Protein-Total

Calcium:

• 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
• Protein-Total (Calcium) reviews

1 INDICATIONS AND USAGE

Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) acetate capsule.

- Capsule: 667 mg Protein-Total (Calcium) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Protein-Total (Calcium) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Protein-Total (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) 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, Protein-Total (Calcium) acetate has been generally well tolerated.

Protein-Total (Calcium) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Protein-Total (Calcium) 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 Protein-Total (Calcium) concentration could reduce the incidence and severity of Protein-Total (Calcium) 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 Protein-Total (Calcium) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

There are no empirical data on avoiding drug interactions between Protein-Total (Calcium) acetate and most concomitant drugs. When administering an oral medication with Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Protein-Total (Calcium) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

11 DESCRIPTION

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

Protein-Total (Calcium) 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 Protein-Total resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Orally administered Protein-Total (Calcium) 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 Protein-Total (Calcium) acetate.

14 CLINICAL STUDIES

Effectiveness of Protein-Total (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) 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 Protein-Total (Calcium) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Protein-Total (Calcium) 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 Protein-Total (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Protein-Total (Calcium) 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 Protein-Total (Calcium) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Iodine:

• Iodine tincture 7%
• Iodine tincture 7%
• Protein-Total (Iodine) reviews

Protein-Total Tincture 7%

Directions:

Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Protein-Total (Iodine) with a swab.

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

Apply Protein-Total (Iodine) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.

Do not apply under bandage.

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

Storage:

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

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

DANGER - Poison

Caution:

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

activated charcoal. A 5% solutions of sodium thiosulfate

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

rate of 10 ml per kilogram of body weight.

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

Avoid contamination of food.

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

Protein-Total Tincture 7%

image description

Iron (Ferrous Fumarate):

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

1 INDICATIONS AND USAGE

Protein-Total (Iron (Ferrous Fumarate)) is indicated for the treatment of Protein-Total (Iron (Ferrous Fumarate)) deficiency anemia in patients with chronic kidney disease (CKD).

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

2 DOSAGE AND ADMINISTRATION

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

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

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

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

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

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

2.4 Pediatric Patients with HDD-CKD for Protein-Total (Iron (Ferrous Fumarate)) maintenance treatment

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

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

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

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

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

3 DOSAGE FORMS AND STRENGTHS

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

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

4 CONTRAINDICATIONS

• Known hypersensitivity to Protein-Total (Iron (Ferrous Fumarate))

• Known hypersensitivity to Protein-Total (Iron (Ferrous Fumarate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.1 Hypersensitivity Reactions

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

5.2 Hypotension

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

5.3 Protein-Total (Iron (Ferrous Fumarate)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Protein-Total ) are described in other sections .

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

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

6.1 Adverse Reactions in Clinical Trials

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

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Protein-Total ) 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 Protein-Total (Iron (Ferrous Fumarate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

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

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

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

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

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

6.2 Adverse Reactions from Post-Marketing Experience

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

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

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

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

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

7 DRUG INTERACTIONS

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

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

Protein-Total (Iron (Ferrous Fumarate)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

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

10 OVERDOSAGE

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

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

11 DESCRIPTION

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

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

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

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Protein-Total (Iron (Ferrous Fumarate)) sucrose.

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

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

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Protein-Total ).

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 Protein-Total (Iron (Ferrous Fumarate)) treatment and 24 in the historical control group) with Protein-Total (Iron (Ferrous Fumarate)) deficiency anemia. Eligibility criteria for Protein-Total (Iron (Ferrous Fumarate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

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

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

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

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

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

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

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

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

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

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

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

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

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Protein-Total ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Protein-Total (Iron (Ferrous Fumarate)), each 5 mL vial contains 100 mg elemental Protein-Total (Iron (Ferrous Fumarate)), and each 2.5 mL vial contains 50 mg elemental Protein-Total (Iron (Ferrous Fumarate)) (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: Protein-Total (Iron (Ferrous Fumarate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Protein-Total (Iron (Ferrous Fumarate)) per mL, or undiluted (20 mg elemental Protein-Total (Iron (Ferrous Fumarate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

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

Do not dilute to concentrations below 1 mg/mL.

Do not mix Protein-Total (Iron (Ferrous Fumarate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

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

17 PATIENT COUNSELING INFORMATION

Prior to Protein-Total (Iron (Ferrous Fumarate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Protein-Total (Iron (Ferrous Fumarate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Selenium:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Protein-Total (Selenium) reviews

Rx Only

TRACE ELEMENT ADDITIVE FOR IV USE AFTER DILUTION

DESCRIPTION

Protein-Total (Selenium) Injection is a sterile, nonpyrogenic solution for use as an additive to solutions for Total Parenteral Nutrition (TPN).

Each mL contains Selenious Acid 65.4 mcg (equivalent to elemental Protein-Total (Selenium) 40 mcg/mL) and Water for Injection q.s. pH may be adjusted with nitric acid to 1.8 to 2.4.

CLINICAL PHARMACOLOGY

Protein-Total (Selenium) is part of glutathione peroxidase which protects cell components from oxidative damage due to peroxides produced in cellular metabolism.

Prolonged TPN support in humans has resulted in Protein-Total (Selenium) deficiency symptoms which include muscle pain and tenderness. The symptoms have been reported to respond to supplementation of TPN solutions with Protein-Total (Selenium).

Pediatric conditions, Keshan disease, and Kwashiorkor, have been associated with low dietary intake of Protein-Total (Selenium). The conditions are endemic to geographical areas with low Protein-Total (Selenium) soil content. Dietary supplementation with Protein-Total (Selenium) salts has been reported to reduce the incidence of the conditions among affected children.

Normal blood levels of Protein-Total (Selenium) in different human populations have been found to vary and depend on the Protein-Total (Selenium) content of the food consumed. Results of surveys carried out in some countries are tabulated below:

Plasma Protein-Total (Selenium) levels of 0.3 and 0.9 mcg/100 mL have been reported to produce deficiency symptoms in humans.

Protein-Total (Selenium) is eliminated primarily in urine. However, significant endogenous losses through feces also occur. The rate of excretion and the relative importance of two routes varies with the chemical form of Protein-Total (Selenium) used in supplementation. Ancillary routes of elimination are lungs and skin.

INDICATIONS AND USAGE

Protein-Total (Selenium) Injection is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN). Administration of Protein-Total (Selenium) in TPN solutions helps to maintain plasma Protein-Total (Selenium) levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

Protein-Total (Selenium) Injection should not be given undiluted by direct injection into a peripheral vein because of the potential for infusion phlebitis.

WARNINGS

Protein-Total (Selenium) Injection can be toxic if given in excessive amounts. Supplementation of TPN solution with Protein-Total (Selenium) should be immediately discontinued if toxicity symptoms are observed. Frequent determination of plasma Protein-Total (Selenium) levels during TPN support and close medical supervision is recommended.

Protein-Total (Selenium) Injection is a hypotonic solution and should be administered in admixtures only.

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

As Protein-Total is eliminated in urine and feces, Protein-Total (Selenium) supplements may be adjusted, reduced or omitted in renal dysfunction and/or gastrointestinal malfunction. In patients receiving blood transfusions, contribution from such transfusions should also be considered. Frequent Protein-Total (Selenium) plasma level determinations are suggested as a guideline.

In animals, Protein-Total (Selenium) has been reported to enhance the action of Vitamin E and decrease the toxicity of mercury, cadmium and arsenic.

Pregnancy

Teratogenic Effects

Pregnancy Category C: Protein-Total (Selenium) at high dose levels (15-30 mcg/egg) has been reported to have adverse embryological effects among chickens. There are however, no adequate and wellcontrolled studies in pregnant women. Protein-Total (Selenium) Injection should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

Presence of Protein-Total (Selenium) in placenta and umbilical cord blood has been reported in humans.

ADVERSE REACTIONS

The amount of Protein-Total (Selenium) present in Protein-Total (Selenium) Injection is small. Symptoms of toxicity from Protein-Total (Selenium) are unlikely to occur at the recommended dosage level.

OVERDOSAGE

Chronic toxicity in humans resulting from exposure to Protein-Total (Selenium) in industrial environments, intake of foods grown in seleniferous soils, use of selenium-contaminated water, and application of cosmetics containing Protein-Total (Selenium) has been reported in literature. Toxicity symptoms include hair loss, weakened nails, dermatitis, dental defects, gastrointestinal disorders, nervousness, mental depression, metallic taste, vomiting, and garlic odor of breath and sweat. Acute poisoning due to ingestion of large amounts of Protein-Total (Selenium) compounds has resulted in death with histopathological changes including fulminating peripheral vascular collapse, internal vascular congestion, diffusely hemorrhagic, congested and edematus lungs, brick-red color gastric mucosa. The death was preceded by coma.

No effective antidote to Protein-Total (Selenium) poisoning in humans is known. Animal studies have shown casein and linseed oil in feeds, reduced glutathione, arsenic, magnesium sulfate, and bromobenzene to afford limited protection.

DOSAGE AND ADMINISTRATION

Protein-Total (Selenium) Injection provides 40 mcg selenium/mL. For metabolically stable adults receiving TPN, the suggested additive dosage level is 20 to 40 mcg selenium/day. For pediatric patients, the suggested additive dosage level is 3 mcg/kg/day.

In adults, Protein-Total (Selenium) deficiency states resulting from long-term TPN support, Protein-Total (Selenium) as selenomethionine or selenious acid, administered intravenously at 100 mcg/day for a period of 24 and 31 days, respectively, has been reported to reverse deficiency symptoms without toxicity.

Aseptic addition of Protein-Total (Selenium) Injection to the TPN solution under laminar flow hood is recommended. Protein-Total (Selenium) is physically compatible with the electrolytes and other trace elements usually present in amino-acid/dextrose solution used for TPN. Frequent monitoring of plasma Protein-Total (Selenium) levels is suggested as a guideline for subsequent administration. The normal whole blood range for Protein-Total (Selenium) is approximately 10 to 37 mcg/100 mL.

Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit.

HOW SUPPLIED

Protein-Total (Selenium) Injection containing selenious acid 65.4 mcg/mL (equivalent to elemental Protein-Total (Selenium) 40 mcg/mL).

NDC 0517-6510-25 10 mL Single Dose Vial Packaged in boxes of 25

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

IN6510

Rev. 11/15

PRINCIPAL DISPLAY PANEL - Container

NDC 0517-6510-25

Protein-Total (Selenium) INJECTION

Protein-Total (Selenium) 400 mcg/10 mL

(40 mcg/mL)

10 mL

SINGLE DOSE VIAL

Trace Element Additive

FOR IV USE AFTER DILUTION

PRESERVATIVE FREE

Rx Only

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

PRINCIPAL DISPLAY PANEL - Carton

Protein-Total (Selenium) INJECTION

Protein-Total (Selenium) 400 mcg/10 mL

(40 mcg/mL)

Trace Element Additive

NDC 0517-6510-25

25 x 10 mL

SINGLE DOSE VIALS

FOR INTRAVENOUS USE AFTER DILUTION PRESERVATIVE FREE Rx Only

Each mL contains: Selenious Acid 65.4 mcg, Water for Injection q.s.

pH adjusted with Nitric Acid. Sterile, nonpyrogenic.

WARNING: DISCARD UNUSED PORTION. Store at 20°-25°C (68°-77°F); excursions

permitted to 15°-30°C (59°-86°F).

Directions for Use: See Package Insert.

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

Rev. 11/05

Container Carton

Vitamin A (Retinol):

• Dosage and administration
• Warning
• Clinical pharmacology
• Dietary supplementation
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Protein-Total (Vitamin A (Retinol)) reviews

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

In case of accidental overdose, seek professional assistance or contact a Poison Control Center immediately.

Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, Protein-Total (Vitamin A (Retinol)) acetate, vitamin B12 and vitamin E acetate.

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

Significant decrease in the incidence of dental caries can be linked to the fluoridation of the water supply (1ppm fluoride) during the period of tooth development.

Protein-Total (Vitamin A (Retinol)) Tablets provide sodium fluoride and ten essential vitamins in a chewable tablet. Because the tablets are chewable, they provide a topical as well as systemic source of fluoride. Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the Hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite.

The reaction may be expressed by the equation:

Three stages of fluoride deposition in tooth enamel can be distinguished:

• Small amounts (reflecting the low levels of fluoride in tissue fluids) are incorporated into the enamel crystals while they are being formed.
• After enamel has been laid down, fluoride deposition continues in the surface enamel. Diffusion of fluoride from the surface inward is apparently restricted.
• After eruption, the surface enamel acquires fluoride from the water, food, supplementary fluoride and smaller amounts of saliva.

DIETARY SUPPLEMENTATION

Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.

WARNINGS

AS IN THE CASE OF ALL MEDICATIONS, KEEP OUT OF THE REACH OF CHILDREN. This tablet should be chewed. This product, as with all chewable tablets are not recommended for children under the age of 4 due to risk of choking.

PRECAUTIONS

The suggested dose of Protein-Total (Vitamin A (Retinol)) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Protein-Total (Vitamin A (Retinol)) Tablets

• Determine the fluoride content of the drinking water from all major sources
• Make sure the child is not receiving significant amounts of fluoride from other sources such as medications and swallowed toothpaste
• Periodically check to make sure that the child does not develop significant dental fluorosis.

ADVERSE REACTIONS

Allergic rash and other idiosyncrasies have been rarely reported.

To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1 (866) 592-6438 or FDA at 1 (800) 332-1088 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

Protein-Total ) Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Protein-Total (Vitamin A (Retinol)) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Protein-Total (Vitamin A (Retinol)) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

Store at controlled room temperature 20ºC-25ºC (68º-77ºF), excursions permitted between 15º-30ºC (59º-86ºF).

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H²pharma

Vitamin B12 (Cyanocobalamin):

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

Pharmacological action

Protein-Total ) refers to a group of water-soluble vitamins. It has high biological activity. Protein-Total (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 Protein-Total (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 Protein-Total ) 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 Protein-Total (Vitamin B12 (Cyanocobalamin)) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Protein-Total ) is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Protein-Total (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 Protein-Total (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 Protein-Total (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.

Protein-Total (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.

Protein-Total ) contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Protein-Total ) 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 Protein-Total ) 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.

Protein-Total (Vitamin B12 (Cyanocobalamin)) drug interactions

In an application of Protein-Total (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 Protein-Total (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.

Vitamin C (Ascorbic Acid):

• Pharmacological action
• Pharmacokinetics
• Why is Protein-Total ) prescribed?
• Dosage and administration
• Protein-Total (Vitamin C (Ascorbic Acid)) side effects, adverse reactions
• Protein-Total ) contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Protein-Total ) drug interactions
• Protein-Total ) in case of emergency / overdose
• Protein-Total (Vitamin C (Ascorbic Acid)) reviews

Pharmacological action

Protein-Total ) (vitamin c) is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Protein-Total (Vitamin C (Ascorbic Acid)) participates in redox reactions, the metabolism of tyrosine, converting folic acid into folinic acid, metabolism of carbohydrates, the synthesis of lipids and proteins, iron metabolism, processes of cellular respiration. Reduces the need for vitamins B1, B2, A, E, folic acid, pantothenic acid, enhances the body's resistance to infections; enhances iron absorption, contributing to its sequestration in reduced form. Protein-Total (Vitamin C (Ascorbic Acid)) has antioxidant properties.

With intravaginal application of Protein-Total (Vitamin C (Ascorbic Acid)) lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).

Pharmacokinetics

After oral administration Protein-Total (Vitamin C (Ascorbic Acid)) is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

The concentration of Protein-Total (Vitamin C (Ascorbic Acid)) in blood plasma in normal amounts to approximately 10-20 mg / ml.

The concentration of Protein-Total (Vitamin C (Ascorbic Acid)) in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.

Plasma protein binding is about 25%.

Protein-Total (Vitamin C (Ascorbic Acid)) is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.

Protein-Total (Vitamin C (Ascorbic Acid)) taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.

Why is Protein-Total ) prescribed?

For systemic use of Protein-Total (Vitamin C (Ascorbic Acid)) RiteMED Phils: prevention and treatment of hypo- and avitaminosis of vitamin C; providing increased need for vitamin C during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.

For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.

Dosage and administration

This medication administered orally, IM, IV, intravaginally.

For the prevention of deficiency conditions Protein-Total ) dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used Protein-Total (Vitamin C (Ascorbic Acid)) drugs in appropriate dosage forms.

Protein-Total (Vitamin C (Ascorbic Acid)) side effects, adverse reactions

CNS: headache, fatigue, insomnia.

Digestive system: stomach cramps, nausea and vomiting.

Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.

Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.

Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.

Protein-Total ) contraindications

Increased sensitivity to Protein-Total (Vitamin C (Ascorbic Acid)).

Using during pregnancy and breastfeeding

The minimum daily requirement of Protein-Total ) in the II and III trimester of pregnancy is about 60 mg.

Protein-Total (Vitamin C (Ascorbic Acid)) crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of Protein-Total (Vitamin C (Ascorbic Acid)), which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take Protein-Total (Vitamin C (Ascorbic Acid)) in high doses, except in cases where the expected benefit outweighs the potential risk.

The minimum daily requirement during lactation (breastfeeding) is 80 mg. Protein-Total (Vitamin C (Ascorbic Acid)) is excreted in breast milk. A mother's diet that contains adequate amounts of Protein-Total (Vitamin C (Ascorbic Acid)), is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of Protein-Total (Vitamin C (Ascorbic Acid)) in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to Protein-Total (Vitamin C (Ascorbic Acid)), except when the expected benefit outweighs the potential risk.

Special instructions

Protein-Total (Vitamin C (Ascorbic Acid)) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because Protein-Total (Vitamin C (Ascorbic Acid)) increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.

Patients with high content body iron should apply Protein-Total (Vitamin C (Ascorbic Acid)) in minimal doses.

Protein-Total (Vitamin C (Ascorbic Acid)) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

The use of Protein-Total (Vitamin C (Ascorbic Acid)) in high doses can cause exacerbation of sickle cell anemia.

Data on the diabetogenic action of Protein-Total (Vitamin C (Ascorbic Acid)) are contradictory. However, prolonged use of Protein-Total (Vitamin C (Ascorbic Acid)) should periodically monitor your blood glucose levels.

It is believed that the use of Protein-Total (Vitamin C (Ascorbic Acid)) in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in Protein-Total (Vitamin C (Ascorbic Acid)) in patients with advanced cancer.

Absorption of Protein-Total (Vitamin C (Ascorbic Acid)) decreased while use of fresh fruit or vegetable juices, alkaline drinking.

Protein-Total ) drug interactions

In an application with barbiturates, primidone increases the excretion of Protein-Total (Vitamin C (Ascorbic Acid)) in the urine.

With the simultaneous use of oral contraceptives reduces the concentration of Protein-Total (Vitamin C (Ascorbic Acid)) in blood plasma.

In an application of Protein-Total (Vitamin C (Ascorbic Acid)) with iron preparations Protein-Total (Vitamin C (Ascorbic Acid)), due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

Protein-Total (Vitamin C (Ascorbic Acid)) in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.

With the simultaneous use of aspirin reduces the absorption of Protein-Total (Vitamin C (Ascorbic Acid)) by about a third.

Protein-Total (Vitamin C (Ascorbic Acid)) in an application with warfarin may decrease effects of warfarin.

With the simultaneous application of Protein-Total (Vitamin C (Ascorbic Acid)) increases the excretion of iron in patients receiving deferoxamine. In the application of Protein-Total (Vitamin C (Ascorbic Acid)) at a dose of 500 mg / day possibly left ventricular dysfunction.

In an application with tetracycline is increased excretion of Protein-Total (Vitamin C (Ascorbic Acid)) in the urine.

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with Protein-Total (Vitamin C (Ascorbic Acid)) 500 mg 2 times / day.

May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.

Protein-Total ) in case of emergency / overdose

Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).

Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).

When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.

Zinc:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Protein-Total (Zinc) reviews

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Protein-Total (Zinc) 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 Protein-Total (Zinc) 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 Protein-Total (Zinc) from a bolus injection. Administration of Protein-Total (Zinc) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Protein-Total (Zinc) are suggested as a guideline for subsequent Protein-Total (Zinc) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Protein-Total 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 Protein-Total (Zinc) 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 Protein-Total chloride. It is also not known whether Protein-Total (Zinc) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Protein-Total (Zinc) 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 Protein-Total (Zinc) 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 Protein-Total (Zinc) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Protein-Total (Zinc) 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 Protein-Total (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.

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

Calcium supplements may confer a protective effect against Protein-Total (Zinc) toxicity.

DOSAGE AND ADMINISTRATION

Protein-Total (Zinc) 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 Protein-Total (Zinc) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Protein-Total (Zinc).

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

Protein-Total (Zinc) 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

Protein-Total (Zinc)

1 mg/mL

Protein-Total (Zinc) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA