Prorocal Plus

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
• Prorocal Plus (Calcium Gluconate) reviews

1 INDICATIONS AND USAGE

Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (Calcium Gluconate) acetate capsule.

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

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Prorocal Plus acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Prorocal Plus (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 Prorocal Plus (Calcium Gluconate), including Prorocal Plus (Calcium Gluconate) acetate. Avoid the use of Prorocal Plus (Calcium Gluconate) supplements, including Prorocal Plus (Calcium Gluconate) based nonprescription antacids, concurrently with Prorocal Plus (Calcium Gluconate) acetate.

An overdose of Prorocal Plus (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 Prorocal Plus (Calcium Gluconate) levels twice weekly. Should hypercalcemia develop, reduce the Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (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, Prorocal Plus (Calcium Gluconate) acetate has been generally well tolerated.

Prorocal Plus (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 Prorocal Plus (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.

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 Prorocal Plus (Calcium Gluconate) concentration could reduce the incidence and severity of Prorocal Plus (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 Prorocal Plus (Calcium Gluconate) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

There are no empirical data on avoiding drug interactions between Prorocal Plus (Calcium Gluconate) acetate and most concomitant drugs. When administering an oral medication with Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (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:

Prorocal Plus acetate capsules contains Prorocal Plus (Calcium Gluconate) acetate. Animal reproduction studies have not been conducted with Prorocal Plus (Calcium Gluconate) acetate, and there are no adequate and well controlled studies of Prorocal Plus (Calcium Gluconate) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Prorocal Plus (Calcium Gluconate) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Prorocal Plus (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. Prorocal Plus (Calcium Gluconate) acetate treatment, as recommended, is not expected to harm a fetus if maternal Prorocal Plus (Calcium Gluconate) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

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

8.3 Nursing Mothers

Prorocal Plus Acetate Capsules contains Prorocal Plus (Calcium Gluconate) acetate and is excreted in human milk. Human milk feeding by a mother receiving Prorocal Plus (Calcium Gluconate) acetate is not expected to harm an infant, provided maternal serum Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (Calcium Gluconate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Prorocal Plus (Calcium Gluconate) acetate acts as a phosphate binder. Its chemical name is Prorocal Plus (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 Prorocal Plus (Calcium Gluconate) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Prorocal Plus (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.

Prorocal Plus (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 Prorocal 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

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

12.2 Pharmacodynamics

Orally administered Prorocal Plus (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 Prorocal Plus (Calcium Gluconate) acetate.

14 CLINICAL STUDIES

Effectiveness of Prorocal Plus (Calcium Gluconate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (Calcium Gluconate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Prorocal Plus (Calcium Gluconate) levels are also presented.

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 Prorocal Plus (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 Prorocal Plus (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 Prorocal Plus (Calcium Gluconate) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Prorocal Plus (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 Prorocal Plus (Calcium Gluconate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Prorocal Plus (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 Prorocal Plus (Calcium Gluconate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Folic Acid:

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

INDICATIONS AND USAGE

Prorocal 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.

PRECAUTIONS

Prorocal 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 Prorocal 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

Prorocal 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.

Prorocal Plus (Folic Acid) and the BIFERA logo are registered trademarks and the Prorocal 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

Iron:

• 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
• Prorocal Plus (Iron) reviews

1 INDICATIONS AND USAGE

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

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

2 DOSAGE AND ADMINISTRATION

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

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

Administer Prorocal Plus (Iron) 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. Prorocal Plus (Iron) should be administered early during the dialysis session. The usual total treatment course of Prorocal Plus (Iron) is 1000 mg. Prorocal Plus (Iron) treatment may be repeated if Prorocal Plus (Iron) deficiency reoccurs.

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

Administer Prorocal Plus (Iron) 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 Prorocal Plus (Iron), 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. Prorocal Plus (Iron) treatment may be repeated if Prorocal Plus (Iron) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Prorocal Plus (Iron) 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 Prorocal Plus (Iron) in a maximum of 250 mL of 0.9% NaCl. Prorocal Plus (Iron) treatment may be repeated if Prorocal Plus (Iron) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Prorocal Plus (Iron) maintenance treatment

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

For Prorocal Plus (Iron) maintenance treatment: Administer Prorocal Plus (Iron) 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. Prorocal Plus (Iron) treatment may be repeated if necessary.

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

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

For Prorocal Plus (Iron) maintenance treatment: Administer Prorocal Plus (Iron) 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. Prorocal Plus (Iron) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

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

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

4 CONTRAINDICATIONS

• Known hypersensitivity to Prorocal Plus (Iron)

• Known hypersensitivity to Prorocal Plus (Iron) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Prorocal Plus (Iron) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Prorocal Plus are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Prorocal Plus (Iron) 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 Prorocal 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 Prorocal Plus (Iron) 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.

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 Prorocal Plus (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Prorocal Plus (Iron) product). When these patients were treated with Prorocal Plus (Iron) there were no occurrences of adverse reactions that precluded further use of Prorocal Plus (Iron) .

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 Prorocal Plus (Iron) maintenance treatment with Prorocal Plus (Iron) 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 Prorocal Plus (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Prorocal Plus (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Prorocal Plus (Iron) 2.0 mg/kg.

A total of 5 (11%) subjects in the Prorocal Plus (Iron) 0.5 mg/kg group, 10 (21%) patients in the Prorocal Plus (Iron) 1.0 mg/kg group, and 10 (21%) patients in the Prorocal Plus (Iron) 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 Prorocal Plus (Iron). 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 Prorocal Plus (Iron) 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 Prorocal Plus (Iron) injection. Reactions have occurred following the first dose or subsequent doses of Prorocal Plus (Iron). 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 Prorocal Plus (Iron) have not been studied. However, Prorocal Plus (Iron) may reduce the absorption of concomitantly administered oral Prorocal Plus (Iron) 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, Prorocal Plus sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Prorocal Plus (Iron) (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 Prorocal Plus (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, Prorocal Plus (Iron) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

Safety and effectiveness of Prorocal Plus (Iron) for Prorocal Plus (Iron) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Prorocal Plus (Iron) 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)]

Prorocal Plus (Iron) has not been studied in patients younger than 2 years of age.

In a country where Prorocal Plus (Iron) 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 Prorocal Plus (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Prorocal Plus (Iron) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Prorocal Plus (Iron) 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 Prorocal Plus (Iron), 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 Prorocal Plus (Iron) in humans. Excessive dosages of Prorocal Plus (Iron) may lead to accumulation of Prorocal Plus (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Prorocal Plus (Iron) to patients with Prorocal Plus (Iron) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Prorocal Plus (Iron) 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

Prorocal Plus (Iron) (iron sucrose injection, USP), an Prorocal Plus (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear Prorocal Plus (Iron) (III)-hydroxide in sucrose for intravenous use. Prorocal Plus (Iron) 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 Prorocal Plus (Iron) polymerization and m is the number of sucrose molecules associated with the Prorocal Plus (Iron) (III)-hydroxide.

Each mL contains 20 mg elemental Prorocal Plus (Iron) as Prorocal Plus (Iron) sucrose in water for injection. Prorocal Plus (Iron) is available in 10 mL single-use vials (200 mg elemental Prorocal Plus (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental Prorocal Plus (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Prorocal Plus (Iron) 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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Prorocal Plus, its Prorocal Plus (Iron) 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 Prorocal Plus (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Prorocal Plus (Iron) containing 100 mg of Prorocal Plus (Iron) labeled with ⁵²Fe/⁵⁹Fe in patients with Prorocal Plus (Iron) deficiency showed that a significant amount of the administered Prorocal Plus (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Prorocal Plus (Iron) trapping compartment.

Following intravenous administration of Prorocal Plus (Iron), Prorocal Plus (Iron) sucrose is dissociated into Prorocal Plus (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Prorocal Plus (Iron) containing 1,510 mg of sucrose and 100 mg of Prorocal Plus (Iron) 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 Prorocal Plus (Iron) 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 Prorocal Plus (Iron) sucrose containing 500 to 700 mg of Prorocal Plus (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Prorocal Plus (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Prorocal Plus (Iron) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Prorocal Plus (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Prorocal Plus (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Prorocal Plus (Iron), the half-life of total serum Prorocal Plus (Iron) 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.

Prorocal Plus (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Prorocal Plus (Iron) 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 Prorocal Plus (Iron) sucrose.

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

Prorocal Plus (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Prorocal Plus (Iron) (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 Prorocal 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 Prorocal Plus (Iron) treatment and 24 in the historical control group) with Prorocal Plus (Iron) deficiency anemia. Eligibility criteria for Prorocal Plus (Iron) 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.

