Restor BIG EF

Calcium Chloride:

• 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
• Restor BIG EF (Calcium Chloride) reviews

1 INDICATIONS AND USAGE

Restor BIG EF (Calcium Chloride) 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 Restor BIG EF (Calcium Chloride) 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 Restor BIG EF (Calcium Chloride) acetate capsule.

- Capsule: 667 mg Restor BIG EF (Calcium Chloride) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

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

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

7 DRUG INTERACTIONS

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

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Restor BIG EF (Calcium Chloride) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

11 DESCRIPTION

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

Restor BIG EF (Calcium Chloride) 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 Restor BIG EF resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Orally administered Restor BIG EF (Calcium Chloride) 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 Restor BIG EF (Calcium Chloride) acetate.

14 CLINICAL STUDIES

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Restor BIG EF (Calcium Chloride) 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 Restor BIG EF (Calcium Chloride) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Restor BIG EF (Calcium Chloride) 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 Restor BIG EF (Calcium Chloride) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Iron (Iron Polymaltose):

• 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
• Restor BIG EF (Iron (Iron Polymaltose)) reviews

1 INDICATIONS AND USAGE

Restor BIG EF (Iron (Iron Polymaltose)) is indicated for the treatment of Restor BIG EF (Iron (Iron Polymaltose)) deficiency anemia in patients with chronic kidney disease (CKD).

Restor BIG EF (Iron (Iron Polymaltose)) is an Restor BIG EF (Iron (Iron Polymaltose)) replacement product indicated for the treatment of Restor BIG EF (Iron (Iron Polymaltose)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

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

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

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

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

Administer Restor BIG EF (Iron (Iron Polymaltose)) 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 Restor BIG EF (Iron (Iron Polymaltose)), 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. Restor BIG EF (Iron (Iron Polymaltose)) treatment may be repeated if Restor BIG EF (Iron (Iron Polymaltose)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Restor BIG EF (Iron (Iron Polymaltose)) 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 Restor BIG EF (Iron (Iron Polymaltose)) in a maximum of 250 mL of 0.9% NaCl. Restor BIG EF (Iron (Iron Polymaltose)) treatment may be repeated if Restor BIG EF (Iron (Iron Polymaltose)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Restor BIG EF (Iron (Iron Polymaltose)) maintenance treatment

The dosing for Restor BIG EF (Iron (Iron Polymaltose)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Restor BIG EF (Iron (Iron Polymaltose)) maintenance treatment: Administer Restor BIG EF (Iron (Iron Polymaltose)) 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. Restor BIG EF (Iron (Iron Polymaltose)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Restor BIG EF (Iron (Iron Polymaltose)) maintenance treatment

The dosing for Restor BIG EF (Iron (Iron Polymaltose)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Restor BIG EF (Iron (Iron Polymaltose)) maintenance treatment: Administer Restor BIG EF (Iron (Iron Polymaltose)) 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. Restor BIG EF (Iron (Iron Polymaltose)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Restor BIG EF (Iron (Iron Polymaltose)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Restor BIG EF (Iron (Iron Polymaltose)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Restor BIG EF (Iron (Iron Polymaltose)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Restor BIG EF (Iron (Iron Polymaltose)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Restor BIG EF (Iron (Iron Polymaltose)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Restor BIG EF (Iron (Iron Polymaltose)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Restor BIG EF (Iron (Iron Polymaltose))

• Known hypersensitivity to Restor BIG EF (Iron (Iron Polymaltose)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Restor BIG EF (Iron (Iron Polymaltose)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Restor BIG EF ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Restor BIG EF (Iron (Iron Polymaltose)) 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 Restor BIG EF ) 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 Restor BIG EF (Iron (Iron Polymaltose)) 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 Restor BIG EF (Iron (Iron Polymaltose)) therapy and were reported to be intolerant (defined as precluding further use of that Restor BIG EF (Iron (Iron Polymaltose)) product). When these patients were treated with Restor BIG EF (Iron (Iron Polymaltose)) there were no occurrences of adverse reactions that precluded further use of Restor BIG EF (Iron (Iron Polymaltose)) .

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

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

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

Restor BIG EF (Iron (Iron Polymaltose)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

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

Toxicities in single-dose studies in mice and rats, at intravenous Restor BIG EF (Iron (Iron Polymaltose)) 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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

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

Restor BIG EF (Iron (Iron Polymaltose)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Restor BIG EF (Iron (Iron Polymaltose)) (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 Restor BIG EF ).

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 Restor BIG EF (Iron (Iron Polymaltose)) treatment and 24 in the historical control group) with Restor BIG EF (Iron (Iron Polymaltose)) deficiency anemia. Eligibility criteria for Restor BIG EF (Iron (Iron Polymaltose)) 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.

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

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

Restor BIG EF ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Restor BIG EF (Iron (Iron Polymaltose)), each 5 mL vial contains 100 mg elemental Restor BIG EF (Iron (Iron Polymaltose)), and each 2.5 mL vial contains 50 mg elemental Restor BIG EF (Iron (Iron Polymaltose)) (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: Restor BIG EF (Iron (Iron Polymaltose)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Restor BIG EF (Iron (Iron Polymaltose)) per mL, or undiluted (20 mg elemental Restor BIG EF (Iron (Iron Polymaltose)) 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: Restor BIG EF (Iron (Iron Polymaltose)), 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 Restor BIG EF (Iron (Iron Polymaltose)) 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 Restor BIG EF (Iron (Iron Polymaltose)) 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 Restor BIG EF (Iron (Iron Polymaltose)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Restor BIG EF (Iron (Iron Polymaltose)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Lysine:

• Boxed warning
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Restor BIG EF (Lysine) reviews

BOXED WARNING

Pharmacy Bulk Package

Not For Direct Infusion

DESCRIPTION

Restor BIG EF (Lysine)^® 15% Amino Acids Injection in a Pharmacy Bulk Package is a sterile, clear, nonpyrogenic solution of essential and nonessential amino acids for intravenous infusion in parenteral nutrition following appropriate dilution.

Restor BIG EF (Lysine)^® 15% in a Pharmacy Bulk Package is not for direct infusion. It is a sterile dosage from which contains several single doses for use in a pharmacy admixture program in the preparation of intravenous parenteral fluids.

Each 100 mL contains:

The formulas for the individual amino acids are as follows:

Formulas for individual amino acids

CLINICAL PHARMACOLOGY

Restor BIG EF (Lysine)^® 15% Amino Acids Injection providesseventeen crystalline amino acids. This completely utilizable substrate promotesprotein synthesis and wound healing and reduces the rate of protein catabolism.

A.Total Parenteral Nutrition (Central Infusion)

When enteralfeeding is inadvisable, Restor BIG EF (Lysine)^® 15% given by central venousinfusion in combination with energy sources, vitamins, trace elements andelectrolytes, will completely satisfy the requirements for weight maintenanceor weight gain, depending upon the dose selected. The energy component inparenteral nutrition by central infusion may be derived solely from dextroseor may be provided by a combination of dextrose and intravenous fat emulsion. The addition of intravenous fat emulsion provides essential fatty acids andpermits a dietary balance of fat and carbohydrate, at the same time offeringthe option of reducing the dextrose load and/or increasing the total caloricinput. An adequate energy supply is essential for optimal utilization of aminoacids.

B. Total Parenteral Nutrition (Peripheral Infusion)

Restor BIG EF (Lysine)^® 15%can also be administered as part of a total parenteral nutrition program byperipheral vein when the enteral route is inadvisable and use of the centralvenous catheter is contraindicated.

Reduction of proteinloss can be achieved by use of diluted Restor BIG EF (Lysine)^® 15% in combinationwith dextrose or with dextrose and intravenous fat emulsion by peripheralinfusion. Complete peripheral intravenous nutrition can be achieved in patientswith low caloric requirements by a Restor BIG EF (Lysine)^®15%-dextrose-fatregimen.

INDICATIONS AND USAGE

Restor BIG EF (Lysine)^® 15% is indicated as an amino acid(nitrogen) source in parenteral nutrition regimens. This use is appropriatewhen the enteral route is inadvisable, inadequate or not possible, as when:

-Gastrointestinal absorption is impaired by obstruction, inflammatory diseaseor its complications, or antineoplastic therapy;

-Bowel rest is needed because of gastrointestinal surgery or its complicationssuch as ileus, fistulae or anastomotic leaks;

-Tube feeding methods alone cannot provide adequate nutrition.

CONTRAINDICATIONS

This solution should not be used in patients in hepatic coma,severe renal failure, metabolic disorders involving impaired nitrogen utilizationor hypersensitivity to one or more amino acids.

WARNINGS

Administration of amino acids solutions at excessive ratesor to patients with hepatic insufficiency may result in plasma amino acidimbalances, hyperammonemia, prerenal azotemia, stupor and coma. Conservativedoses of amino acids should be given to these patients, dictated by the nutritionalstatus of the patient. Should symptoms of hyperammonemia develop, amino acidadministration should be discontinued and the patient’s clinical statusre-evaluated.

Contains sodium metabisulfite, a sulfitethat may cause allergic-type reactions including anaphylactic symptoms andlife-threatening or less severe asthmatic episodes in certain susceptiblepeople. The overall prevalence of sulfite sensitivity in the general populationis unknown and probably low.

Sulfite sensitivity isseen more frequently in asthmatic than in nonasthmatic people.

WARNING: This product contains aluminum that maybe toxic. Aluminum may reach toxic levels with prolonged parenteral administrationif kidney function is impaired. Premature neonates are particularly at riskbecause their kidneys are immature, and they require large amounts of calciumand phosphate solutions, which contain aluminum.

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

PRECAUTIONS

A. GENERAL

It is essential to provide adequate calories concurrently if parenterally administered amino acids are to be retained by the body and utilized for protein synthesis.

The administration of Restor BIG EF (Lysine)^® 15% Amino Acids Injection as part of total parenteral nutrition (TPN) with large volumes of hyperosmotic fluids requires periodic monitoring of the patient for signs of hyperosmolarity, hyperglycemia, glycosuria and hypertriglyceridemia.

During parenteral nutrition with concentrated dextrose and amino acids solutions, essential fatty acid deficiency syndrome may develop but may not be clinically apparent. Early demonstration of this condition can only be accomplished by gas liquid chromatographic analysis of plasma lipids. The syndrome may be prevented or corrected by appropriate treatment with intravenous fat emulsions.

For complete nutritional support, TPN regimens must also include multiple vitamins and trace elements. Potentially incompatible ions such as calcium and phosphate may be added to alternate infusate bottles to avoid precipitation. Although the metabolizable acetate ion in Restor BIG EF (Lysine)^® 15% diminishes the risk of acidosis, the physician must be alert to the potential appearance of this disorder.

Initiation and termination of infusions of TPN fluids must be gradual to permit adjustment of endogenous insulin release.

Undiluted Restor BIG EF (Lysine)^® 15% should not be administered peripherally. When administered centrally, it should be diluted with appropriate diluents, e.g., dextrose, electrolytes and other nutrient components, to at least half strength. See DOSAGE AND ADMINISTRATION.

Caution against volume overload should be exercised.

Drug product contains no more than 25 mcg/L of aluminum.

B. Laboratory Tests

Infusion of Restor BIG EF (Lysine)^® 15% without concomitant infusion of an adequate number of non-protein calories may result in elevated BUN. Monitoring of BUN is required and the balance between Restor BIG EF (Lysine)^® 15% and the calorie source may require adjustment. Frequent clinical evaluations and laboratory determinations are required to prevent the complications which may occur during the administration of solutions used in TPN. Laboratory tests should include blood glucose, serum electrolytes, liver and kidney function, serum osmolarity, blood ammonia, serum protein, pH, hematocrit, WBC and urinary glucose. When Restor BIG EF (Lysine)^® 15% is combined with electrolytes, care should be used in administering this solution to patients with congestive heart failure, renal failure, edema, adrenal hyperactivity, acid-base imbalance and those receiving diuretics or antihypertensive therapy. Total volume infused should be closely monitored. Serum electrolytes should be monitored daily in these patients.

C. Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Restor BIG EF (Lysine)^® 15% have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

D. Pregnancy Category C

Animal reproduction studies have not been conducted with Restor BIG EF (Lysine)^® 15%. It is also not known whether Restor BIG EF (Lysine)^® 15% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Restor BIG EF (Lysine)^® 15% should be given to a pregnant woman only if clearly needed.

E. Nursing Mothers

Caution should be exercised when Restor BIG EF (Lysine)^® 15% is administered to a nursing woman.

F. Pediatric Use

Safety and effectiveness of Restor BIG EF (Lysine)^® 15% Amino Acids Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acids injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature.

G. Special Precautions for Central Infusion

TPN delivered by indwelling catheter through a central or large peripheral vein is a special technique requiring a team effort by physician, nurse and pharmacist. The responsibility for administering this therapy should be confined to those trained in the procedures and alert to signs of complications. Complications known to occur from the placement of central venous catheter are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis, and air/catheter emboli. The risk of sepsis is present during intravenous therapy, especially when using central venous catheters for prolonged periods. It is imperative that the preparation of admixtures and the placement and care of the catheters be accomplished under controlled aseptic conditions.

H. Admixtures

Admixtures should be prepared under a laminar flow hood using aseptic technique.

Admixtures should be stored under refrigeration and must be administered within 24 hours after removal from refrigerator.

Filters of less than 1.2 micron pore size must not be used with admixtures containing fat emulsion.

I. Do not administer unless solution is clear and the seal is intact.

IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.

ADVERSE REACTIONS

OVERDOSAGE

In the event of overhydration or solute overload, re-evaluatethe patient and institute appropriate corrective measures. See WARNINGS andPRECAUTIONS.

DOSAGE AND ADMINISTRATION

The appropriate daily dose of amino acids to be used withdextrose or with dextrose and intravenous fat emulsion will depend upon themetabolic status and clinical response of the patient as therapy proceeds. Doses which achieve nitrogen equilibrium or positive balance are the mostdesirable. The dosage on the first day should be approximately half the anticipatedoptimal dosage and should be increased gradually to minimize glycosuria; similarly,withdrawal should be accomplished gradually to avoid rebound hypoglycemia.

Fatemulsion coadministration should be considered when prolonged (more than 5days) parenteral nutrition is required in order to prevent essential fattyacid deficiency (EFAD). Serum lipids should be monitored for evidence of EFADin patients maintained on fat free TPN.

The amount administeredis dosed on the basis of amino acids/kg of body weight/day. In general, twoto three g/kg of body weight for neonates and infants with adequate caloriesare sufficient to satisfy protein needs and promote positive nitrogen balance. In pediatric patients, the final solution should not exceed twice normal serumosmolarity (718 mOsmol/L).

DIRECTIONSFOR PROPER USE OF PHARMACY BULK PACKAGE

Restor BIG EF (Lysine)^® 15%in a Pharmacy Bulk Package is not intended for direct infusion. The containerclosure may be penetrated only once using a suitable sterile transfer deviceor dispensing set which allows measured dispensing of the contents. The PharmacyBulk Package is to be used only in a suitable work area such as a laminarflow hood (or an equivalent clean air compounding area). Once the closureis penetrated, the contents should be dispensed as soon as possible; the transferof contents must be completed within 4 hours of closure entry. The bottlemay be stored at room temperature (25°C) after the closure has been entered. Date and time of container entry should be noted in the area designated onthe container label.

When using Restor BIG EF (Lysine)^® 15%in patients with a need for fluid volume restriction, it can be diluted asfollows:

This will provide 1395 kilocalories (kcal) per 1000 mLof admixture with a ratio of 118 non-protein calories per gram of nitrogenand an osmolarity of 1561 mOsmol/L.

In patients wherethe need for fluid restriction is not so marked, either of the following regimensmay be used dependent upon the energy needs of the patient.

This will provide 1500 kcal per 1000 mL of admixture witha ratio of 228 non-protein calories per gram of nitrogen and an osmolarityof 1633 mOsmol/L.

This will provide 935 kcal per 1000 mL of admixture witha ratio of 158 non-protein calories per gram of nitrogen and an osmolarityof 1128.5 mOsmol/L.

A. Total Parenteral Nutrition (CentralInfusion)

In unstressed adult patients with no unusualnitrogen losses, a minimum dosage of 0.1 gram nitrogen (4.2 mL of Restor BIG EF (Lysine)^® 15%)plus 4.4 grams (15 calories) of dextrose per kilogram of body weight per dayare required to achieve nitrogen balance and weight stability. Intravenousfat emulsion may be used as a partial substitute for dextrose. This regimenprovides a ratio of 150 non-protein calories per gram of nitrogen.

Forpatients stressed by surgery, trauma or sepsis, and those with unusual nitrogenlosses, the dosage required for maintenance may be as high as 0.3 to 0.4 gramsof nitrogen (13 to 17 mL Restor BIG EF (Lysine)^® 15%) per kilogram of bodyweight per day, with proportionate increases in non-protein calories. Periodicassessment of nitrogen balance of the individual patient is the best indicatorof proper dosage. Volume overload and glycosuria may be encountered at highdosage, and nitrogen balance may not be achieved in extremely hypermetabolicpatients under these constraints. Concomitant insulin administration may berequired to minimize glycosuria. Daily laboratory monitoring is essential.

Useof an infusion pump is advisable to maintain a steady infusion rate duringcentral venous infusion.

B. Peripheral Nutrition

Inpatients for whom central venous catheterization is not advisable, proteincatabolism can be reduced by peripheral use of diluted Restor BIG EF (Lysine)^® 15%plus non-protein calorie sources. Dilution of 250 mL Restor BIG EF (Lysine)^® 15%in 750 mL of 10% dextrose will reduce the osmolarity to a level (724 mOsmol/L)which is more favorable to the maintenance of the integrity of the walls ofthe veins. Intravenous fat emulsion can be infused separately or simultaneously;if infused simultaneously the fat emulsion will provide a dilution effectupon the osmolarity while increasing the energy supply.

Parenteraldrug products should be inspected visually for particulate matter and discolorationprior to administration, whenever solution and container permit.

Toreduce the risk of bacterial contamination, all intravenous administrationsets should be replaced at least every 24 hours. Usage of admixtures mustbe initiated within 24 hours after mixing. If storage is necessary duringthis 24 hour period, admixtures must be refrigerated and completely used within24 hours of beginning administration.

HOW SUPPLIED

Restor BIG EF (Lysine)^® 15% Amino Acids Injection is suppliedas a Pharmacy Bulk Package in 500 mL containers.

500mL NDC 0409-0468-05

STORAGE

Store inthe closed carton; do not expose solution to light until ready for use. Exposureof pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that the product be stored at 20 to 25°C (68 to 77°F). Brief exposure to temperatures above25°C during transport and storage will not adversely affect the product. Solution that has been frozen must not be used.

Hospira, Inc., Lake Forest, IL 60045 USA

RL-1450

Vitamin A:

• Dosage and administration
• Warning
• Clinical pharmacology
• Dietary supplementation
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Restor BIG EF (Vitamin A) 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, Restor BIG EF (Vitamin A) 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.

Restor BIG EF (Vitamin A) 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 Restor BIG EF (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Restor BIG EF (Vitamin A) 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

Restor BIG EF Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Restor BIG EF (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Restor BIG EF (Vitamin A) 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:

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

Pharmacological action

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

Dosage and administration

Restor BIG EF is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Restor BIG EF (Vitamin B12) 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 Restor BIG EF (Vitamin B12) 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 Restor BIG EF (Vitamin B12) 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.

Restor BIG EF (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

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

Allergic reactions: rarely - urticaria.

Restor BIG EF contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Restor BIG EF 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 Restor BIG EF 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.

Restor BIG EF (Vitamin B12) drug interactions

In an application of Restor BIG EF (Vitamin B12) 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 Restor BIG EF (Vitamin B12) 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:

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

Pharmacological action

Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Restor BIG EF (Vitamin C) 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. Restor BIG EF (Vitamin C) has antioxidant properties.

With intravaginal application of 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 ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.

The concentration of 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%.

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.

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 Restor BIG EF prescribed?

For systemic use of Restor BIG EF (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Restor BIG EF (Vitamin C); providing increased need for Restor BIG EF (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 Restor BIG EF dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used ascorbic acid drugs in appropriate dosage forms.

Restor BIG EF (Vitamin C) 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.

Restor BIG EF contraindications

Increased sensitivity to ascorbic acid.

Using during pregnancy and breastfeeding

The minimum daily requirement of ascorbic acid in the II and III trimester of pregnancy is about 60 mg.

Ascorbic acid crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of 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 ascorbic acid in high doses, except in cases where the expected benefit outweighs the potential risk.

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

Special instructions

Restor BIG EF (Vitamin C) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because 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 ascorbic acid in minimal doses.

Restor BIG EF (Vitamin C) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

The use of ascorbic acid in high doses can cause exacerbation of sickle cell anemia.

Data on the diabetogenic action of ascorbic acid are contradictory. However, prolonged use of ascorbic acid should periodically monitor your blood glucose levels.

It is believed that the use of ascorbic acid in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in ascorbic acid in patients with advanced cancer.

Absorption of ascorbic acid decreased while use of fresh fruit or vegetable juices, alkaline drinking.

Restor BIG EF drug interactions

In an application with barbiturates, primidone increases the excretion of ascorbic acid in the urine.

With the simultaneous use of oral contraceptives reduces the concentration of ascorbic acid in blood plasma.

In an application of Restor BIG EF (Vitamin C) with iron preparations ascorbic acid, due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

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 ascorbic acid by about a third.

Restor BIG EF (Vitamin C) in an application with warfarin may decrease effects of warfarin.

With the simultaneous application of ascorbic acid increases the excretion of iron in patients receiving deferoxamine. In the application of ascorbic acid at a dose of 500 mg / day possibly left ventricular dysfunction.

In an application with tetracycline is increased excretion of ascorbic acid in the urine.

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with 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.

Restor BIG EF 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 Lactate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Restor BIG EF (Zinc Lactate) reviews

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Restor BIG EF (Zinc Lactate) 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 Restor BIG EF (Zinc Lactate) 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 Restor BIG EF (Zinc Lactate) from a bolus injection. Administration of Restor BIG EF (Zinc Lactate) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Restor BIG EF (Zinc Lactate) are suggested as a guideline for subsequent Restor BIG EF (Zinc Lactate) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

Hyperamylasemia may be a sign of impending Restor BIG EF (Zinc Lactate) 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 Restor BIG EF (Zinc Lactate) was delivered intravenously over the course of 60 hours to a 72 year old patient.

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

Calcium supplements may confer a protective effect against Restor BIG EF (Zinc Lactate) toxicity.

DOSAGE AND ADMINISTRATION

Restor BIG EF (Zinc Lactate) 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 Restor BIG EF (Zinc Lactate) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Restor BIG EF (Zinc Lactate).

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

Restor BIG EF (Zinc Lactate) 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

Restor BIG EF (Zinc Lactate)

1 mg/mL

Restor BIG EF (Zinc Lactate) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA