Prevencal + D et Fer

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Prevencal + D et Fer uses

Prevencal + D et Fer consists of Calcium (Calcium Carbonate), Iron (Ferrous Fumarate), Vitamin D.

Calcium (Calcium Carbonate):


1 INDICATIONS AND USAGE

Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

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

2 DOSAGE AND ADMINISTRATION

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

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

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

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate capsule.

- Capsule: 667 mg Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Prevencal + D et Fer ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Prevencal + D et Fer (Calcium (Calcium Carbonate)), including Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate. Avoid the use of Prevencal + D et Fer (Calcium (Calcium Carbonate)) supplements, including Prevencal + D et Fer (Calcium (Calcium Carbonate)) based nonprescription antacids, concurrently with Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate.

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

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

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

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

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

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

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

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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 Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate therapy. (6)

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

6.1 Clinical Trial Experience

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

In clinical studies, Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate has been generally well tolerated.

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


Preferred Term


Total adverse reactions reported for Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate

N=167

N (%)


3 month, open label study of Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate

N=69


Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


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

6.2 Postmarketing Experience

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

The following additional adverse reactions have been identified during post-approval of Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

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

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

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

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

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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

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10 OVERDOSAGE

Administration of Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate acts as a phosphate binder. Its chemical name is Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:


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

Prevencal + D et Fer (Calcium (Calcium Carbonate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Prevencal + D et Fer ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Prevencal + D et Fer (Calcium (Calcium Carbonate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

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

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13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate solid oral dosage form.

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

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

The data presented in Table 2 demonstrate the efficacy of Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Prevencal + D et Fer (Calcium (Calcium Carbonate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Prevencal + D et Fer (Calcium (Calcium Carbonate)) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


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

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

The phosphate binding effect of Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate is shown in the Table 3.


* ANOVA of Prevencal + D et Fer (Calcium (Calcium Carbonate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Prevencal + D et Fer (Calcium (Calcium Carbonate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Prevencal + D et Fer (Calcium (Calcium Carbonate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


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

16 HOW SUPPLIED/STORAGE AND HANDLING

Prevencal + D et Fer (Calcium (Calcium Carbonate)) Acetate Capsules

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

NDC 0615-2303-39: Blistercards of 30 Capsules

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

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

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

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

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Iron (Ferrous Fumarate):


1 INDICATIONS AND USAGE

Prevencal + D et Fer (Iron (Ferrous Fumarate)) is indicated for the treatment of Prevencal + D et Fer (Iron (Ferrous Fumarate)) deficiency anemia in patients with chronic kidney disease (CKD).

Prevencal + D et Fer (Iron (Ferrous Fumarate)) is an Prevencal + D et Fer (Iron (Ferrous Fumarate)) replacement product indicated for the treatment of Prevencal + D et Fer (Iron (Ferrous Fumarate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Prevencal + D et Fer ) must only be administered intravenously either by slow injection or by infusion. The dosage of Prevencal + D et Fer (Iron (Ferrous Fumarate)) is expressed in mg of elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)). Each mL contains 20 mg of elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)).

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

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

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

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

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

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

2.4 Pediatric Patients with HDD-CKD for Prevencal + D et Fer (Iron (Ferrous Fumarate)) maintenance treatment

The dosing for Prevencal + D et Fer (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

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

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Prevencal + D et Fer (Iron (Ferrous Fumarate)) maintenance treatment

The dosing for Prevencal + D et Fer (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

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

3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Prevencal + D et Fer (Iron (Ferrous Fumarate))
  • Known hypersensitivity to Prevencal + D et Fer (Iron (Ferrous Fumarate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.1 Hypersensitivity Reactions

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

5.2 Hypotension

Prevencal + D et Fer ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Prevencal + D et Fer (Iron (Ferrous Fumarate)). Hypotension following administration of Prevencal + D et Fer (Iron (Ferrous Fumarate)) may be related to the rate of administration and/or total dose administered .

5.3 Prevencal + D et Fer (Iron (Ferrous Fumarate)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Prevencal + D et Fer ) are described in other sections .

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

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

6.1 Adverse Reactions in Clinical Trials

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

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

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


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

HDD-CKD NDD-CKD PDD-CKD
Prevencal + D et Fer (Iron (Ferrous Fumarate)) Prevencal + D et Fer (Iron (Ferrous Fumarate)) Oral Prevencal + D et Fer (Iron (Ferrous Fumarate)) Prevencal + D et Fer (Iron (Ferrous Fumarate)) EPO* Only
(N=231) (N=139) (N=139) (N=75) (N=46)
% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2.7 0
Gastrointestinal Disorders
Abdominal pain 3.5 1.4 2.9 4.0 6.5
Diarrhea 5.2 7.2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8.6 12.2 5.3 4.3
Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Feeling abnormal 3.0 0 0 0 0
Infusion site pain or burning 0 5.8 0 0 0
Injection site extravasation 0 2.2 0 0 0
Peripheral edema 2.6 7.2 5.0 5.3 10.9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper

respiratory tract infections, Pharyngitis

2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and Procedural
Complications
Graft complication 9.5 1.4 0 0 0
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 0
Gout 0 2.9 1.4 0 0
Hyperglycemia 0 2.9 0 0 2.2
Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Back pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 0
Myalgia 0 3.6 0 1.3 0
Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 0
Dyspnea 3.5 5.8 1.4 1.3 2.2
Nasal congestion 0 1.4 2.2 1.3 0
Skin and Subcutaneous
Tissue Disorders
Pruritus 3.9 2.2 4.3 2.7 0
Vascular Disorders
Hypertension 6.5 6.5 4.3 8.0 6.5
Hypotension 39.4 2.2 0.7 2.7 2.2

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

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

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

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

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

6.2 Adverse Reactions from Post-Marketing Experience

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

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

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

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

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

7 DRUG INTERACTIONS

Drug interactions involving Prevencal + D et Fer (Iron (Ferrous Fumarate)) have not been studied. However, Prevencal + D et Fer (Iron (Ferrous Fumarate)) may reduce the absorption of concomitantly administered oral Prevencal + D et Fer (Iron (Ferrous Fumarate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Prevencal + D et Fer ) for Prevencal + D et Fer (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

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

Prevencal + D et Fer (Iron (Ferrous Fumarate)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

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

10 OVERDOSAGE

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

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

11 DESCRIPTION

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

[Na2Fe5O8(OH) ·3(H2O)]n ·m(C12H22O11)

where: n is the degree of Prevencal + D et Fer (Iron (Ferrous Fumarate)) polymerization and m is the number of sucrose molecules associated with the Prevencal + D et Fer (Iron (Ferrous Fumarate)) (III)-hydroxide.

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Prevencal + D et Fer (Iron (Ferrous Fumarate)) sucrose.

Prevencal + D et Fer (Iron (Ferrous Fumarate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Prevencal + D et Fer (Iron (Ferrous Fumarate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

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

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Prevencal + D et Fer ).

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

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

Patients in the Prevencal + D et Fer (Iron (Ferrous Fumarate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Prevencal + D et Fer (Iron (Ferrous Fumarate)) (n=69 Historical Control (n=18) Prevencal + D et Fer (Iron (Ferrous Fumarate))

(n=73)

Historical Control

(n=18)

Prevencal + D et Fer (Iron (Ferrous Fumarate))

(n=71)

Historical

Control

(n=15)

Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86

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

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

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

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

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

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

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

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

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

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

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

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

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

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Prevencal + D et Fer ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)), each 5 mL vial contains 100 mg elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)), and each 2.5 mL vial contains 50 mg elemental Prevencal + D et Fer (Iron (Ferrous Fumarate)) (20 mg/mL).

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

16.2 Stability and Storage

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

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

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

Do not dilute to concentrations below 1 mg/mL.

Do not mix Prevencal + D et Fer (Iron (Ferrous Fumarate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

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

17 PATIENT COUNSELING INFORMATION

Prior to Prevencal + D et Fer (Iron (Ferrous Fumarate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Prevencal + D et Fer (Iron (Ferrous Fumarate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx®

IN2340

MG #15727

Different Prevencal + D et Fer products with other ingredients:


Prevencal + D et Fer pharmaceutical active ingredients containing related brand and generic drugs:


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References

  1. Dailymed."CALCIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "Calcium". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "Iron". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Prevencal + D et Fer?

Depending on the reaction of the Prevencal + D et Fer after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Prevencal + D et Fer not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Prevencal + D et Fer addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Prevencal + D et Fer, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Prevencal + D et Fer consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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