Prorocal Plus (Iron) 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 Prorocal Plus (Iron), who were off intravenous Prorocal Plus (Iron) 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 Prorocal Plus (Iron) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

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 Prorocal Plus (Iron) in 23 patients with Prorocal Plus (Iron) deficiency and HDD-CKD who had been discontinued from Prorocal Plus (Iron) 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 Prorocal Plus (Iron). Exclusion criteria were similar to those in studies A and B. Prorocal Plus (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Prorocal Plus (Iron) 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 Prorocal Plus (Iron) versus Prorocal Plus (Iron) 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 Prorocal Plus (Iron) (325 mg ferrous sulfate three times daily for 56 days); or Prorocal Plus (Iron) (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 Prorocal Plus (Iron) 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 Prorocal Plus (Iron) group.

A statistically significantly greater proportion of Prorocal Plus (Iron) subjects (35/79; 44.3%) compared to oral Prorocal Plus (Iron) 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 Prorocal Plus (Iron) to patients with PDD-CKD receiving an erythropoietin alone without Prorocal Plus (Iron) 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 Prorocal Plus (Iron) or Prorocal Plus (Iron) (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 Prorocal Plus (Iron) / 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 Prorocal Plus (Iron) / 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 Prorocal Plus (Iron) / 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: Prorocal 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 Prorocal Plus (Iron) 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 Prorocal Plus (Iron) (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 Prorocal Plus (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Prorocal Plus (Iron) 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 Prorocal Plus (Iron) 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

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

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: Prorocal Plus (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Prorocal Plus (Iron) per mL, or undiluted (20 mg elemental Prorocal Plus (Iron) 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: Prorocal Plus (Iron), 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 Prorocal Plus (Iron) 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 Prorocal Plus (Iron) 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 Prorocal Plus (Iron) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Prorocal Plus (Iron) 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 Aminoate):

• 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
• Prorocal Plus (Iron (Ferrous Aminoate)) reviews

1 INDICATIONS AND USAGE

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

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

2 DOSAGE AND ADMINISTRATION

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

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

Administer Prorocal Plus (Iron (Ferrous Aminoate)) 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. Prorocal Plus (Iron (Ferrous Aminoate)) should be administered early during the dialysis session. The usual total treatment course of Prorocal Plus (Iron (Ferrous Aminoate)) is 1000 mg. Prorocal Plus (Iron (Ferrous Aminoate)) treatment may be repeated if Prorocal Plus (Iron (Ferrous Aminoate)) deficiency reoccurs.

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

Administer Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)), 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. Prorocal Plus (Iron (Ferrous Aminoate)) treatment may be repeated if Prorocal Plus (Iron (Ferrous Aminoate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) in a maximum of 250 mL of 0.9% NaCl. Prorocal Plus (Iron (Ferrous Aminoate)) treatment may be repeated if Prorocal Plus (Iron (Ferrous Aminoate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Prorocal Plus (Iron (Ferrous Aminoate)) maintenance treatment

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

For Prorocal Plus (Iron (Ferrous Aminoate)) maintenance treatment: Administer Prorocal Plus (Iron (Ferrous Aminoate)) 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. Prorocal Plus (Iron (Ferrous Aminoate)) treatment may be repeated if necessary.

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

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

For Prorocal Plus (Iron (Ferrous Aminoate)) maintenance treatment: Administer Prorocal Plus (Iron (Ferrous Aminoate)) 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. Prorocal Plus (Iron (Ferrous Aminoate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

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

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

4 CONTRAINDICATIONS

• Known hypersensitivity to Prorocal Plus (Iron (Ferrous Aminoate))

• Known hypersensitivity to Prorocal Plus (Iron (Ferrous Aminoate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Prorocal Plus (Iron (Ferrous Aminoate)) Overload

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

6 ADVERSE REACTIONS

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

• The most common adverse reactions (≥2%) following the administration of Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal 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 Prorocal Plus (Iron (Ferrous Aminoate)) 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.

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 Prorocal Plus (Iron (Ferrous Aminoate)) therapy and were reported to be intolerant (defined as precluding further use of that Prorocal Plus (Iron (Ferrous Aminoate)) product). When these patients were treated with Prorocal Plus (Iron (Ferrous Aminoate)) there were no occurrences of adverse reactions that precluded further use of Prorocal Plus (Iron (Ferrous Aminoate)) .

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 Prorocal Plus (Iron (Ferrous Aminoate)) maintenance treatment with Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Prorocal Plus (Iron (Ferrous Aminoate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Prorocal Plus (Iron (Ferrous Aminoate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Prorocal Plus (Iron (Ferrous Aminoate)) 0.5 mg/kg group, 10 (21%) patients in the Prorocal Plus (Iron (Ferrous Aminoate)) 1.0 mg/kg group, and 10 (21%) patients in the Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)). 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 Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) injection. Reactions have occurred following the first dose or subsequent doses of Prorocal Plus (Iron (Ferrous Aminoate)). 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 Prorocal Plus (Iron (Ferrous Aminoate)) have not been studied. However, Prorocal Plus (Iron (Ferrous Aminoate)) may reduce the absorption of concomitantly administered oral Prorocal Plus (Iron (Ferrous Aminoate)) 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, Prorocal Plus ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Prorocal Plus (Iron (Ferrous Aminoate)) (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 Prorocal Plus (Iron (Ferrous Aminoate)) sucrose. Because animal reproductive studies are not always predictive of human response, Prorocal Plus (Iron (Ferrous Aminoate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

Safety and effectiveness of Prorocal Plus (Iron (Ferrous Aminoate)) for Prorocal Plus (Iron (Ferrous Aminoate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Prorocal Plus (Iron (Ferrous Aminoate)) 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)]

Prorocal Plus (Iron (Ferrous Aminoate)) has not been studied in patients younger than 2 years of age.

In a country where Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Prorocal Plus (Iron (Ferrous Aminoate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)), 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 Prorocal Plus (Iron (Ferrous Aminoate)) in humans. Excessive dosages of Prorocal Plus (Iron (Ferrous Aminoate)) may lead to accumulation of Prorocal Plus (Iron (Ferrous Aminoate)) in storage sites potentially leading to hemosiderosis. Do not administer Prorocal Plus (Iron (Ferrous Aminoate)) to patients with Prorocal Plus (Iron (Ferrous Aminoate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Prorocal Plus (Iron (Ferrous Aminoate)) 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

Prorocal Plus (Iron (Ferrous Aminoate)) (iron sucrose injection, USP), an Prorocal Plus (Iron (Ferrous Aminoate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Prorocal Plus (Iron (Ferrous Aminoate)) (III)-hydroxide in sucrose for intravenous use. Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) polymerization and m is the number of sucrose molecules associated with the Prorocal Plus (Iron (Ferrous Aminoate)) (III)-hydroxide.

Each mL contains 20 mg elemental Prorocal Plus (Iron (Ferrous Aminoate)) as Prorocal Plus (Iron (Ferrous Aminoate)) sucrose in water for injection. Prorocal Plus (Iron (Ferrous Aminoate)) is available in 10 mL single-use vials (200 mg elemental Prorocal Plus (Iron (Ferrous Aminoate)) per 10 mL), 5 mL single-use vials (100 mg elemental Prorocal Plus (Iron (Ferrous Aminoate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Prorocal Plus (Iron (Ferrous Aminoate)) 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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Prorocal Plus ), its Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Prorocal Plus (Iron (Ferrous Aminoate)) containing 100 mg of Prorocal Plus (Iron (Ferrous Aminoate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Prorocal Plus (Iron (Ferrous Aminoate)) deficiency showed that a significant amount of the administered Prorocal Plus (Iron (Ferrous Aminoate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Prorocal Plus (Iron (Ferrous Aminoate)) trapping compartment.

Following intravenous administration of Prorocal Plus (Iron (Ferrous Aminoate)), Prorocal Plus (Iron (Ferrous Aminoate)) sucrose is dissociated into Prorocal Plus (Iron (Ferrous Aminoate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Prorocal Plus (Iron (Ferrous Aminoate)) containing 1,510 mg of sucrose and 100 mg of Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) sucrose containing 500 to 700 mg of Prorocal Plus (Iron (Ferrous Aminoate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Prorocal Plus (Iron (Ferrous Aminoate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Prorocal Plus (Iron (Ferrous Aminoate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Prorocal Plus (Iron (Ferrous Aminoate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Prorocal Plus (Iron (Ferrous Aminoate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Prorocal Plus (Iron (Ferrous Aminoate)), the half-life of total serum Prorocal Plus (Iron (Ferrous Aminoate)) 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.

Prorocal Plus (Iron (Ferrous Aminoate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) sucrose.

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

Prorocal Plus (Iron (Ferrous Aminoate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Prorocal Plus (Iron (Ferrous Aminoate)) (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 Prorocal 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 Prorocal Plus (Iron (Ferrous Aminoate)) treatment and 24 in the historical control group) with Prorocal Plus (Iron (Ferrous Aminoate)) deficiency anemia. Eligibility criteria for Prorocal Plus (Iron (Ferrous Aminoate)) 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.

Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)), who were off intravenous Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

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 Prorocal Plus (Iron (Ferrous Aminoate)) in 23 patients with Prorocal Plus (Iron (Ferrous Aminoate)) deficiency and HDD-CKD who had been discontinued from Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)). Exclusion criteria were similar to those in studies A and B. Prorocal Plus (Iron (Ferrous Aminoate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) versus Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) (325 mg ferrous sulfate three times daily for 56 days); or Prorocal Plus (Iron (Ferrous Aminoate)) (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 Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) group.

A statistically significantly greater proportion of Prorocal Plus (Iron (Ferrous Aminoate)) subjects (35/79; 44.3%) compared to oral Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) to patients with PDD-CKD receiving an erythropoietin alone without Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) or Prorocal Plus (Iron (Ferrous Aminoate)) (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 Prorocal Plus (Iron (Ferrous Aminoate)) / 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 Prorocal Plus (Iron (Ferrous Aminoate)) / 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 Prorocal Plus (Iron (Ferrous Aminoate)) / 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: Prorocal 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 Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) (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 Prorocal Plus (Iron (Ferrous Aminoate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) 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

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

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: Prorocal Plus (Iron (Ferrous Aminoate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Prorocal Plus (Iron (Ferrous Aminoate)) per mL, or undiluted (20 mg elemental Prorocal Plus (Iron (Ferrous Aminoate)) 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: Prorocal Plus (Iron (Ferrous Aminoate)), 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 Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) 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 Prorocal Plus (Iron (Ferrous Aminoate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Prorocal Plus (Iron (Ferrous Aminoate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

L-Lysine Monohydrochloride:

• Prorocal Plus (L-Lysine Monohydrochloride) reviews

Indication: Supplemental Prorocal Plus (L-Lysine Monohydrochloride) has putative anti-herpes simplex virus activity. There is preliminary research suggesting that it may have some anti-osteoporotic activity.

Insures the adequate absorption of calcium; helps form collagen ( which makes up bone cartilage & connective tissues); aids in the production of antibodies, hormones & enzymes. Recent studies have shown that Lysine may be effective against herpes by improving the balance of nutrients that reduce viral growth. A deficiency may result in tiredness, inability to concentrate, irritability, bloodshot eyes, retarded growth, hair loss, anemia & reproductive problems.

Vitamin B12 (Cyanocobalamin):

• Pharmacological action
• Pharmacokinetics
• Why is Prorocal Plus ) prescribed?
• Dosage and administration
• Prorocal Plus (Vitamin B12 (Cyanocobalamin)) side effects, adverse reactions
• Prorocal Plus ) contraindications
• Prorocal Plus ) using during pregnancy and breastfeeding
• Special instructions
• Prorocal Plus (Vitamin B12 (Cyanocobalamin)) drug interactions
• Prorocal Plus (Vitamin B12 (Cyanocobalamin)) reviews

Pharmacological action

Prorocal Plus ) refers to a group of water-soluble vitamins. It has high biological activity. Prorocal Plus (Vitamin B12 (Cyanocobalamin)) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.

Pharmacokinetics

After oral administration Prorocal Plus (Vitamin B12 (Cyanocobalamin)) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.

Why is Prorocal Plus ) prescribed?

Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of Prorocal Plus (Vitamin B12 (Cyanocobalamin)) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Prorocal Plus ) is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Prorocal Plus (Vitamin B12 (Cyanocobalamin)) deficiency is introduced on 100-200 mcg in 2 days. In anemia with symptoms of funicular myelosis and megalocytic anemia with diseases of the nervous system - 400-500 micrograms in the first 7 days daily, then 1 time every 5-7 days. In the period of remission in the absence of events funicular myelosis maintenance dose - 100 mcg 2 times a month, in the presence of neurological symptoms - at 200-400 mcg 2-4 times a month. In acute post-hemorrhagic anemia and iron anemia by 30-100 mcg 2-3 times a week. When aplastic anemia (especially in children) - 100 micrograms before clinical improvement. When nutritional anemia in infants and preterm - 30 mcg / day during 15 days.

In diseases of the central and peripheral nervous system and neurological diseases with a pain syndrome is administered in increasing doses - 200-500 mcg, with the improvement in the state - 100 mcg / day. The course of treatment with Prorocal Plus (Vitamin B12 (Cyanocobalamin)) is 2 weeks. In traumatic lesions of peripheral nervous system - at 200-400 mcg every other day for 40-45 days.

When hepatitis and cirrhosis - 30-60 mcg / day or 100 mg every other day for 25-40 days.

Dystrophy in young children, Down syndrome and cerebral palsy - by 15-30 mcg every other day.

When funicular myelosis, amyotrophic lateral sclerosis can be introduced into the spinal canal at 15-30 mcg, gradually increasing the dose of 200-250 micrograms.

In radiation sickness, diabetic neuropathy, sprue - by 60-100 mcg daily for 20-30 days.

When deficiency of Prorocal Plus (Vitamin B12 (Cyanocobalamin)) to prevent - IV or IM for 1 mg 1 time a month; for treatment - IV or IM for 1 mg daily for 1-2 weeks, the maintenance dose is 1-2 mg IV or IM from 1 per week, up to 1 per month. Duration of treatment is determined individually.

Prorocal Plus (Vitamin B12 (Cyanocobalamin)) side effects, adverse reactions

CNS: rarely - a state of arousal.

Cardiovascular system: rarely - pain in the heart, tachycardia.

Allergic reactions: rarely - urticaria.

Prorocal Plus ) contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Prorocal Plus ) using during pregnancy and breastfeeding

Cyanocobalamin can be used in pregnancy according to prescriptions.

Special instructions

When stenocardia should be used with caution in a single dose of Prorocal Plus ) 100 mcg. During treatment should regularly monitor the blood picture and coagulation. It is unacceptable to enter in the same syringe with cyanocobalamin solutions of thiamine and pyridoxine.

Prorocal Plus (Vitamin B12 (Cyanocobalamin)) drug interactions

In an application of Prorocal Plus (Vitamin B12 (Cyanocobalamin)) with hormonal contraceptives for oral administration may decrease the concentration of cyanocobalamin in plasma.

In an application with anticonvulsant drugs decreased cyanocobalamin absorption from the gut.

In an Prorocal Plus (Vitamin B12 (Cyanocobalamin)) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.

Cyanocobalamin may exacerbate allergic reactions caused by thiamine.

When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.

Pharmaceutical incompatibility

Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.

Zinc Sulfate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Prorocal Plus (Zinc Sulfate) reviews

INDICATIONS AND USAGE

Prorocal Plus (Zinc Sulfate) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain Prorocal Plus (Zinc Sulfate) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Prorocal Plus (Zinc Sulfate) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and Prorocal Plus (Zinc Sulfate) doses because these elements are primarily eliminated in the urine.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

Do not use unless the solution is clear and the seal is intact.

Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Prorocal Plus (Zinc Sulfate) from a bolus injection. Administration of Prorocal Plus (Zinc Sulfate) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Prorocal Plus (Zinc Sulfate) are suggested as a guideline for subsequent Prorocal Plus (Zinc Sulfate) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Prorocal Plus 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Prorocal Plus (Zinc Sulfate) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

Pregnancy Category C. Animal reproduction studies have not been conducted with Prorocal Plus chloride. It is also not known whether Prorocal Plus (Zinc Sulfate) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Prorocal Plus (Zinc Sulfate) chloride should be given to a pregnant woman only if clearly needed.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response 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.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Prorocal Plus (Zinc Sulfate) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum Prorocal Plus (Zinc Sulfate) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Prorocal Plus (Zinc Sulfate) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).

Death resulted from an overdosage in which 1683 mg Prorocal Plus (Zinc Sulfate) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Prorocal Plus (Zinc Sulfate) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Prorocal Plus (Zinc Sulfate) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Prorocal Plus (Zinc Sulfate) toxicity.

DOSAGE AND ADMINISTRATION

Prorocal Plus (Zinc Sulfate) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of Prorocal Plus (Zinc Sulfate) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Prorocal Plus (Zinc Sulfate).

For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS.

HOW SUPPLIED

Prorocal Plus (Zinc Sulfate) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004

© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Prorocal Plus (Zinc Sulfate)

1 mg/mL

Prorocal Plus (Zinc Sulfate) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA