Stress B Plus (Iron (Ferrous Citrate)) group.

A statistically significantly greater proportion of Stress B Plus (Iron (Ferrous Citrate)) subjects (35/79; 44.3%) compared to oral Stress B Plus (Iron (Ferrous Citrate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Stress B Plus (Iron (Ferrous Citrate)) to patients with PDD-CKD receiving an erythropoietin alone without Stress B Plus (Iron (Ferrous Citrate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Stress B Plus (Iron (Ferrous Citrate)) or Stress B Plus (Iron (Ferrous Citrate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Stress B Plus (Iron (Ferrous Citrate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Stress B Plus (Iron (Ferrous Citrate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Stress B Plus (Iron (Ferrous Citrate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Stress B Plus ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Stress B Plus (Iron (Ferrous Citrate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Stress B Plus (Iron (Ferrous Citrate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Stress B Plus (Iron (Ferrous Citrate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Stress B Plus (Iron (Ferrous Citrate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Stress B Plus (Iron (Ferrous Citrate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Stress B Plus ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Stress B Plus (Iron (Ferrous Citrate)), each 5 mL vial contains 100 mg elemental Stress B Plus (Iron (Ferrous Citrate)), and each 2.5 mL vial contains 50 mg elemental Stress B Plus (Iron (Ferrous Citrate)) (20 mg/mL).

NDC-0517-2310-05	200 mg/10 mL Single-Use Vial	Packages of 5
NDC-0517-2310-10	200 mg/10 mL Single-Use Vial	Packages of 10
NDC-0517-2340-01	100 mg/5 mL Single-Use Vial	Individually Boxed
NDC-0517-2340-10	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2340-25	100 mg/5 mL Single-Use Vial	Packages of 25
NDC-0517-2340-99	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-10	50 mg/2.5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-25	50 mg/2.5 mL Single-Use Vial	Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Stress B Plus (Iron (Ferrous Citrate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Stress B Plus (Iron (Ferrous Citrate)) per mL, or undiluted (20 mg elemental Stress B Plus (Iron (Ferrous Citrate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Stress B Plus (Iron (Ferrous Citrate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Stress B Plus (Iron (Ferrous Citrate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Stress B Plus (Iron (Ferrous Citrate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Stress B Plus (Iron (Ferrous Citrate)) administration:

• Question patients regarding any prior history of reactions to parenteral Stress B Plus (Iron (Ferrous Citrate)) products
• Advise patients of the risks associated with Stress B Plus (Iron (Ferrous Citrate))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Stress B Plus (Iron (Ferrous Citrate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Stress B Plus (Iron (Ferrous Citrate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727

Iron (Ferrous Fumarate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stress B Plus (Iron (Ferrous Fumarate)) reviews

1 INDICATIONS AND USAGE

Stress B Plus (Iron (Ferrous Fumarate)) is indicated for the treatment of Stress B Plus (Iron (Ferrous Fumarate)) deficiency anemia in patients with chronic kidney disease (CKD).

Stress B Plus (Iron (Ferrous Fumarate)) is an Stress B Plus (Iron (Ferrous Fumarate)) replacement product indicated for the treatment of Stress B Plus (Iron (Ferrous Fumarate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Stress B Plus ) must only be administered intravenously either by slow injection or by infusion. The dosage of Stress B Plus (Iron (Ferrous Fumarate)) is expressed in mg of elemental Stress B Plus (Iron (Ferrous Fumarate)). Each mL contains 20 mg of elemental Stress B Plus (Iron (Ferrous Fumarate)).

Population		Dose
Adult patients	Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1)	100 mg slow intravenous injection or infusion
	Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2)	200 mg slow intravenous injection or infusion
	Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3)	300 mg or 400 mg intravenous infusion
Pediatric patients	HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5)	0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Stress B Plus (Iron (Ferrous Fumarate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Stress B Plus (Iron (Ferrous Fumarate)) should be administered early during the dialysis session. The usual total treatment course of Stress B Plus (Iron (Ferrous Fumarate)) is 1000 mg. Stress B Plus (Iron (Ferrous Fumarate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Fumarate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Stress B Plus (Iron (Ferrous Fumarate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Stress B Plus (Iron (Ferrous Fumarate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Stress B Plus (Iron (Ferrous Fumarate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Fumarate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Stress B Plus (Iron (Ferrous Fumarate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Stress B Plus (Iron (Ferrous Fumarate)) in a maximum of 250 mL of 0.9% NaCl. Stress B Plus (Iron (Ferrous Fumarate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Fumarate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Stress B Plus (Iron (Ferrous Fumarate)) maintenance treatment

The dosing for Stress B Plus (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Stress B Plus (Iron (Ferrous Fumarate)) maintenance treatment: Administer Stress B Plus (Iron (Ferrous Fumarate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Stress B Plus (Iron (Ferrous Fumarate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Stress B Plus (Iron (Ferrous Fumarate)) maintenance treatment

The dosing for Stress B Plus (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Stress B Plus (Iron (Ferrous Fumarate)) maintenance treatment: Administer Stress B Plus (Iron (Ferrous Fumarate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Stress B Plus (Iron (Ferrous Fumarate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Stress B Plus (Iron (Ferrous Fumarate))

• Known hypersensitivity to Stress B Plus (Iron (Ferrous Fumarate)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Stress B Plus ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Stress B Plus (Iron (Ferrous Fumarate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Stress B Plus (Iron (Ferrous Fumarate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Stress B Plus (Iron (Ferrous Fumarate)). (5.2)
• Stress B Plus (Iron (Ferrous Fumarate)) Overload: Regularly monitor hematologic responses during Stress B Plus (Iron (Ferrous Fumarate)) therapy. Do not administer Stress B Plus (Iron (Ferrous Fumarate)) to patients with Stress B Plus (Iron (Ferrous Fumarate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Stress B Plus (Iron (Ferrous Fumarate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Stress B Plus (Iron (Ferrous Fumarate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Stress B Plus (Iron (Ferrous Fumarate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Stress B Plus (Iron (Ferrous Fumarate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Stress B Plus (Iron (Ferrous Fumarate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Stress B Plus ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Stress B Plus (Iron (Ferrous Fumarate)). Hypotension following administration of Stress B Plus (Iron (Ferrous Fumarate)) may be related to the rate of administration and/or total dose administered .

5.3 Stress B Plus (Iron (Ferrous Fumarate)) Overload

Excessive therapy with parenteral Stress B Plus (Iron (Ferrous Fumarate)) can lead to excess storage of Stress B Plus (Iron (Ferrous Fumarate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Stress B Plus (Iron (Ferrous Fumarate)) require periodic monitoring of hematologic and Stress B Plus (Iron (Ferrous Fumarate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Stress B Plus (Iron (Ferrous Fumarate)) to patients with evidence of Stress B Plus (Iron (Ferrous Fumarate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Stress B Plus (Iron (Ferrous Fumarate)) sucrose; do not perform serum Stress B Plus (Iron (Ferrous Fumarate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Stress B Plus ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Stress B Plus (Iron (Ferrous Fumarate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Stress B Plus ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Stress B Plus (Iron (Ferrous Fumarate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

* EPO=Erythropoietin
Adverse Reactions (Preferred Term)	HDD-CKD	NDD-CKD		PDD-CKD
	Stress B Plus (Iron (Ferrous Fumarate))	Stress B Plus (Iron (Ferrous Fumarate))	Oral Stress B Plus (Iron (Ferrous Fumarate))	Stress B Plus (Iron (Ferrous Fumarate))	EPO* Only
	(N=231)	(N=139)	(N=139)	(N=75)	(N=46)
	%	%	%	%	%
Subjects with any adverse reaction	78.8	76.3	73.4	72.0	65.2
Ear and Labyrinth Disorders
Ear Pain	0	2.2	0.7	0	0
Eye Disorders
Conjunctivitis	0.4	0	0	2.7	0
Gastrointestinal Disorders
Abdominal pain	3.5	1.4	2.9	4.0	6.5
Diarrhea	5.2	7.2	10.1	8.0	4.3
Dysgeusia	0.9	7.9	0	0	0
Nausea	14.7	8.6	12.2	5.3	4.3
Vomiting	9.1	5.0	8.6	8.0	2.2
General Disorders and
Administration Site Conditions
Asthenia	2.2	0.7	2.2	2.7	0
Chest pain	6.1	1.4	0	2.7	0
Feeling abnormal	3.0	0	0	0	0
Infusion site pain or burning	0	5.8	0	0	0
Injection site extravasation	0	2.2	0	0	0
Peripheral edema	2.6	7.2	5.0	5.3	10.9
Pyrexia	3.0	0.7	0.7	1.3	0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis	2.6	2.2	4.3	16.0	4.3
Injury, Poisoning and Procedural
Complications
Graft complication	9.5	1.4	0	0	0
Metabolism and Nutrition Disorders
Fluid overload	3.0	1.4	0.7	1.3	0
Gout	0	2.9	1.4	0	0
Hyperglycemia	0	2.9	0	0	2.2
Hypoglycemia	0.4	0.7	0.7	4.0	0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia	3.5	1.4	2.2	4.0	4.3
Back pain	2.2	2.2	3.6	1.3	4.3
Muscle cramp	29.4	0.7	0.7	2.7	0
Myalgia	0	3.6	0	1.3	0
Pain in extremity	5.6	4.3	0	2.7	6.5
Nervous System Disorders
Dizziness	6.5	6.5	1.4	1.3	4.3
Headache	12.6	2.9	0.7	4.0	0
Respiratory, Thoracic and
Mediastinal Disorders
Cough	3.0	2.2	0.7	1.3	0
Dyspnea	3.5	5.8	1.4	1.3	2.2
Nasal congestion	0	1.4	2.2	1.3	0
Skin and Subcutaneous
Tissue Disorders
Pruritus	3.9	2.2	4.3	2.7	0
Vascular Disorders
Hypertension	6.5	6.5	4.3	8.0	6.5
Hypotension	39.4	2.2	0.7	2.7	2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Stress B Plus (Iron (Ferrous Fumarate)) therapy and were reported to be intolerant (defined as precluding further use of that Stress B Plus (Iron (Ferrous Fumarate)) product). When these patients were treated with Stress B Plus (Iron (Ferrous Fumarate)) there were no occurrences of adverse reactions that precluded further use of Stress B Plus (Iron (Ferrous Fumarate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Stress B Plus (Iron (Ferrous Fumarate)) maintenance treatment with Stress B Plus (Iron (Ferrous Fumarate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Stress B Plus (Iron (Ferrous Fumarate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Stress B Plus (Iron (Ferrous Fumarate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Stress B Plus (Iron (Ferrous Fumarate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Stress B Plus (Iron (Ferrous Fumarate)) 0.5 mg/kg group, 10 (21%) patients in the Stress B Plus (Iron (Ferrous Fumarate)) 1.0 mg/kg group, and 10 (21%) patients in the Stress B Plus (Iron (Ferrous Fumarate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Stress B Plus (Iron (Ferrous Fumarate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Stress B Plus (Iron (Ferrous Fumarate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Stress B Plus (Iron (Ferrous Fumarate)) injection. Reactions have occurred following the first dose or subsequent doses of Stress B Plus (Iron (Ferrous Fumarate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Stress B Plus (Iron (Ferrous Fumarate)) have not been studied. However, Stress B Plus (Iron (Ferrous Fumarate)) may reduce the absorption of concomitantly administered oral Stress B Plus (Iron (Ferrous Fumarate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Stress B Plus ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Stress B Plus (Iron (Ferrous Fumarate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Stress B Plus (Iron (Ferrous Fumarate)) sucrose. Because animal reproductive studies are not always predictive of human response, Stress B Plus (Iron (Ferrous Fumarate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Stress B Plus (Iron (Ferrous Fumarate)) sucrose is excreted in human milk. Stress B Plus (Iron (Ferrous Fumarate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Stress B Plus (Iron (Ferrous Fumarate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Stress B Plus ) for Stress B Plus (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Stress B Plus (Iron (Ferrous Fumarate)) for Stress B Plus (Iron (Ferrous Fumarate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Stress B Plus (Iron (Ferrous Fumarate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Stress B Plus (Iron (Ferrous Fumarate)) has not been studied in patients younger than 2 years of age.

In a country where Stress B Plus (Iron (Ferrous Fumarate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Stress B Plus (Iron (Ferrous Fumarate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Stress B Plus (Iron (Ferrous Fumarate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Stress B Plus (Iron (Ferrous Fumarate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Stress B Plus (Iron (Ferrous Fumarate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Stress B Plus (Iron (Ferrous Fumarate)) in humans. Excessive dosages of Stress B Plus (Iron (Ferrous Fumarate)) may lead to accumulation of Stress B Plus (Iron (Ferrous Fumarate)) in storage sites potentially leading to hemosiderosis. Do not administer Stress B Plus (Iron (Ferrous Fumarate)) to patients with Stress B Plus (Iron (Ferrous Fumarate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Stress B Plus (Iron (Ferrous Fumarate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Stress B Plus (Iron (Ferrous Fumarate)) (iron sucrose injection, USP), an Stress B Plus (Iron (Ferrous Fumarate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Stress B Plus (Iron (Ferrous Fumarate)) (III)-hydroxide in sucrose for intravenous use. Stress B Plus (Iron (Ferrous Fumarate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Stress B Plus (Iron (Ferrous Fumarate)) polymerization and m is the number of sucrose molecules associated with the Stress B Plus (Iron (Ferrous Fumarate)) (III)-hydroxide.

Each mL contains 20 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) as Stress B Plus (Iron (Ferrous Fumarate)) sucrose in water for injection. Stress B Plus (Iron (Ferrous Fumarate)) is available in 10 mL single-use vials (200 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) per 10 mL), 5 mL single-use vials (100 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Stress B Plus ) is an aqueous complex of poly-nuclear Stress B Plus (Iron (Ferrous Fumarate)) (III)-hydroxide in sucrose. Following intravenous administration, Stress B Plus (Iron (Ferrous Fumarate)) is dissociated into Stress B Plus (Iron (Ferrous Fumarate)) and sucrose and the Stress B Plus (Iron (Ferrous Fumarate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Stress B Plus (Iron (Ferrous Fumarate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Stress B Plus (Iron (Ferrous Fumarate)) is dissociated into Stress B Plus (Iron (Ferrous Fumarate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Stress B Plus (Iron (Ferrous Fumarate)) sucrose containing 100 mg of Stress B Plus (Iron (Ferrous Fumarate)), three times weekly for three weeks, significant increases in serum Stress B Plus (Iron (Ferrous Fumarate)) and serum ferritin and significant decreases in total Stress B Plus (Iron (Ferrous Fumarate)) binding capacity occurred four weeks from the initiation of Stress B Plus (Iron (Ferrous Fumarate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Stress B Plus ), its Stress B Plus (Iron (Ferrous Fumarate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Stress B Plus (Iron (Ferrous Fumarate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Stress B Plus (Iron (Ferrous Fumarate)) containing 100 mg of Stress B Plus (Iron (Ferrous Fumarate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Stress B Plus (Iron (Ferrous Fumarate)) deficiency showed that a significant amount of the administered Stress B Plus (Iron (Ferrous Fumarate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Stress B Plus (Iron (Ferrous Fumarate)) trapping compartment.

Following intravenous administration of Stress B Plus (Iron (Ferrous Fumarate)), Stress B Plus (Iron (Ferrous Fumarate)) sucrose is dissociated into Stress B Plus (Iron (Ferrous Fumarate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Stress B Plus (Iron (Ferrous Fumarate)) containing 1,510 mg of sucrose and 100 mg of Stress B Plus (Iron (Ferrous Fumarate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Stress B Plus (Iron (Ferrous Fumarate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Stress B Plus (Iron (Ferrous Fumarate)) sucrose containing 500 to 700 mg of Stress B Plus (Iron (Ferrous Fumarate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Stress B Plus (Iron (Ferrous Fumarate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Stress B Plus (Iron (Ferrous Fumarate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Stress B Plus (Iron (Ferrous Fumarate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Stress B Plus (Iron (Ferrous Fumarate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Stress B Plus (Iron (Ferrous Fumarate)), the half-life of total serum Stress B Plus (Iron (Ferrous Fumarate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Stress B Plus (Iron (Ferrous Fumarate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Stress B Plus (Iron (Ferrous Fumarate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Stress B Plus (Iron (Ferrous Fumarate)) sucrose.

Stress B Plus (Iron (Ferrous Fumarate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Stress B Plus (Iron (Ferrous Fumarate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Stress B Plus (Iron (Ferrous Fumarate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Stress B Plus (Iron (Ferrous Fumarate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Stress B Plus ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Stress B Plus (Iron (Ferrous Fumarate)) treatment and 24 in the historical control group) with Stress B Plus (Iron (Ferrous Fumarate)) deficiency anemia. Eligibility criteria for Stress B Plus (Iron (Ferrous Fumarate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Stress B Plus (Iron (Ferrous Fumarate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Stress B Plus (Iron (Ferrous Fumarate)), who were off intravenous Stress B Plus (Iron (Ferrous Fumarate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Stress B Plus (Iron (Ferrous Fumarate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.
Efficacy parameters	End of treatment		2 week follow-up		5 week follow-up
	Stress B Plus (Iron (Ferrous Fumarate)) (n=69	Historical Control (n=18)	Stress B Plus (Iron (Ferrous Fumarate)) (n=73)	Historical Control (n=18)	Stress B Plus (Iron (Ferrous Fumarate)) (n=71)	Historical Control (n=15)
Hemoglobin (g/dL)	1.0 ± 0.12**	0.0 ± 0.21	1.3 ± 0.14**	-0.6 ± 0.24	1.2 ± 0.17*	-0.1 ± 0.23
Hematocrit (%)	3.1 ± 0.37**	-0.3 ± 0.65	3.6 ± 0.44**	-1.2 ± 0.76	3.3 ± 0.54	0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Stress B Plus (Iron (Ferrous Fumarate)) in 23 patients with Stress B Plus (Iron (Ferrous Fumarate)) deficiency and HDD-CKD who had been discontinued from Stress B Plus (Iron (Ferrous Fumarate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Stress B Plus (Iron (Ferrous Fumarate)). Exclusion criteria were similar to those in studies A and B. Stress B Plus (Iron (Ferrous Fumarate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Stress B Plus (Iron (Ferrous Fumarate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Stress B Plus (Iron (Ferrous Fumarate)) versus Stress B Plus (Iron (Ferrous Fumarate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Stress B Plus (Iron (Ferrous Fumarate)) (325 mg ferrous sulfate three times daily for 56 days); or Stress B Plus (Iron (Ferrous Fumarate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Stress B Plus (Iron (Ferrous Fumarate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Stress B Plus (Iron (Ferrous Fumarate)) group.

A statistically significantly greater proportion of Stress B Plus (Iron (Ferrous Fumarate)) subjects (35/79; 44.3%) compared to oral Stress B Plus (Iron (Ferrous Fumarate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Stress B Plus (Iron (Ferrous Fumarate)) to patients with PDD-CKD receiving an erythropoietin alone without Stress B Plus (Iron (Ferrous Fumarate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Stress B Plus (Iron (Ferrous Fumarate)) or Stress B Plus (Iron (Ferrous Fumarate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Stress B Plus (Iron (Ferrous Fumarate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Stress B Plus (Iron (Ferrous Fumarate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Stress B Plus (Iron (Ferrous Fumarate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Stress B Plus ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Stress B Plus (Iron (Ferrous Fumarate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Stress B Plus (Iron (Ferrous Fumarate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Stress B Plus (Iron (Ferrous Fumarate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Stress B Plus (Iron (Ferrous Fumarate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Stress B Plus (Iron (Ferrous Fumarate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Stress B Plus ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Stress B Plus (Iron (Ferrous Fumarate)), each 5 mL vial contains 100 mg elemental Stress B Plus (Iron (Ferrous Fumarate)), and each 2.5 mL vial contains 50 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) (20 mg/mL).

NDC-0517-2310-05	200 mg/10 mL Single-Use Vial	Packages of 5
NDC-0517-2310-10	200 mg/10 mL Single-Use Vial	Packages of 10
NDC-0517-2340-01	100 mg/5 mL Single-Use Vial	Individually Boxed
NDC-0517-2340-10	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2340-25	100 mg/5 mL Single-Use Vial	Packages of 25
NDC-0517-2340-99	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-10	50 mg/2.5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-25	50 mg/2.5 mL Single-Use Vial	Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Stress B Plus (Iron (Ferrous Fumarate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Stress B Plus (Iron (Ferrous Fumarate)) per mL, or undiluted (20 mg elemental Stress B Plus (Iron (Ferrous Fumarate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Stress B Plus (Iron (Ferrous Fumarate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Stress B Plus (Iron (Ferrous Fumarate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Stress B Plus (Iron (Ferrous Fumarate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Stress B Plus (Iron (Ferrous Fumarate)) administration:

• Question patients regarding any prior history of reactions to parenteral Stress B Plus (Iron (Ferrous Fumarate)) products
• Advise patients of the risks associated with Stress B Plus (Iron (Ferrous Fumarate))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Stress B Plus (Iron (Ferrous Fumarate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Stress B Plus (Iron (Ferrous Fumarate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727

Iron (Ferrous Gluconate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stress B Plus (Iron (Ferrous Gluconate)) reviews

1 INDICATIONS AND USAGE

Stress B Plus (Iron (Ferrous Gluconate)) is indicated for the treatment of Stress B Plus (Iron (Ferrous Gluconate)) deficiency anemia in patients with chronic kidney disease (CKD).

Stress B Plus (Iron (Ferrous Gluconate)) is an Stress B Plus (Iron (Ferrous Gluconate)) replacement product indicated for the treatment of Stress B Plus (Iron (Ferrous Gluconate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Stress B Plus ) must only be administered intravenously either by slow injection or by infusion. The dosage of Stress B Plus (Iron (Ferrous Gluconate)) is expressed in mg of elemental Stress B Plus (Iron (Ferrous Gluconate)). Each mL contains 20 mg of elemental Stress B Plus (Iron (Ferrous Gluconate)).

Population		Dose
Adult patients	Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1)	100 mg slow intravenous injection or infusion
	Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2)	200 mg slow intravenous injection or infusion
	Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3)	300 mg or 400 mg intravenous infusion
Pediatric patients	HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5)	0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Stress B Plus (Iron (Ferrous Gluconate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Stress B Plus (Iron (Ferrous Gluconate)) should be administered early during the dialysis session. The usual total treatment course of Stress B Plus (Iron (Ferrous Gluconate)) is 1000 mg. Stress B Plus (Iron (Ferrous Gluconate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Gluconate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Stress B Plus (Iron (Ferrous Gluconate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Stress B Plus (Iron (Ferrous Gluconate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Stress B Plus (Iron (Ferrous Gluconate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Gluconate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Stress B Plus (Iron (Ferrous Gluconate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Stress B Plus (Iron (Ferrous Gluconate)) in a maximum of 250 mL of 0.9% NaCl. Stress B Plus (Iron (Ferrous Gluconate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Gluconate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Stress B Plus (Iron (Ferrous Gluconate)) maintenance treatment

The dosing for Stress B Plus (Iron (Ferrous Gluconate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Stress B Plus (Iron (Ferrous Gluconate)) maintenance treatment: Administer Stress B Plus (Iron (Ferrous Gluconate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Stress B Plus (Iron (Ferrous Gluconate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Stress B Plus (Iron (Ferrous Gluconate)) maintenance treatment

The dosing for Stress B Plus (Iron (Ferrous Gluconate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Stress B Plus (Iron (Ferrous Gluconate)) maintenance treatment: Administer Stress B Plus (Iron (Ferrous Gluconate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Stress B Plus (Iron (Ferrous Gluconate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Stress B Plus (Iron (Ferrous Gluconate))

• Known hypersensitivity to Stress B Plus (Iron (Ferrous Gluconate)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Stress B Plus ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Stress B Plus (Iron (Ferrous Gluconate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Stress B Plus (Iron (Ferrous Gluconate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Stress B Plus (Iron (Ferrous Gluconate)). (5.2)
• Stress B Plus (Iron (Ferrous Gluconate)) Overload: Regularly monitor hematologic responses during Stress B Plus (Iron (Ferrous Gluconate)) therapy. Do not administer Stress B Plus (Iron (Ferrous Gluconate)) to patients with Stress B Plus (Iron (Ferrous Gluconate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Stress B Plus (Iron (Ferrous Gluconate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Stress B Plus (Iron (Ferrous Gluconate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Stress B Plus (Iron (Ferrous Gluconate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Stress B Plus (Iron (Ferrous Gluconate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Stress B Plus (Iron (Ferrous Gluconate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Stress B Plus ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Stress B Plus (Iron (Ferrous Gluconate)). Hypotension following administration of Stress B Plus (Iron (Ferrous Gluconate)) may be related to the rate of administration and/or total dose administered .

5.3 Stress B Plus (Iron (Ferrous Gluconate)) Overload

Excessive therapy with parenteral Stress B Plus (Iron (Ferrous Gluconate)) can lead to excess storage of Stress B Plus (Iron (Ferrous Gluconate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Stress B Plus (Iron (Ferrous Gluconate)) require periodic monitoring of hematologic and Stress B Plus (Iron (Ferrous Gluconate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Stress B Plus (Iron (Ferrous Gluconate)) to patients with evidence of Stress B Plus (Iron (Ferrous Gluconate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Stress B Plus (Iron (Ferrous Gluconate)) sucrose; do not perform serum Stress B Plus (Iron (Ferrous Gluconate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Stress B Plus ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Stress B Plus (Iron (Ferrous Gluconate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Stress B Plus ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Stress B Plus (Iron (Ferrous Gluconate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

* EPO=Erythropoietin
Adverse Reactions (Preferred Term)	HDD-CKD	NDD-CKD		PDD-CKD
	Stress B Plus (Iron (Ferrous Gluconate))	Stress B Plus (Iron (Ferrous Gluconate))	Oral Stress B Plus (Iron (Ferrous Gluconate))	Stress B Plus (Iron (Ferrous Gluconate))	EPO* Only
	(N=231)	(N=139)	(N=139)	(N=75)	(N=46)
	%	%	%	%	%
Subjects with any adverse reaction	78.8	76.3	73.4	72.0	65.2
Ear and Labyrinth Disorders
Ear Pain	0	2.2	0.7	0	0
Eye Disorders
Conjunctivitis	0.4	0	0	2.7	0
Gastrointestinal Disorders
Abdominal pain	3.5	1.4	2.9	4.0	6.5
Diarrhea	5.2	7.2	10.1	8.0	4.3
Dysgeusia	0.9	7.9	0	0	0
Nausea	14.7	8.6	12.2	5.3	4.3
Vomiting	9.1	5.0	8.6	8.0	2.2
General Disorders and
Administration Site Conditions
Asthenia	2.2	0.7	2.2	2.7	0
Chest pain	6.1	1.4	0	2.7	0
Feeling abnormal	3.0	0	0	0	0
Infusion site pain or burning	0	5.8	0	0	0
Injection site extravasation	0	2.2	0	0	0
Peripheral edema	2.6	7.2	5.0	5.3	10.9
Pyrexia	3.0	0.7	0.7	1.3	0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis	2.6	2.2	4.3	16.0	4.3
Injury, Poisoning and Procedural
Complications
Graft complication	9.5	1.4	0	0	0
Metabolism and Nutrition Disorders
Fluid overload	3.0	1.4	0.7	1.3	0
Gout	0	2.9	1.4	0	0
Hyperglycemia	0	2.9	0	0	2.2
Hypoglycemia	0.4	0.7	0.7	4.0	0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia	3.5	1.4	2.2	4.0	4.3
Back pain	2.2	2.2	3.6	1.3	4.3
Muscle cramp	29.4	0.7	0.7	2.7	0
Myalgia	0	3.6	0	1.3	0
Pain in extremity	5.6	4.3	0	2.7	6.5
Nervous System Disorders
Dizziness	6.5	6.5	1.4	1.3	4.3
Headache	12.6	2.9	0.7	4.0	0
Respiratory, Thoracic and
Mediastinal Disorders
Cough	3.0	2.2	0.7	1.3	0
Dyspnea	3.5	5.8	1.4	1.3	2.2
Nasal congestion	0	1.4	2.2	1.3	0
Skin and Subcutaneous
Tissue Disorders
Pruritus	3.9	2.2	4.3	2.7	0
Vascular Disorders
Hypertension	6.5	6.5	4.3	8.0	6.5
Hypotension	39.4	2.2	0.7	2.7	2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Stress B Plus (Iron (Ferrous Gluconate)) therapy and were reported to be intolerant (defined as precluding further use of that Stress B Plus (Iron (Ferrous Gluconate)) product). When these patients were treated with Stress B Plus (Iron (Ferrous Gluconate)) there were no occurrences of adverse reactions that precluded further use of Stress B Plus (Iron (Ferrous Gluconate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Stress B Plus (Iron (Ferrous Gluconate)) maintenance treatment with Stress B Plus (Iron (Ferrous Gluconate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Stress B Plus (Iron (Ferrous Gluconate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Stress B Plus (Iron (Ferrous Gluconate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Stress B Plus (Iron (Ferrous Gluconate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Stress B Plus (Iron (Ferrous Gluconate)) 0.5 mg/kg group, 10 (21%) patients in the Stress B Plus (Iron (Ferrous Gluconate)) 1.0 mg/kg group, and 10 (21%) patients in the Stress B Plus (Iron (Ferrous Gluconate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Stress B Plus (Iron (Ferrous Gluconate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Stress B Plus (Iron (Ferrous Gluconate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Stress B Plus (Iron (Ferrous Gluconate)) injection. Reactions have occurred following the first dose or subsequent doses of Stress B Plus (Iron (Ferrous Gluconate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Stress B Plus (Iron (Ferrous Gluconate)) have not been studied. However, Stress B Plus (Iron (Ferrous Gluconate)) may reduce the absorption of concomitantly administered oral Stress B Plus (Iron (Ferrous Gluconate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Stress B Plus ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Stress B Plus (Iron (Ferrous Gluconate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Stress B Plus (Iron (Ferrous Gluconate)) sucrose. Because animal reproductive studies are not always predictive of human response, Stress B Plus (Iron (Ferrous Gluconate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Stress B Plus (Iron (Ferrous Gluconate)) sucrose is excreted in human milk. Stress B Plus (Iron (Ferrous Gluconate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Stress B Plus (Iron (Ferrous Gluconate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Stress B Plus ) for Stress B Plus (Iron (Ferrous Gluconate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Stress B Plus (Iron (Ferrous Gluconate)) for Stress B Plus (Iron (Ferrous Gluconate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Stress B Plus (Iron (Ferrous Gluconate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Stress B Plus (Iron (Ferrous Gluconate)) has not been studied in patients younger than 2 years of age.

In a country where Stress B Plus (Iron (Ferrous Gluconate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Stress B Plus (Iron (Ferrous Gluconate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Stress B Plus (Iron (Ferrous Gluconate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Stress B Plus (Iron (Ferrous Gluconate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Stress B Plus (Iron (Ferrous Gluconate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Stress B Plus (Iron (Ferrous Gluconate)) in humans. Excessive dosages of Stress B Plus (Iron (Ferrous Gluconate)) may lead to accumulation of Stress B Plus (Iron (Ferrous Gluconate)) in storage sites potentially leading to hemosiderosis. Do not administer Stress B Plus (Iron (Ferrous Gluconate)) to patients with Stress B Plus (Iron (Ferrous Gluconate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Stress B Plus (Iron (Ferrous Gluconate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Stress B Plus (Iron (Ferrous Gluconate)) (iron sucrose injection, USP), an Stress B Plus (Iron (Ferrous Gluconate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Stress B Plus (Iron (Ferrous Gluconate)) (III)-hydroxide in sucrose for intravenous use. Stress B Plus (Iron (Ferrous Gluconate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Stress B Plus (Iron (Ferrous Gluconate)) polymerization and m is the number of sucrose molecules associated with the Stress B Plus (Iron (Ferrous Gluconate)) (III)-hydroxide.

Each mL contains 20 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) as Stress B Plus (Iron (Ferrous Gluconate)) sucrose in water for injection. Stress B Plus (Iron (Ferrous Gluconate)) is available in 10 mL single-use vials (200 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) per 10 mL), 5 mL single-use vials (100 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Stress B Plus ) is an aqueous complex of poly-nuclear Stress B Plus (Iron (Ferrous Gluconate)) (III)-hydroxide in sucrose. Following intravenous administration, Stress B Plus (Iron (Ferrous Gluconate)) is dissociated into Stress B Plus (Iron (Ferrous Gluconate)) and sucrose and the Stress B Plus (Iron (Ferrous Gluconate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Stress B Plus (Iron (Ferrous Gluconate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Stress B Plus (Iron (Ferrous Gluconate)) is dissociated into Stress B Plus (Iron (Ferrous Gluconate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Stress B Plus (Iron (Ferrous Gluconate)) sucrose containing 100 mg of Stress B Plus (Iron (Ferrous Gluconate)), three times weekly for three weeks, significant increases in serum Stress B Plus (Iron (Ferrous Gluconate)) and serum ferritin and significant decreases in total Stress B Plus (Iron (Ferrous Gluconate)) binding capacity occurred four weeks from the initiation of Stress B Plus (Iron (Ferrous Gluconate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Stress B Plus ), its Stress B Plus (Iron (Ferrous Gluconate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Stress B Plus (Iron (Ferrous Gluconate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Stress B Plus (Iron (Ferrous Gluconate)) containing 100 mg of Stress B Plus (Iron (Ferrous Gluconate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Stress B Plus (Iron (Ferrous Gluconate)) deficiency showed that a significant amount of the administered Stress B Plus (Iron (Ferrous Gluconate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Stress B Plus (Iron (Ferrous Gluconate)) trapping compartment.

Following intravenous administration of Stress B Plus (Iron (Ferrous Gluconate)), Stress B Plus (Iron (Ferrous Gluconate)) sucrose is dissociated into Stress B Plus (Iron (Ferrous Gluconate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Stress B Plus (Iron (Ferrous Gluconate)) containing 1,510 mg of sucrose and 100 mg of Stress B Plus (Iron (Ferrous Gluconate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Stress B Plus (Iron (Ferrous Gluconate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Stress B Plus (Iron (Ferrous Gluconate)) sucrose containing 500 to 700 mg of Stress B Plus (Iron (Ferrous Gluconate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Stress B Plus (Iron (Ferrous Gluconate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Stress B Plus (Iron (Ferrous Gluconate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Stress B Plus (Iron (Ferrous Gluconate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Stress B Plus (Iron (Ferrous Gluconate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Stress B Plus (Iron (Ferrous Gluconate)), the half-life of total serum Stress B Plus (Iron (Ferrous Gluconate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Stress B Plus (Iron (Ferrous Gluconate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Stress B Plus (Iron (Ferrous Gluconate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Stress B Plus (Iron (Ferrous Gluconate)) sucrose.

Stress B Plus (Iron (Ferrous Gluconate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Stress B Plus (Iron (Ferrous Gluconate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Stress B Plus (Iron (Ferrous Gluconate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Stress B Plus (Iron (Ferrous Gluconate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Stress B Plus ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Stress B Plus (Iron (Ferrous Gluconate)) treatment and 24 in the historical control group) with Stress B Plus (Iron (Ferrous Gluconate)) deficiency anemia. Eligibility criteria for Stress B Plus (Iron (Ferrous Gluconate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Stress B Plus (Iron (Ferrous Gluconate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Stress B Plus (Iron (Ferrous Gluconate)), who were off intravenous Stress B Plus (Iron (Ferrous Gluconate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Stress B Plus (Iron (Ferrous Gluconate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.
Efficacy parameters	End of treatment		2 week follow-up		5 week follow-up
	Stress B Plus (Iron (Ferrous Gluconate)) (n=69	Historical Control (n=18)	Stress B Plus (Iron (Ferrous Gluconate)) (n=73)	Historical Control (n=18)	Stress B Plus (Iron (Ferrous Gluconate)) (n=71)	Historical Control (n=15)
Hemoglobin (g/dL)	1.0 ± 0.12**	0.0 ± 0.21	1.3 ± 0.14**	-0.6 ± 0.24	1.2 ± 0.17*	-0.1 ± 0.23
Hematocrit (%)	3.1 ± 0.37**	-0.3 ± 0.65	3.6 ± 0.44**	-1.2 ± 0.76	3.3 ± 0.54	0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Stress B Plus (Iron (Ferrous Gluconate)) in 23 patients with Stress B Plus (Iron (Ferrous Gluconate)) deficiency and HDD-CKD who had been discontinued from Stress B Plus (Iron (Ferrous Gluconate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Stress B Plus (Iron (Ferrous Gluconate)). Exclusion criteria were similar to those in studies A and B. Stress B Plus (Iron (Ferrous Gluconate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Stress B Plus (Iron (Ferrous Gluconate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Stress B Plus (Iron (Ferrous Gluconate)) versus Stress B Plus (Iron (Ferrous Gluconate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Stress B Plus (Iron (Ferrous Gluconate)) (325 mg ferrous sulfate three times daily for 56 days); or Stress B Plus (Iron (Ferrous Gluconate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Stress B Plus (Iron (Ferrous Gluconate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Stress B Plus (Iron (Ferrous Gluconate)) group.

A statistically significantly greater proportion of Stress B Plus (Iron (Ferrous Gluconate)) subjects (35/79; 44.3%) compared to oral Stress B Plus (Iron (Ferrous Gluconate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Stress B Plus (Iron (Ferrous Gluconate)) to patients with PDD-CKD receiving an erythropoietin alone without Stress B Plus (Iron (Ferrous Gluconate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Stress B Plus (Iron (Ferrous Gluconate)) or Stress B Plus (Iron (Ferrous Gluconate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Stress B Plus (Iron (Ferrous Gluconate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Stress B Plus (Iron (Ferrous Gluconate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Stress B Plus (Iron (Ferrous Gluconate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Stress B Plus ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Stress B Plus (Iron (Ferrous Gluconate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Stress B Plus (Iron (Ferrous Gluconate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Stress B Plus (Iron (Ferrous Gluconate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Stress B Plus (Iron (Ferrous Gluconate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Stress B Plus (Iron (Ferrous Gluconate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Stress B Plus ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Stress B Plus (Iron (Ferrous Gluconate)), each 5 mL vial contains 100 mg elemental Stress B Plus (Iron (Ferrous Gluconate)), and each 2.5 mL vial contains 50 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) (20 mg/mL).

NDC-0517-2310-05	200 mg/10 mL Single-Use Vial	Packages of 5
NDC-0517-2310-10	200 mg/10 mL Single-Use Vial	Packages of 10
NDC-0517-2340-01	100 mg/5 mL Single-Use Vial	Individually Boxed
NDC-0517-2340-10	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2340-25	100 mg/5 mL Single-Use Vial	Packages of 25
NDC-0517-2340-99	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-10	50 mg/2.5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-25	50 mg/2.5 mL Single-Use Vial	Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Stress B Plus (Iron (Ferrous Gluconate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Stress B Plus (Iron (Ferrous Gluconate)) per mL, or undiluted (20 mg elemental Stress B Plus (Iron (Ferrous Gluconate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Stress B Plus (Iron (Ferrous Gluconate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Stress B Plus (Iron (Ferrous Gluconate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Stress B Plus (Iron (Ferrous Gluconate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Stress B Plus (Iron (Ferrous Gluconate)) administration:

• Question patients regarding any prior history of reactions to parenteral Stress B Plus (Iron (Ferrous Gluconate)) products
• Advise patients of the risks associated with Stress B Plus (Iron (Ferrous Gluconate))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Stress B Plus (Iron (Ferrous Gluconate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Stress B Plus (Iron (Ferrous Gluconate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727

Iron (Ferrous HVP Chelate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stress B Plus (Iron (Ferrous HVP Chelate)) reviews

1 INDICATIONS AND USAGE

Stress B Plus (Iron (Ferrous HVP Chelate)) is indicated for the treatment of Stress B Plus (Iron (Ferrous HVP Chelate)) deficiency anemia in patients with chronic kidney disease (CKD).

Stress B Plus (Iron (Ferrous HVP Chelate)) is an Stress B Plus (Iron (Ferrous HVP Chelate)) replacement product indicated for the treatment of Stress B Plus (Iron (Ferrous HVP Chelate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Stress B Plus ) must only be administered intravenously either by slow injection or by infusion. The dosage of Stress B Plus (Iron (Ferrous HVP Chelate)) is expressed in mg of elemental Stress B Plus (Iron (Ferrous HVP Chelate)). Each mL contains 20 mg of elemental Stress B Plus (Iron (Ferrous HVP Chelate)).

Population		Dose
Adult patients	Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1)	100 mg slow intravenous injection or infusion
	Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2)	200 mg slow intravenous injection or infusion
	Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3)	300 mg or 400 mg intravenous infusion
Pediatric patients	HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5)	0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Stress B Plus (Iron (Ferrous HVP Chelate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Stress B Plus (Iron (Ferrous HVP Chelate)) should be administered early during the dialysis session. The usual total treatment course of Stress B Plus (Iron (Ferrous HVP Chelate)) is 1000 mg. Stress B Plus (Iron (Ferrous HVP Chelate)) treatment may be repeated if Stress B Plus (Iron (Ferrous HVP Chelate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Stress B Plus (Iron (Ferrous HVP Chelate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Stress B Plus (Iron (Ferrous HVP Chelate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Stress B Plus (Iron (Ferrous HVP Chelate)) treatment may be repeated if Stress B Plus (Iron (Ferrous HVP Chelate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Stress B Plus (Iron (Ferrous HVP Chelate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Stress B Plus (Iron (Ferrous HVP Chelate)) in a maximum of 250 mL of 0.9% NaCl. Stress B Plus (Iron (Ferrous HVP Chelate)) treatment may be repeated if Stress B Plus (Iron (Ferrous HVP Chelate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Stress B Plus (Iron (Ferrous HVP Chelate)) maintenance treatment

The dosing for Stress B Plus (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Stress B Plus (Iron (Ferrous HVP Chelate)) maintenance treatment: Administer Stress B Plus (Iron (Ferrous HVP Chelate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Stress B Plus (Iron (Ferrous HVP Chelate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Stress B Plus (Iron (Ferrous HVP Chelate)) maintenance treatment

The dosing for Stress B Plus (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Stress B Plus (Iron (Ferrous HVP Chelate)) maintenance treatment: Administer Stress B Plus (Iron (Ferrous HVP Chelate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Stress B Plus (Iron (Ferrous HVP Chelate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Stress B Plus (Iron (Ferrous HVP Chelate))

• Known hypersensitivity to Stress B Plus (Iron (Ferrous HVP Chelate)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Stress B Plus ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Stress B Plus (Iron (Ferrous HVP Chelate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Stress B Plus (Iron (Ferrous HVP Chelate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Stress B Plus (Iron (Ferrous HVP Chelate)). (5.2)
• Stress B Plus (Iron (Ferrous HVP Chelate)) Overload: Regularly monitor hematologic responses during Stress B Plus (Iron (Ferrous HVP Chelate)) therapy. Do not administer Stress B Plus (Iron (Ferrous HVP Chelate)) to patients with Stress B Plus (Iron (Ferrous HVP Chelate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Stress B Plus (Iron (Ferrous HVP Chelate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Stress B Plus (Iron (Ferrous HVP Chelate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Stress B Plus (Iron (Ferrous HVP Chelate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Stress B Plus (Iron (Ferrous HVP Chelate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Stress B Plus (Iron (Ferrous HVP Chelate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Stress B Plus ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Stress B Plus (Iron (Ferrous HVP Chelate)). Hypotension following administration of Stress B Plus (Iron (Ferrous HVP Chelate)) may be related to the rate of administration and/or total dose administered .

5.3 Stress B Plus (Iron (Ferrous HVP Chelate)) Overload

Excessive therapy with parenteral Stress B Plus (Iron (Ferrous HVP Chelate)) can lead to excess storage of Stress B Plus (Iron (Ferrous HVP Chelate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Stress B Plus (Iron (Ferrous HVP Chelate)) require periodic monitoring of hematologic and Stress B Plus (Iron (Ferrous HVP Chelate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Stress B Plus (Iron (Ferrous HVP Chelate)) to patients with evidence of Stress B Plus (Iron (Ferrous HVP Chelate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose; do not perform serum Stress B Plus (Iron (Ferrous HVP Chelate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Stress B Plus ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Stress B Plus (Iron (Ferrous HVP Chelate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Stress B Plus ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Stress B Plus (Iron (Ferrous HVP Chelate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

* EPO=Erythropoietin
Adverse Reactions (Preferred Term)	HDD-CKD	NDD-CKD		PDD-CKD
	Stress B Plus (Iron (Ferrous HVP Chelate))	Stress B Plus (Iron (Ferrous HVP Chelate))	Oral Stress B Plus (Iron (Ferrous HVP Chelate))	Stress B Plus (Iron (Ferrous HVP Chelate))	EPO* Only
	(N=231)	(N=139)	(N=139)	(N=75)	(N=46)
	%	%	%	%	%
Subjects with any adverse reaction	78.8	76.3	73.4	72.0	65.2
Ear and Labyrinth Disorders
Ear Pain	0	2.2	0.7	0	0
Eye Disorders
Conjunctivitis	0.4	0	0	2.7	0
Gastrointestinal Disorders
Abdominal pain	3.5	1.4	2.9	4.0	6.5
Diarrhea	5.2	7.2	10.1	8.0	4.3
Dysgeusia	0.9	7.9	0	0	0
Nausea	14.7	8.6	12.2	5.3	4.3
Vomiting	9.1	5.0	8.6	8.0	2.2
General Disorders and
Administration Site Conditions
Asthenia	2.2	0.7	2.2	2.7	0
Chest pain	6.1	1.4	0	2.7	0
Feeling abnormal	3.0	0	0	0	0
Infusion site pain or burning	0	5.8	0	0	0
Injection site extravasation	0	2.2	0	0	0
Peripheral edema	2.6	7.2	5.0	5.3	10.9
Pyrexia	3.0	0.7	0.7	1.3	0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis	2.6	2.2	4.3	16.0	4.3
Injury, Poisoning and Procedural
Complications
Graft complication	9.5	1.4	0	0	0
Metabolism and Nutrition Disorders
Fluid overload	3.0	1.4	0.7	1.3	0
Gout	0	2.9	1.4	0	0
Hyperglycemia	0	2.9	0	0	2.2
Hypoglycemia	0.4	0.7	0.7	4.0	0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia	3.5	1.4	2.2	4.0	4.3
Back pain	2.2	2.2	3.6	1.3	4.3
Muscle cramp	29.4	0.7	0.7	2.7	0
Myalgia	0	3.6	0	1.3	0
Pain in extremity	5.6	4.3	0	2.7	6.5
Nervous System Disorders
Dizziness	6.5	6.5	1.4	1.3	4.3
Headache	12.6	2.9	0.7	4.0	0
Respiratory, Thoracic and
Mediastinal Disorders
Cough	3.0	2.2	0.7	1.3	0
Dyspnea	3.5	5.8	1.4	1.3	2.2
Nasal congestion	0	1.4	2.2	1.3	0
Skin and Subcutaneous
Tissue Disorders
Pruritus	3.9	2.2	4.3	2.7	0
Vascular Disorders
Hypertension	6.5	6.5	4.3	8.0	6.5
Hypotension	39.4	2.2	0.7	2.7	2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Stress B Plus (Iron (Ferrous HVP Chelate)) therapy and were reported to be intolerant (defined as precluding further use of that Stress B Plus (Iron (Ferrous HVP Chelate)) product). When these patients were treated with Stress B Plus (Iron (Ferrous HVP Chelate)) there were no occurrences of adverse reactions that precluded further use of Stress B Plus (Iron (Ferrous HVP Chelate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Stress B Plus (Iron (Ferrous HVP Chelate)) maintenance treatment with Stress B Plus (Iron (Ferrous HVP Chelate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Stress B Plus (Iron (Ferrous HVP Chelate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Stress B Plus (Iron (Ferrous HVP Chelate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Stress B Plus (Iron (Ferrous HVP Chelate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Stress B Plus (Iron (Ferrous HVP Chelate)) 0.5 mg/kg group, 10 (21%) patients in the Stress B Plus (Iron (Ferrous HVP Chelate)) 1.0 mg/kg group, and 10 (21%) patients in the Stress B Plus (Iron (Ferrous HVP Chelate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Stress B Plus (Iron (Ferrous HVP Chelate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Stress B Plus (Iron (Ferrous HVP Chelate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Stress B Plus (Iron (Ferrous HVP Chelate)) injection. Reactions have occurred following the first dose or subsequent doses of Stress B Plus (Iron (Ferrous HVP Chelate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Stress B Plus (Iron (Ferrous HVP Chelate)) have not been studied. However, Stress B Plus (Iron (Ferrous HVP Chelate)) may reduce the absorption of concomitantly administered oral Stress B Plus (Iron (Ferrous HVP Chelate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Stress B Plus ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Stress B Plus (Iron (Ferrous HVP Chelate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose. Because animal reproductive studies are not always predictive of human response, Stress B Plus (Iron (Ferrous HVP Chelate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose is excreted in human milk. Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Stress B Plus (Iron (Ferrous HVP Chelate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Stress B Plus ) for Stress B Plus (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Stress B Plus (Iron (Ferrous HVP Chelate)) for Stress B Plus (Iron (Ferrous HVP Chelate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Stress B Plus (Iron (Ferrous HVP Chelate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Stress B Plus (Iron (Ferrous HVP Chelate)) has not been studied in patients younger than 2 years of age.

In a country where Stress B Plus (Iron (Ferrous HVP Chelate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Stress B Plus (Iron (Ferrous HVP Chelate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Stress B Plus (Iron (Ferrous HVP Chelate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Stress B Plus (Iron (Ferrous HVP Chelate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Stress B Plus (Iron (Ferrous HVP Chelate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Stress B Plus (Iron (Ferrous HVP Chelate)) in humans. Excessive dosages of Stress B Plus (Iron (Ferrous HVP Chelate)) may lead to accumulation of Stress B Plus (Iron (Ferrous HVP Chelate)) in storage sites potentially leading to hemosiderosis. Do not administer Stress B Plus (Iron (Ferrous HVP Chelate)) to patients with Stress B Plus (Iron (Ferrous HVP Chelate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Stress B Plus (Iron (Ferrous HVP Chelate)) (iron sucrose injection, USP), an Stress B Plus (Iron (Ferrous HVP Chelate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Stress B Plus (Iron (Ferrous HVP Chelate)) (III)-hydroxide in sucrose for intravenous use. Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Stress B Plus (Iron (Ferrous HVP Chelate)) polymerization and m is the number of sucrose molecules associated with the Stress B Plus (Iron (Ferrous HVP Chelate)) (III)-hydroxide.

Each mL contains 20 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) as Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose in water for injection. Stress B Plus (Iron (Ferrous HVP Chelate)) is available in 10 mL single-use vials (200 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) per 10 mL), 5 mL single-use vials (100 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Stress B Plus ) is an aqueous complex of poly-nuclear Stress B Plus (Iron (Ferrous HVP Chelate)) (III)-hydroxide in sucrose. Following intravenous administration, Stress B Plus (Iron (Ferrous HVP Chelate)) is dissociated into Stress B Plus (Iron (Ferrous HVP Chelate)) and sucrose and the Stress B Plus (Iron (Ferrous HVP Chelate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Stress B Plus (Iron (Ferrous HVP Chelate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Stress B Plus (Iron (Ferrous HVP Chelate)) is dissociated into Stress B Plus (Iron (Ferrous HVP Chelate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose containing 100 mg of Stress B Plus (Iron (Ferrous HVP Chelate)), three times weekly for three weeks, significant increases in serum Stress B Plus (Iron (Ferrous HVP Chelate)) and serum ferritin and significant decreases in total Stress B Plus (Iron (Ferrous HVP Chelate)) binding capacity occurred four weeks from the initiation of Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Stress B Plus ), its Stress B Plus (Iron (Ferrous HVP Chelate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Stress B Plus (Iron (Ferrous HVP Chelate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Stress B Plus (Iron (Ferrous HVP Chelate)) containing 100 mg of Stress B Plus (Iron (Ferrous HVP Chelate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Stress B Plus (Iron (Ferrous HVP Chelate)) deficiency showed that a significant amount of the administered Stress B Plus (Iron (Ferrous HVP Chelate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Stress B Plus (Iron (Ferrous HVP Chelate)) trapping compartment.

Following intravenous administration of Stress B Plus (Iron (Ferrous HVP Chelate)), Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose is dissociated into Stress B Plus (Iron (Ferrous HVP Chelate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Stress B Plus (Iron (Ferrous HVP Chelate)) containing 1,510 mg of sucrose and 100 mg of Stress B Plus (Iron (Ferrous HVP Chelate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Stress B Plus (Iron (Ferrous HVP Chelate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose containing 500 to 700 mg of Stress B Plus (Iron (Ferrous HVP Chelate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Stress B Plus (Iron (Ferrous HVP Chelate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Stress B Plus (Iron (Ferrous HVP Chelate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Stress B Plus (Iron (Ferrous HVP Chelate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Stress B Plus (Iron (Ferrous HVP Chelate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Stress B Plus (Iron (Ferrous HVP Chelate)), the half-life of total serum Stress B Plus (Iron (Ferrous HVP Chelate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Stress B Plus (Iron (Ferrous HVP Chelate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose.

Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Stress B Plus (Iron (Ferrous HVP Chelate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Stress B Plus (Iron (Ferrous HVP Chelate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Stress B Plus ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Stress B Plus (Iron (Ferrous HVP Chelate)) treatment and 24 in the historical control group) with Stress B Plus (Iron (Ferrous HVP Chelate)) deficiency anemia. Eligibility criteria for Stress B Plus (Iron (Ferrous HVP Chelate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Stress B Plus (Iron (Ferrous HVP Chelate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Stress B Plus (Iron (Ferrous HVP Chelate)), who were off intravenous Stress B Plus (Iron (Ferrous HVP Chelate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Stress B Plus (Iron (Ferrous HVP Chelate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.
Efficacy parameters	End of treatment		2 week follow-up		5 week follow-up
	Stress B Plus (Iron (Ferrous HVP Chelate)) (n=69	Historical Control (n=18)	Stress B Plus (Iron (Ferrous HVP Chelate)) (n=73)	Historical Control (n=18)	Stress B Plus (Iron (Ferrous HVP Chelate)) (n=71)	Historical Control (n=15)
Hemoglobin (g/dL)	1.0 ± 0.12**	0.0 ± 0.21	1.3 ± 0.14**	-0.6 ± 0.24	1.2 ± 0.17*	-0.1 ± 0.23
Hematocrit (%)	3.1 ± 0.37**	-0.3 ± 0.65	3.6 ± 0.44**	-1.2 ± 0.76	3.3 ± 0.54	0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Stress B Plus (Iron (Ferrous HVP Chelate)) in 23 patients with Stress B Plus (Iron (Ferrous HVP Chelate)) deficiency and HDD-CKD who had been discontinued from Stress B Plus (Iron (Ferrous HVP Chelate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Stress B Plus (Iron (Ferrous HVP Chelate)). Exclusion criteria were similar to those in studies A and B. Stress B Plus (Iron (Ferrous HVP Chelate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Stress B Plus (Iron (Ferrous HVP Chelate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Stress B Plus (Iron (Ferrous HVP Chelate)) versus Stress B Plus (Iron (Ferrous HVP Chelate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Stress B Plus (Iron (Ferrous HVP Chelate)) (325 mg ferrous sulfate three times daily for 56 days); or Stress B Plus (Iron (Ferrous HVP Chelate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Stress B Plus (Iron (Ferrous HVP Chelate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Stress B Plus (Iron (Ferrous HVP Chelate)) group.

A statistically significantly greater proportion of Stress B Plus (Iron (Ferrous HVP Chelate)) subjects (35/79; 44.3%) compared to oral Stress B Plus (Iron (Ferrous HVP Chelate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Stress B Plus (Iron (Ferrous HVP Chelate)) to patients with PDD-CKD receiving an erythropoietin alone without Stress B Plus (Iron (Ferrous HVP Chelate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Stress B Plus (Iron (Ferrous HVP Chelate)) or Stress B Plus (Iron (Ferrous HVP Chelate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Stress B Plus (Iron (Ferrous HVP Chelate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Stress B Plus (Iron (Ferrous HVP Chelate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Stress B Plus (Iron (Ferrous HVP Chelate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Stress B Plus ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Stress B Plus (Iron (Ferrous HVP Chelate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Stress B Plus (Iron (Ferrous HVP Chelate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Stress B Plus (Iron (Ferrous HVP Chelate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Stress B Plus (Iron (Ferrous HVP Chelate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Stress B Plus (Iron (Ferrous HVP Chelate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Stress B Plus ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)), each 5 mL vial contains 100 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)), and each 2.5 mL vial contains 50 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) (20 mg/mL).

NDC-0517-2310-05	200 mg/10 mL Single-Use Vial	Packages of 5
NDC-0517-2310-10	200 mg/10 mL Single-Use Vial	Packages of 10
NDC-0517-2340-01	100 mg/5 mL Single-Use Vial	Individually Boxed
NDC-0517-2340-10	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2340-25	100 mg/5 mL Single-Use Vial	Packages of 25
NDC-0517-2340-99	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-10	50 mg/2.5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-25	50 mg/2.5 mL Single-Use Vial	Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Stress B Plus (Iron (Ferrous HVP Chelate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Stress B Plus (Iron (Ferrous HVP Chelate)) per mL, or undiluted (20 mg elemental Stress B Plus (Iron (Ferrous HVP Chelate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Stress B Plus (Iron (Ferrous HVP Chelate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Stress B Plus (Iron (Ferrous HVP Chelate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Stress B Plus (Iron (Ferrous HVP Chelate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Stress B Plus (Iron (Ferrous HVP Chelate)) administration:

• Question patients regarding any prior history of reactions to parenteral Stress B Plus (Iron (Ferrous HVP Chelate)) products
• Advise patients of the risks associated with Stress B Plus (Iron (Ferrous HVP Chelate))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Stress B Plus (Iron (Ferrous HVP Chelate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Stress B Plus (Iron (Ferrous HVP Chelate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727

Iron (Ferrous Malate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stress B Plus (Iron (Ferrous Malate)) reviews

1 INDICATIONS AND USAGE

Stress B Plus (Iron (Ferrous Malate)) is indicated for the treatment of Stress B Plus (Iron (Ferrous Malate)) deficiency anemia in patients with chronic kidney disease (CKD).

Stress B Plus (Iron (Ferrous Malate)) is an Stress B Plus (Iron (Ferrous Malate)) replacement product indicated for the treatment of Stress B Plus (Iron (Ferrous Malate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Stress B Plus ) must only be administered intravenously either by slow injection or by infusion. The dosage of Stress B Plus (Iron (Ferrous Malate)) is expressed in mg of elemental Stress B Plus (Iron (Ferrous Malate)). Each mL contains 20 mg of elemental Stress B Plus (Iron (Ferrous Malate)).

Population		Dose
Adult patients	Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1)	100 mg slow intravenous injection or infusion
	Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2)	200 mg slow intravenous injection or infusion
	Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3)	300 mg or 400 mg intravenous infusion
Pediatric patients	HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5)	0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Stress B Plus (Iron (Ferrous Malate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Stress B Plus (Iron (Ferrous Malate)) should be administered early during the dialysis session. The usual total treatment course of Stress B Plus (Iron (Ferrous Malate)) is 1000 mg. Stress B Plus (Iron (Ferrous Malate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Malate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Stress B Plus (Iron (Ferrous Malate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Stress B Plus (Iron (Ferrous Malate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Stress B Plus (Iron (Ferrous Malate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Malate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Stress B Plus (Iron (Ferrous Malate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Stress B Plus (Iron (Ferrous Malate)) in a maximum of 250 mL of 0.9% NaCl. Stress B Plus (Iron (Ferrous Malate)) treatment may be repeated if Stress B Plus (Iron (Ferrous Malate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Stress B Plus (Iron (Ferrous Malate)) maintenance treatment

The dosing for Stress B Plus (Iron (Ferrous Malate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Stress B Plus (Iron (Ferrous Malate)) maintenance treatment: Administer Stress B Plus (Iron (Ferrous Malate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Stress B Plus (Iron (Ferrous Malate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Stress B Plus (Iron (Ferrous Malate)) maintenance treatment

The dosing for Stress B Plus (Iron (Ferrous Malate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Stress B Plus (Iron (Ferrous Malate)) maintenance treatment: Administer Stress B Plus (Iron (Ferrous Malate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Stress B Plus (Iron (Ferrous Malate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Stress B Plus (Iron (Ferrous Malate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Stress B Plus (Iron (Ferrous Malate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Stress B Plus (Iron (Ferrous Malate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Stress B Plus (Iron (Ferrous Malate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Stress B Plus (Iron (Ferrous Malate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Stress B Plus (Iron (Ferrous Malate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Stress B Plus (Iron (Ferrous Malate))

• Known hypersensitivity to Stress B Plus (Iron (Ferrous Malate)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Stress B Plus ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Stress B Plus (Iron (Ferrous Malate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Stress B Plus (Iron (Ferrous Malate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Stress B Plus (Iron (Ferrous Malate)). (5.2)
• Stress B Plus (Iron (Ferrous Malate)) Overload: Regularly monitor hematologic responses during Stress B Plus (Iron (Ferrous Malate)) therapy. Do not administer Stress B Plus (Iron (Ferrous Malate)) to patients with Stress B Plus (Iron (Ferrous Malate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Stress B Plus (Iron (Ferrous Malate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Stress B Plus (Iron (Ferrous Malate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Stress B Plus (Iron (Ferrous Malate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Stress B Plus (Iron (Ferrous Malate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Stress B Plus (Iron (Ferrous Malate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Stress B Plus ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Stress B Plus (Iron (Ferrous Malate)). Hypotension following administration of Stress B Plus (Iron (Ferrous Malate)) may be related to the rate of administration and/or total dose administered .

5.3 Stress B Plus (Iron (Ferrous Malate)) Overload

Excessive therapy with parenteral Stress B Plus (Iron (Ferrous Malate)) can lead to excess storage of Stress B Plus (Iron (Ferrous Malate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Stress B Plus (Iron (Ferrous Malate)) require periodic monitoring of hematologic and Stress B Plus (Iron (Ferrous Malate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Stress B Plus (Iron (Ferrous Malate)) to patients with evidence of Stress B Plus (Iron (Ferrous Malate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Stress B Plus (Iron (Ferrous Malate)) sucrose; do not perform serum Stress B Plus (Iron (Ferrous Malate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Stress B Plus ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Stress B Plus (Iron (Ferrous Malate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Stress B Plus ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Stress B Plus (Iron (Ferrous Malate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

* EPO=Erythropoietin
Adverse Reactions (Preferred Term)	HDD-CKD	NDD-CKD		PDD-CKD
	Stress B Plus (Iron (Ferrous Malate))	Stress B Plus (Iron (Ferrous Malate))	Oral Stress B Plus (Iron (Ferrous Malate))	Stress B Plus (Iron (Ferrous Malate))	EPO* Only
	(N=231)	(N=139)	(N=139)	(N=75)	(N=46)
	%	%	%	%	%
Subjects with any adverse reaction	78.8	76.3	73.4	72.0	65.2
Ear and Labyrinth Disorders
Ear Pain	0	2.2	0.7	0	0
Eye Disorders
Conjunctivitis	0.4	0	0	2.7	0
Gastrointestinal Disorders
Abdominal pain	3.5	1.4	2.9	4.0	6.5
Diarrhea	5.2	7.2	10.1	8.0	4.3
Dysgeusia	0.9	7.9	0	0	0
Nausea	14.7	8.6	12.2	5.3	4.3
Vomiting	9.1	5.0	8.6	8.0	2.2
General Disorders and
Administration Site Conditions
Asthenia	2.2	0.7	2.2	2.7	0
Chest pain	6.1	1.4	0	2.7	0
Feeling abnormal	3.0	0	0	0	0
Infusion site pain or burning	0	5.8	0	0	0
Injection site extravasation	0	2.2	0	0	0
Peripheral edema	2.6	7.2	5.0	5.3	10.9
Pyrexia	3.0	0.7	0.7	1.3	0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis	2.6	2.2	4.3	16.0	4.3
Injury, Poisoning and Procedural
Complications
Graft complication	9.5	1.4	0	0	0
Metabolism and Nutrition Disorders
Fluid overload	3.0	1.4	0.7	1.3	0
Gout	0	2.9	1.4	0	0
Hyperglycemia	0	2.9	0	0	2.2
Hypoglycemia	0.4	0.7	0.7	4.0	0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia	3.5	1.4	2.2	4.0	4.3
Back pain	2.2	2.2	3.6	1.3	4.3
Muscle cramp	29.4	0.7	0.7	2.7	0
Myalgia	0	3.6	0	1.3	0
Pain in extremity	5.6	4.3	0	2.7	6.5
Nervous System Disorders
Dizziness	6.5	6.5	1.4	1.3	4.3
Headache	12.6	2.9	0.7	4.0	0
Respiratory, Thoracic and
Mediastinal Disorders
Cough	3.0	2.2	0.7	1.3	0
Dyspnea	3.5	5.8	1.4	1.3	2.2
Nasal congestion	0	1.4	2.2	1.3	0
Skin and Subcutaneous
Tissue Disorders
Pruritus	3.9	2.2	4.3	2.7	0
Vascular Disorders
Hypertension	6.5	6.5	4.3	8.0	6.5
Hypotension	39.4	2.2	0.7	2.7	2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Stress B Plus (Iron (Ferrous Malate)) therapy and were reported to be intolerant (defined as precluding further use of that Stress B Plus (Iron (Ferrous Malate)) product). When these patients were treated with Stress B Plus (Iron (Ferrous Malate)) there were no occurrences of adverse reactions that precluded further use of Stress B Plus (Iron (Ferrous Malate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Stress B Plus (Iron (Ferrous Malate)) maintenance treatment with Stress B Plus (Iron (Ferrous Malate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Stress B Plus (Iron (Ferrous Malate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Stress B Plus (Iron (Ferrous Malate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Stress B Plus (Iron (Ferrous Malate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Stress B Plus (Iron (Ferrous Malate)) 0.5 mg/kg group, 10 (21%) patients in the Stress B Plus (Iron (Ferrous Malate)) 1.0 mg/kg group, and 10 (21%) patients in the Stress B Plus (Iron (Ferrous Malate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Stress B Plus (Iron (Ferrous Malate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Stress B Plus (Iron (Ferrous Malate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Stress B Plus (Iron (Ferrous Malate)) injection. Reactions have occurred following the first dose or subsequent doses of Stress B Plus (Iron (Ferrous Malate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Stress B Plus (Iron (Ferrous Malate)) have not been studied. However, Stress B Plus (Iron (Ferrous Malate)) may reduce the absorption of concomitantly administered oral Stress B Plus (Iron (Ferrous Malate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Stress B Plus ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Stress B Plus (Iron (Ferrous Malate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Stress B Plus (Iron (Ferrous Malate)) sucrose. Because animal reproductive studies are not always predictive of human response, Stress B Plus (Iron (Ferrous Malate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Stress B Plus (Iron (Ferrous Malate)) sucrose is excreted in human milk. Stress B Plus (Iron (Ferrous Malate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Stress B Plus (Iron (Ferrous Malate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Stress B Plus ) for Stress B Plus (Iron (Ferrous Malate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Stress B Plus (Iron (Ferrous Malate)) for Stress B Plus (Iron (Ferrous Malate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Stress B Plus (Iron (Ferrous Malate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Stress B Plus (Iron (Ferrous Malate)) has not been studied in patients younger than 2 years of age.

In a country where Stress B Plus (Iron (Ferrous Malate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Stress B Plus (Iron (Ferrous Malate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Stress B Plus (Iron (Ferrous Malate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Stress B Plus (Iron (Ferrous Malate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Stress B Plus (Iron (Ferrous Malate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Stress B Plus (Iron (Ferrous Malate)) in humans. Excessive dosages of Stress B Plus (Iron (Ferrous Malate)) may lead to accumulation of Stress B Plus (Iron (Ferrous Malate)) in storage sites potentially leading to hemosiderosis. Do not administer Stress B Plus (Iron (Ferrous Malate)) to patients with Stress B Plus (Iron (Ferrous Malate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Stress B Plus (Iron (Ferrous Malate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Stress B Plus (Iron (Ferrous Malate)) (iron sucrose injection, USP), an Stress B Plus (Iron (Ferrous Malate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Stress B Plus (Iron (Ferrous Malate)) (III)-hydroxide in sucrose for intravenous use. Stress B Plus (Iron (Ferrous Malate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Stress B Plus (Iron (Ferrous Malate)) polymerization and m is the number of sucrose molecules associated with the Stress B Plus (Iron (Ferrous Malate)) (III)-hydroxide.

Each mL contains 20 mg elemental Stress B Plus (Iron (Ferrous Malate)) as Stress B Plus (Iron (Ferrous Malate)) sucrose in water for injection. Stress B Plus (Iron (Ferrous Malate)) is available in 10 mL single-use vials (200 mg elemental Stress B Plus (Iron (Ferrous Malate)) per 10 mL), 5 mL single-use vials (100 mg elemental Stress B Plus (Iron (Ferrous Malate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Stress B Plus (Iron (Ferrous Malate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Stress B Plus ) is an aqueous complex of poly-nuclear Stress B Plus (Iron (Ferrous Malate)) (III)-hydroxide in sucrose. Following intravenous administration, Stress B Plus (Iron (Ferrous Malate)) is dissociated into Stress B Plus (Iron (Ferrous Malate)) and sucrose and the Stress B Plus (Iron (Ferrous Malate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Stress B Plus (Iron (Ferrous Malate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Stress B Plus (Iron (Ferrous Malate)) is dissociated into Stress B Plus (Iron (Ferrous Malate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Stress B Plus (Iron (Ferrous Malate)) sucrose containing 100 mg of Stress B Plus (Iron (Ferrous Malate)), three times weekly for three weeks, significant increases in serum Stress B Plus (Iron (Ferrous Malate)) and serum ferritin and significant decreases in total Stress B Plus (Iron (Ferrous Malate)) binding capacity occurred four weeks from the initiation of Stress B Plus (Iron (Ferrous Malate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Stress B Plus ), its Stress B Plus (Iron (Ferrous Malate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Stress B Plus (Iron (Ferrous Malate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Stress B Plus (Iron (Ferrous Malate)) containing 100 mg of Stress B Plus (Iron (Ferrous Malate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Stress B Plus (Iron (Ferrous Malate)) deficiency showed that a significant amount of the administered Stress B Plus (Iron (Ferrous Malate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Stress B Plus (Iron (Ferrous Malate)) trapping compartment.

Following intravenous administration of Stress B Plus (Iron (Ferrous Malate)), Stress B Plus (Iron (Ferrous Malate)) sucrose is dissociated into Stress B Plus (Iron (Ferrous Malate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Stress B Plus (Iron (Ferrous Malate)) containing 1,510 mg of sucrose and 100 mg of Stress B Plus (Iron (Ferrous Malate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Stress B Plus (Iron (Ferrous Malate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Stress B Plus (Iron (Ferrous Malate)) sucrose containing 500 to 700 mg of Stress B Plus (Iron (Ferrous Malate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Stress B Plus (Iron (Ferrous Malate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Stress B Plus (Iron (Ferrous Malate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Stress B Plus (Iron (Ferrous Malate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Stress B Plus (Iron (Ferrous Malate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Stress B Plus (Iron (Ferrous Malate)), the half-life of total serum Stress B Plus (Iron (Ferrous Malate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Stress B Plus (Iron (Ferrous Malate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Stress B Plus (Iron (Ferrous Malate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Stress B Plus (Iron (Ferrous Malate)) sucrose.

Stress B Plus (Iron (Ferrous Malate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Stress B Plus (Iron (Ferrous Malate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Stress B Plus (Iron (Ferrous Malate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Stress B Plus (Iron (Ferrous Malate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Stress B Plus ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Stress B Plus (Iron (Ferrous Malate)) treatment and 24 in the historical control group) with Stress B Plus (Iron (Ferrous Malate)) deficiency anemia. Eligibility criteria for Stress B Plus (Iron (Ferrous Malate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Stress B Plus (Iron (Ferrous Malate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Stress B Plus (Iron (Ferrous Malate)), who were off intravenous Stress B Plus (Iron (Ferrous Malate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Stress B Plus (Iron (Ferrous Malate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.
Efficacy parameters	End of treatment		2 week follow-up		5 week follow-up
	Stress B Plus (Iron (Ferrous Malate)) (n=69	Historical Control (n=18)	Stress B Plus (Iron (Ferrous Malate)) (n=73)	Historical Control (n=18)	Stress B Plus (Iron (Ferrous Malate)) (n=71)	Historical Control (n=15)
Hemoglobin (g/dL)	1.0 ± 0.12**	0.0 ± 0.21	1.3 ± 0.14**	-0.6 ± 0.24	1.2 ± 0.17*	-0.1 ± 0.23
Hematocrit (%)	3.1 ± 0.37**	-0.3 ± 0.65	3.6 ± 0.44**	-1.2 ± 0.76	3.3 ± 0.54	0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Stress B Plus (Iron (Ferrous Malate)) in 23 patients with Stress B Plus (Iron (Ferrous Malate)) deficiency and HDD-CKD who had been discontinued from Stress B Plus (Iron (Ferrous Malate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Stress B Plus (Iron (Ferrous Malate)). Exclusion criteria were similar to those in studies A and B. Stress B Plus (Iron (Ferrous Malate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Stress B Plus (Iron (Ferrous Malate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Stress B Plus (Iron (Ferrous Malate)) versus Stress B Plus (Iron (Ferrous Malate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Stress B Plus (Iron (Ferrous Malate)) (325 mg ferrous sulfate three times daily for 56 days); or Stress B Plus (Iron (Ferrous Malate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Stress B Plus (Iron (Ferrous Malate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Stress B Plus (Iron (Ferrous Malate)) group.

A statistically significantly greater proportion of Stress B Plus (Iron (Ferrous Malate)) subjects (35/79; 44.3%) compared to oral Stress B Plus (Iron (Ferrous Malate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Stress B Plus (Iron (Ferrous Malate)) to patients with PDD-CKD receiving an erythropoietin alone without Stress B Plus (Iron (Ferrous Malate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Stress B Plus (Iron (Ferrous Malate)) or Stress B Plus (Iron (Ferrous Malate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Stress B Plus (Iron (Ferrous Malate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Stress B Plus (Iron (Ferrous Malate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Stress B Plus (Iron (Ferrous Malate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Stress B Plus ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Stress B Plus (Iron (Ferrous Malate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Stress B Plus (Iron (Ferrous Malate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Stress B Plus (Iron (Ferrous Malate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Stress B Plus (Iron (Ferrous Malate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Stress B Plus (Iron (Ferrous Malate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Stress B Plus ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Stress B Plus (Iron (Ferrous Malate)), each 5 mL vial contains 100 mg elemental Stress B Plus (Iron (Ferrous Malate)), and each 2.5 mL vial contains 50 mg elemental Stress B Plus (Iron (Ferrous Malate)) (20 mg/mL).

NDC-0517-2310-05	200 mg/10 mL Single-Use Vial	Packages of 5
NDC-0517-2310-10	200 mg/10 mL Single-Use Vial	Packages of 10
NDC-0517-2340-01	100 mg/5 mL Single-Use Vial	Individually Boxed
NDC-0517-2340-10	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2340-25	100 mg/5 mL Single-Use Vial	Packages of 25
NDC-0517-2340-99	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-10	50 mg/2.5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-25	50 mg/2.5 mL Single-Use Vial	Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Stress B Plus (Iron (Ferrous Malate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Stress B Plus (Iron (Ferrous Malate)) per mL, or undiluted (20 mg elemental Stress B Plus (Iron (Ferrous Malate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Stress B Plus (Iron (Ferrous Malate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Stress B Plus (Iron (Ferrous Malate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Stress B Plus (Iron (Ferrous Malate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Stress B Plus (Iron (Ferrous Malate)) administration:

• Question patients regarding any prior history of reactions to parenteral Stress B Plus (Iron (Ferrous Malate)) products
• Advise patients of the risks associated with Stress B Plus (Iron (Ferrous Malate))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Stress B Plus (Iron (Ferrous Malate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Stress B Plus (Iron (Ferrous Malate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727