Prenagen Ibu Menyusui

Calcium:

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

1 INDICATIONS AND USAGE

Prenagen Ibu Menyusui (Calcium) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

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

2 DOSAGE AND ADMINISTRATION

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

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

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

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Prenagen Ibu Menyusui (Calcium) acetate capsule.

- Capsule: 667 mg Prenagen Ibu Menyusui (Calcium) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Prenagen Ibu Menyusui acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Prenagen Ibu Menyusui (Calcium) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Prenagen Ibu Menyusui (Calcium), including Prenagen Ibu Menyusui (Calcium) acetate. Avoid the use of Prenagen Ibu Menyusui (Calcium) supplements, including Prenagen Ibu Menyusui (Calcium) based nonprescription antacids, concurrently with Prenagen Ibu Menyusui (Calcium) acetate.

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

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

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

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

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

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

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

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

- In clinical studies, patients have occasionally experienced nausea during Prenagen Ibu Menyusui (Calcium) acetate therapy. (6)

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

6.1 Clinical Trial Experience

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

In clinical studies, Prenagen Ibu Menyusui (Calcium) acetate has been generally well tolerated.

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

Preferred Term	Total adverse reactions reported for Prenagen Ibu Menyusui (Calcium) acetate N=167 N (%)	3 month, open label study of Prenagen Ibu Menyusui (Calcium) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Prenagen Ibu Menyusui (Calcium) acetate N=69
			Prenagen Ibu Menyusui (Calcium) 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 Prenagen Ibu Menyusui (Calcium) concentration could reduce the incidence and severity of Prenagen Ibu Menyusui (Calcium) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

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

The following additional adverse reactions have been identified during post-approval of Prenagen Ibu Menyusui (Calcium) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

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

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

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

7.1 Ciprofloxacin

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Prenagen Ibu Menyusui (Calcium) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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

10 OVERDOSAGE

Administration of Prenagen Ibu Menyusui (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Prenagen Ibu Menyusui (Calcium) acetate acts as a phosphate binder. Its chemical name is Prenagen Ibu Menyusui (Calcium) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

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

Prenagen Ibu Menyusui (Calcium) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Prenagen Ibu Menyusui (Calcium) acetate.

14 CLINICAL STUDIES

Effectiveness of Prenagen Ibu Menyusui (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Prenagen Ibu Menyusui (Calcium) acetate solid oral dosage form.

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

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

The data presented in Table 2 demonstrate the efficacy of Prenagen Ibu Menyusui (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Prenagen Ibu Menyusui (Calcium) 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
Prenagen Ibu Menyusui (Calcium) (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 Prenagen Ibu Menyusui (Calcium) increased 9% during the study mostly in the first month of the study.

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

The phosphate binding effect of Prenagen Ibu Menyusui (Calcium) acetate is shown in the Table 3.

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Prenagen Ibu Menyusui (Calcium) Acetate Capsules

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

NDC 0615-2303-39: Blistercards of 30 Capsules

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

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

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

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

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Choline:

• Prenagen Ibu Menyusui (Choline) reviews

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

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

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

Folic Acid:

• Indications and usage
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage
• Prenagen Ibu Menyusui (Folic Acid) reviews

INDICATIONS AND USAGE

Prenagen Ibu Menyusui (Folic Acid)^® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.

CONTRAINDICATIONS

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

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

PRECAUTIONS

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

ADVERSE REACTIONS

Allergic sensitization has been reported following both oral and parenteral administration of Prenagen Ibu Menyusui (Folic Acid) acid.

DOSAGE AND ADMINISTRATION

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

HOW SUPPLIED

Prenagen Ibu Menyusui (Folic Acid)^® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)

KEEP OUT OF REACH OF CHILDREN.

STORAGE

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

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

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

Distributed by:

Meda Pharmaceuticals Inc.

Somerset New Jersey 08873-4120

© 2014 Meda Pharmaceuticals Inc.

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

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

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

MEDA PHARMACEUTICALS mark and logo are trademarks of Meda AB.

IN-6885-02 Rev 6/2014

Iron:

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

1 INDICATIONS AND USAGE

Prenagen Ibu Menyusui (Iron) is indicated for the treatment of Prenagen Ibu Menyusui (Iron) deficiency anemia in patients with chronic kidney disease (CKD).

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

2 DOSAGE AND ADMINISTRATION

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

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

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

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

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

2.4 Pediatric Patients with HDD-CKD for Prenagen Ibu Menyusui (Iron) maintenance treatment

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

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

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

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

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

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Prenagen Ibu Menyusui (Iron) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Prenagen Ibu Menyusui (Iron) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Prenagen Ibu Menyusui (Iron) (20 mg/mL)

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

4 CONTRAINDICATIONS

• Known hypersensitivity to Prenagen Ibu Menyusui (Iron)

• Known hypersensitivity to Prenagen Ibu Menyusui (Iron) (4)

5 WARNINGS AND PRECAUTIONS

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

5.1 Hypersensitivity Reactions

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

5.2 Hypotension

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

5.3 Prenagen Ibu Menyusui (Iron) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Prenagen Ibu Menyusui are described in other sections .

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

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

6.1 Adverse Reactions in Clinical Trials

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

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

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

* EPO=Erythropoietin
Adverse Reactions (Preferred Term)	HDD-CKD	NDD-CKD		PDD-CKD
	Prenagen Ibu Menyusui (Iron)	Prenagen Ibu Menyusui (Iron)	Oral Prenagen Ibu Menyusui (Iron)	Prenagen Ibu Menyusui (Iron)	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 Prenagen Ibu Menyusui (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Prenagen Ibu Menyusui (Iron) product). When these patients were treated with Prenagen Ibu Menyusui (Iron) there were no occurrences of adverse reactions that precluded further use of Prenagen Ibu Menyusui (Iron) .

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

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

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

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

6.2 Adverse Reactions from Post-Marketing Experience

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

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

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

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

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

7 DRUG INTERACTIONS

Drug interactions involving Prenagen Ibu Menyusui (Iron) have not been studied. However, Prenagen Ibu Menyusui (Iron) may reduce the absorption of concomitantly administered oral Prenagen Ibu Menyusui (Iron) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

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

Prenagen Ibu Menyusui (Iron) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

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

10 OVERDOSAGE

No data are available regarding overdosage of Prenagen Ibu Menyusui (Iron) in humans. Excessive dosages of Prenagen Ibu Menyusui (Iron) may lead to accumulation of Prenagen Ibu Menyusui (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Prenagen Ibu Menyusui (Iron) to patients with Prenagen Ibu Menyusui (Iron) overload.

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

11 DESCRIPTION

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

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

where: n is the degree of Prenagen Ibu Menyusui (Iron) polymerization and m is the number of sucrose molecules associated with the Prenagen Ibu Menyusui (Iron) (III)-hydroxide.

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Prenagen Ibu Menyusui (Iron) sucrose.

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

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

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Prenagen Ibu Menyusui.

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

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

Patients in the Prenagen Ibu Menyusui (Iron) 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
	Prenagen Ibu Menyusui (Iron) (n=69	Historical Control (n=18)	Prenagen Ibu Menyusui (Iron) (n=73)	Historical Control (n=18)	Prenagen Ibu Menyusui (Iron) (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 Prenagen Ibu Menyusui (Iron) in 23 patients with Prenagen Ibu Menyusui (Iron) deficiency and HDD-CKD who had been discontinued from Prenagen Ibu Menyusui (Iron) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

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

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

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

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

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

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

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

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

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

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

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

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

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

Do not dilute to concentrations below 1 mg/mL.

Do not mix Prenagen Ibu Menyusui (Iron) with other medications or add to parenteral nutrition solutions for intravenous infusion.

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

17 PATIENT COUNSELING INFORMATION

Prior to Prenagen Ibu Menyusui (Iron) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Prenagen Ibu Menyusui (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Omega-3:

• Prenagen Ibu Menyusui (Omega-3) reviews

Prenagen Ibu Menyusui (Omega-3) fatty acids are thought to help reduce the risk of heart disease and also to promote healthy skin. They are also used along with diet and exercise to help lower levels of a certain blood fat (triglyceride) and to raise levels of "good" cholesterol (HDL). This product may also be used to help treat high blood pressure or rheumatoid arthritis. Some supplement products have been found to contain possibly harmful impurities/additives. Check with your pharmacist for more details about the brand you use. The US Food and Drug Administration has not reviewed this product for safety or effectiveness. Consult your doctor or pharmacist for more details.

Protein:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Prenagen Ibu Menyusui (Protein) reviews

1 INDICATIONS AND USAGE

Prenagen Ibu Menyusui is indicated for pediatric and adult patients with severe congenital Prenagen Ibu Menyusui (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)

1.1 Severe Congenital Prenagen Ibu Menyusui (Protein) C Deficiency

Prenagen Ibu Menyusui (Protein) is indicated for pediatric and adult patients with severe congenital Prenagen Ibu Menyusui (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.

2 DOSAGE AND ADMINISTRATION

Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of Prenagen Ibu Menyusui C activity is feasible. (2.1)

Prenagen Ibu Menyusui (Protein) Dosing Schedule for Acute Episodes, Short-term Prophyaxis and Long-term Prophylaxis Dosing is based upon a pivotal clinical trial of 15 patients
	Initial Dose The dose regimen should be adjusted according to the pharmacokinetic profile for each individual. (2.1, 2.2)	Subsequent # Doses	Maintenance Dose
Acute Episodes, Short-term ProphyaxisPrenagen Ibu Menyusui (Protein) should be continued until desired anticoagulation is achieved.	100-120 IU/kg	60-80 IU/kg Q 6 hours	45-60 IU/kg Q 6 or Q 12 hours
Long-term Prophylaxis	NA	NA	45-60 IU/kg Q 12 hours

Store at 2°C – 8°C (36°F-46°F) and protect from light. Avoid freezing. Administer via intravenous injection within 3 hours of reconstitution. (16)

2.1 General

For intravenous administration only.

Initiate treatment with Prenagen Ibu Menyusui (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Prenagen Ibu Menyusui (Protein) C activity is feasible.

The dose, administration frequency and duration of treatment with Prenagen Ibu Menyusui (Protein) depends on the severity of the Prenagen Ibu Menyusui (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of Prenagen Ibu Menyusui (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: Prenagen Ibu Menyusui (Protein) C Activity Monitoring (2.2).

Table 1 provides the Prenagen Ibu Menyusui (Protein) dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis.

NA = Not applicable; Q = every.
	Initial Dose The dose regimen should be adjusted according to the pharmacokinetic profile for each individual. (2.1, 2.2)	Subsequent 3 Doses	Maintenance Dose
Acute Episode / Short-term ProphylaxisPrenagen Ibu Menyusui (Protein) should be continued until desired anticoagulation is achieved.	100-120 IU/kg	60 - 80 IU/kg Q 6 hours	45 - 60 IU/kg Q 6 or 12 hours
Long-term Prophylaxis	NA	NA	45 - 60 IU/kg Q 12 hours

An initial dose of 100-120 IU/kg for determination of recovery and half-life is recommended for acute episodes and short-term prophylaxis. Subsequently, adjust the dose to maintain a target peak Prenagen Ibu Menyusui (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Prenagen Ibu Menyusui (Protein) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of Prenagen Ibu Menyusui (Protein), higher peak Prenagen Ibu Menyusui (Protein) C activity levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention). Maintenance of trough Prenagen Ibu Menyusui (Protein) C activity levels above 25% is recommended.

These dosing guidelines are also recommended for neonatal and pediatric patients. See USE IN SPECIFIC POPULATIONS: Pediatric Use (8.4 ) and CLINICAL

Pharmacology: Pharmacokinetics (12.3).

2.2 Prenagen Ibu Menyusui C Activity Monitoring

The measurement of Prenagen Ibu Menyusui (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Prenagen Ibu Menyusui (Protein) C before and during treatment with Prenagen Ibu Menyusui (Protein). The half-life of Prenagen Ibu Menyusui (Protein) may be shortened in certain clinical conditions such as acute thrombosis, purpura fulminans and skin necrosis. See CLINICAL

Pharmacology: Pharmacokinetics (12.3). In the case of an acute thrombotic event, it is recommended that Prenagen Ibu Menyusui (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Prenagen Ibu Menyusui (Protein) C levels to maintain the trough Prenagen Ibu Menyusui (Protein) C level above 25%.

Patients treated during the acute phase of their disease may display much lower increases in protein C activity. Coagulation parameters should also be checked; however, in clinical trials data were insufficient to establish correlation between Prenagen Ibu Menyusui (Protein) C activity levels and coagulation parameters.

2.3 Initiation of Vitamin K Antagonists

In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists, a transient hypercoagulable state may arise before the desired anticoagulant effect becomes apparent. This transient effect may be explained by the fact that Prenagen Ibu Menyusui C, itself a vitamin K-dependent plasma Prenagen Ibu Menyusui (Protein), has a shorter half-life than most of the vitamin K-dependent proteins (i.e. Factor II, IX and X).

In the initial phase of treatment, the activity of Prenagen Ibu Menyusui (Protein) C is more rapidly suppressed than that of the procoagulant factors. For this reason, if the patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is obtained. Although warfarin-induced skin necrosis can occur in any patient during the initiation of treatment with oral anticoagulant therapy, individuals with severe congenital Prenagen Ibu Menyusui (Protein) C deficiency are particularly at risk.

During the initiation of oral anticoagulant therapy, it is advisable to start with a low dose of the anticoagulant and adjust this incrementally, rather than use a standard loading dose of the anticoagulant.

2.4 Preparation of Prenagen Ibu Menyusui (Protein) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

• Bring the Prenagen Ibu Menyusui (Protein) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
• Remove caps from the Prenagen Ibu Menyusui (Protein) and diluent vials.
• Cleanse stoppers with germicidal solution, and allow them to dry prior to use.
• Remove protective covering from one end of the double-ended transfer needle and insert exposed needle through the center of the diluent vial stopper.
• Remove protective covering from the other end of the double-ended transfer needle. Invert diluent vial over the upright Prenagen Ibu Menyusui (Protein) vial; then rapidly insert the free end of the needle through the Prenagen Ibu Menyusui (Protein) vial stopper at its center. The vacuum in the vial will draw in the diluent. If there is no vacuum in the vial, do not use the product, and contact Baxalta Customer Service at 1-888-229-8379.
• Disconnect the two vials by removing the needle from the diluent vial stopper. Then, remove the transfer needle from the Prenagen Ibu Menyusui (Protein) vial. Gently swirl the vial until all powder is dissolved. Be sure that Prenagen Ibu Menyusui (Protein) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of Prenagen Ibu Menyusui [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect Prenagen Ibu Menyusui (Protein) for particulate matter and discoloration prior to administration.

After reconstitution, the solution should be colorless to slightly yellowish and clear to slightly opalescent and free of visible particles. Do not use the solution if it does not meet this criteria. Administer Prenagen Ibu Menyusui (Protein) at room temperature not more than 3 hours after reconstitution.

• Attach the filter needle to a sterile, disposable syringe and draw back the plunger to admit air into the syringe.
• Insert the filter needle into the vial of reconstituted Prenagen Ibu Menyusui (Protein).
• Inject air into the vial and then withdraw the reconstituted Prenagen Ibu Menyusui (Protein) into the syringe.
• Remove and discard the filter needle in a hard-walled Sharps container for proper disposal. Filter needles are intended to filter the contents of a single vial of Prenagen Ibu Menyusui (Protein) only.
• Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under Administration by infusion.

Record the name and batch number of the product every time Prenagen Ibu Menyusui (Protein) is administered to a patient.

Administration by Infusion

Administer Prenagen Ibu Menyusui (Protein) at a maximum injection rate of 2 mL per minute except for children with a body weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/minute.

3 DOSAGE FORMS AND STRENGTHS

Prenagen Ibu Menyusui (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Prenagen Ibu Menyusui (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human Prenagen Ibu Menyusui (Protein) C at a concentration of 100 IU/mL.

Prenagen Ibu Menyusui (Protein), when reconstituted with the appropriate volume of diluent, contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride.

BLUE BAR: Approximately 500 IU/vial (3)

GREEN BAR: Approximately 1000 IU/vial (3)

Each single-dose vial contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride when reconstituted with the appropriate amount of diluent. (3)

4 CONTRAINDICATIONS

None known.

None known. (4)

5 WARNINGS AND PRECAUTIONS

• Discontinue administration if symptoms of hypersensitivity/allergic reactions occur.
• Made from pooled human plasma. The possibility of transmitting infectious agents cannot be ruled out. (5.2, 11)
• Simultaneous administration with tPA and/or anticoagulants may increase risk of bleeding. (5.3)
• Contains heparin. If heparin-induced thrombocytopenia is suspected, check platelet counts immediately and discontinue administration. (5.4)
• Contains sodium >200 mg. Inform patients on a low sodium diet and/or patients with renal impairment. (5.5)

5.1 Hypersensitivity/Allergic Reactions

Prenagen Ibu Menyusui (Protein) may contain traces of mouse Prenagen Ibu Menyusui (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Prenagen Ibu Menyusui (Protein) and/or heparin cannot be ruled out. If symptoms of hypersensitivity/allergic reaction occur, discontinue the injection/infusion. In case of anaphylactic shock, the current medical standards for treatment are to be observed.

5.2 Transmission of Infectious Agents

Because Prenagen Ibu Menyusui is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

ALL infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-888-229-8379. Discuss the risks and benefits of this product with your patient.

5.3 Bleeding Episodes

Several bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. However, it cannot be completely ruled out that the administration of Prenagen Ibu Menyusui (Protein) further contributed to these bleeding events.

Simultaneous administration of Prenagen Ibu Menyusui (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

Prenagen Ibu Menyusui (Protein) contains trace amounts of heparin which may lead to Heparin-induced Thrombocytopenia, which can be associated with a rapid decrease of the number of thrombocytes. Identifying HIT is complicated because these symptoms may already be present in acute phase patients with severe congenital Prenagen Ibu Menyusui (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of Prenagen Ibu Menyusui (Protein).

5.5 Low Sodium Diet/Renal Impairment

Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of Prenagen Ibu Menyusui (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to Prenagen Ibu Menyusui treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.

• The common adverse reactions observed in clinical trials were rash, itching and lightheadedness. (2.1, 5.1, 6)

To report SUSPECTED ADVERSE REACTIONS, contact Baxalta US Inc. at 1-800-999-1785 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch .

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in one clinical study of a drug cannot be directly compared with rates in the clinical studies of the same drug or another drug and may not reflect the rates observed in practice.

The safety profile of Prenagen Ibu Menyusui (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital Prenagen Ibu Menyusui (Protein) C deficiency. Duration of exposure ranged from 1 day to 8 years. One patient experienced hypersensitivity/allergic reactions (itching and rash) and lightheadedness which were determined by the investigator to be related to Prenagen Ibu Menyusui (Protein).

No inhibiting antibodies to Prenagen Ibu Menyusui (Protein) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out.

6.2 Post-marketing Experience

The following adverse reactions have been identified during postapproval use of Prenagen Ibu Menyusui (Protein):

Psychiatric Disorders: Restlessness

Skin and Subcutaneous Tissue Disorders: Hyperhydrosis

General Disorders and Administration Site Conditions: Injection Site Reaction

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.

7 DRUG INTERACTIONS

No formal drug interaction studies have been conducted.

See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of Prenagen Ibu Menyusui (Protein) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Prenagen Ibu Menyusui (Protein) and vitamin K antagonists.

• None known. (7)

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Not studied.
• Labor and Delivery: Not studied. (8.2)
• Nursing Mothers: Not studied. (8.3)
• Pediatric Use: Recommended for neonate and pediatric use. (2.1, 8.4, 12.3)
• Renal/Hepatic Impairment: Not studied. (8.6)

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Prenagen Ibu Menyusui (Protein). It is also not known whether Prenagen Ibu Menyusui (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Prenagen Ibu Menyusui (Protein) should be given to pregnant women only if clearly needed.

8.2 Labor and Delivery

Prenagen Ibu Menyusui has not been studied for use during labor and delivery. Use only if clearly needed.

8.3 Nursing Mothers

Prenagen Ibu Menyusui (Protein) has not been studied for use in nursing mothers. Use Prenagen Ibu Menyusui (Protein) only if clearly needed.

8.4 Pediatric Use

Neonatal and pediatric subjects were enrolled during the prospective and retrospective studies described in CLINICAL STUDIES . Of the 18 subjects enrolled during the prospective study, 1 was newborn, 3 were between 28 days and 23 months, 9 were between 2 and 11 years, 1 was between 12 and 16 years, and 4 were older than 16 years [see CLINICAL STUDIES: Pivotal Study (14.1)]. Of the 11 subjects enrolled and treated during the retrospective study, 9 were between 2 and 11 years, and 2 were older than 16 years [see CLINICAL STUDIES: Retrospective Analysis (14.2)].

8.5 Geriatric Use

Clinical studies of Prenagen Ibu Menyusui (Protein) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal/Hepatic Impairment

No experience in the treatment of patients with renal and/or hepatic impairment is available.

11 DESCRIPTION

Prenagen Ibu Menyusui (Protein) [Protein C Concentrate (Human)] is manufactured from human plasma purified by a combination of filtration and chromatographic procedures, including a column of immobilized mouse monoclonal antibodies on gel beads. See WARNINGS/PRECAUTIONS: Transmission of Infectious Agents (5.2).

The manufacturing process for Prenagen Ibu Menyusui (Protein) includes processing steps designed to reduce the risk of viral transmission. The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: Human Immunodeficiency Virus Type 1 (HIV-1), Bovine Viral Diarrhea Virus (BVDV ), Tick-Borne Encephalitis Virus (TBEV), Pseudorabies Virus (PRV), Hepatitis A Virus (HAV) and Mice Minute Virus (MMV). Virus reduction steps consist of detergent treatment (Polysorbate 80, P80), heat inactivation (Vapor Heating) and immunoaffinity chromatography (IAX).

Virus clearance studies for Prenagen Ibu Menyusui (Protein) have demonstrated that the process provides for a robust overall virus clearance capacity. A summary of log₁₀ virus reduction factors per virus and manufacturing step is presented in Table 2.

Abbreviations: IEX, Ion Exchange Chromatography; IAX, Immunoaffinity Chromatography; HIV-1, Human Immunodeficiency Virus Type I; TBEV, Tick-Borne Encephalitis Virus (model for hepatitis C virus); BVDV, Bovine Viral Diarrhea Virus (model virus for HCV and other small, enveloped RNA viruses); PRV, Pseudorabies Virus (model virus for enveloped DNA viruses, e.g. HBV, Hepatitis B Virus); HAV, Hepatitis A Virus; MMV, Mice Minute Virus (model for Human Parvovirus B19 and for non enveloped viruses); n.d., not done.
Manufact-uring Step	HIV-1	HCV Model Viruses		PRV	HAV	MMV
		BVDV	TBEV
P80 Treatment	>5.1	>4.7	n.d.	2.5Coupled with IEX. I	>3.8	1.4
IAX	5.7	n.d.	4.8	5.4	3.1	3.6
Vapor Heating	4.6	>5.9	n.d.	5.9	>4.2	1.2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

Prenagen Ibu Menyusui C is the precursor of a vitamin K-dependent anticoagulant glycoprotein (serine protease) that is synthesized in the liver. See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3). It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to activated Prenagen Ibu Menyusui (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Prenagen Ibu Menyusui (Protein) S. APC exerts its effect by the inactivation of the activated forms of factors V and VIII, which leads to a decrease in thrombin formation. APC has also been shown to have profibrinolytic effects.

The Prenagen Ibu Menyusui (Protein) C pathway provides a natural mechanism for control of the coagulation system and prevention of excessive procoagulant responses to activating stimuli. A complete absence of Prenagen Ibu Menyusui (Protein) C is not compatible with life. A severe deficiency of this anticoagulant Prenagen Ibu Menyusui (Protein) causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.

12.2 Pharmacodynamics

In clinical studies, the intravenous administration of Prenagen Ibu Menyusui (Protein) demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of APC. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.

12.3 Pharmacokinetics

Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with Prenagen Ibu Menyusui (Protein) C deficiency.

PK parameter	N	Median	95% CI for median	Min	Max
Cmax [IU/dL]	21	110	106 to 127	40	141
Tmax [h]	21	0.50	0.50 to 1.05	0.17	1.33
Incremental recovery [(IU/dL)/(IU/kg)]	21	1.42	1.32 to 1.59	0.50	1.76
Initial half-life [h]	21	7.8	5.4 to 9.3	3.0	36.1
Terminal half-life [h]	21	9.9	7.0 to 12.4	4.4	15.8
Half-life by the non-compartmental approach [h]	21	9.8	7.1 to 11.6	4.9	14.7
AUC0-Infinity [IU*h/dL]	21	1500	1289 to 1897	344	2437
MRT [h]	21	14.1	10.3 to 16.7	7.1	21.3
Clearance [dL/kg/h]	21	0.0533	0.0428 to 0.0792	0.0328	0.2324
Volume of distribution at steady state [dL/kg]	21	0.74	0.70 to 0.89	0.44	1.65
Cmax = Maximum concentration after infusion; T max = Time at maximum concentration; AUC 0-Infinity = Area under the curve from 0 to infinity; MRT = Mean residence time; and Incremental recovery = Maximum increase in Prenagen Ibu Menyusui (Protein) C concentration following infusion divided by dose

The Prenagen Ibu Menyusui (Protein) C plasma activity was measured by chromogenic and/or clotting assay. The maximum plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC) appeared to increase dose-linearly between 40 and 80 IU/kg. The median incremental recovery was 1.42 [(IU/dL)/(IU/kg)] after intravenous administration of Prenagen Ibu Menyusui (Protein). The median half-lives, based on non-compartmental method, ranged from 4.9 to 14.7 hours, with a median of 9.8 hours. In patients with acute thrombosis, both the increase in protein C plasma levels as well as half-life may be considerably reduced. No formal study or analysis has been performed to evaluate the effect of covariates such as race and gender on the pharmacokinetics of Prenagen Ibu Menyusui (Protein).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Prenagen Ibu Menyusui (Protein) may be different between very young children and adults. The systemic exposure (C_max and AUC) may be considerably reduced due to a faster clearance, a larger volume of distribution, and/or a shorter half-life of Prenagen Ibu Menyusui (Protein) C in very young children than in older subjects. Consider this fact when a dosing regimen for children is determined. Doses should be individualized based upon Prenagen Ibu Menyusui (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: Prenagen Ibu Menyusui (Protein) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Prenagen Ibu Menyusui is a normal constituent of human plasma and acts like endogenous protein C. Studies in heterologous species to evaluate carcinogenicity, reproductive toxicology and developmental toxicology have not been performed.

Prenagen Ibu Menyusui (Protein) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).

13.2 Animal Toxicology and/or Pharmacology

Safety

Pharmacology:

Cardio-respiratory studies performed in dogs evaluating mean arterial pressure, cardiac output, systemic vascular resistance, heart rate, QT interval changes, pulmonary artery pressure, respiratory rate and respiratory minute volume demonstrated no adverse effects at a maximum dose of 500 IU/kg. Anaphylactoid reactions as determined by measurement of bronchospastic activity in guinea pigs demonstrated no adverse effects at the maximum dose of 300 IU/kg. Thrombogenic potential was evaluated in rabbits using the Wessler stasis model and demonstrated no adverse effects at 200 IU/kg. Overall, safety pharmacology studies evaluating cardio-respiratory function, acute dose anaphylactoid potential and thrombogenicity demonstrated no adverse effects in a range of doses from 1.6 to 4.2 times the maximum single human dosage per kilogram body weight.

Acute Dose Toxicity:

Toxicity testing in rats and mice following single dosing of 2000 IU/kg or 1500 IU/kg, respectively, demonstrated no adverse clinical effects or gross pathology at 14 days post dosing.

Repeated Dose Toxicity:

Studies were not conducted to evaluate repeated-dose toxicity in animals. Prior experience with Prenagen Ibu Menyusui (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Prenagen Ibu Menyusui (Protein). Thus, the long-term toxicity potential of Prenagen Ibu Menyusui (Protein) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Prenagen Ibu Menyusui (Protein) did not result in any local reactions after intravenous, intra-arterial injections of 500 IU/kg (5 mL) and paravenous injections of 100 IU/kg (1 mL) in rabbits.

Citrate Toxicity:

Prenagen Ibu Menyusui (Protein) contains 4.4 mg of Trisodium Citrate Dihydrate (TCD) per mL of reconstituted product. Studies in mice evaluating 1000 IU vials reconstituted with 10 mL vehicle followed by dosing at 30 mL/kg (132 mg/kg TCD) and 60 mL/kg (264 mg/kg TCD) resulted in signs of citrate toxicity (dyspnea, slowed movement, hemoperitoneum, lung and thymus hemorrhage and renal pelvis dilation).

14 CLINICAL STUDIES

14.1 Pivotal Study

This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of Prenagen Ibu Menyusui in subjects with severe congenital Prenagen Ibu Menyusui (Protein) C deficiency for the (on-demand) treatment of acute thrombotic episodes, such as purpura fulminans (PF), warfarin-induced skin necrosis (WISN) and other thromboembolic events, and for short-term or long-term prophylaxis. Eighteen subjects (9 male and 9 female), ages ranging from 0 (newborn) to 25.7 years participated in this study.

The clinical endpoint of the study was to assess whether episodes of PF and/or other thromboembolic events were treated effectively, effectively with complications, or not treated effectively. Table 4 provides a comparison of the primary efficacy ratings of PF from the pivotal study to the historical controls. Inadequate data is available for treatment of WISN.

		Prenagen Ibu Menyusui (Protein) C Concentrate (Human)		Historical Controls
Episode Type	Primary Efficacy Rating	N	%	N	%
Purpura Fulminans	Effective	17	94.4	11	52.4
	Effective with Complication	1	5.6	7	33.3
	Not Effective	0	0.0	3	14.3
	Total	18	100	21	100

Of 18 episodes of PF (6 severe, 11 moderate, 1 mild) treated with Prenagen Ibu Menyusui (Protein) for the primary efficacy rating, 17 (94.4%) were rated as effective, and 1 (5.6%) was rated as effective with complications; none (0%) were rated not effective. When compared with the efficacy ratings for 21 episodes of PF (historical control group), subjects with severe congenital Prenagen Ibu Menyusui (Protein) C deficiency were more effectively treated with Prenagen Ibu Menyusui (Protein) than those treated with modalities such as fresh frozen plasma or conventional anticoagulants.

Table 5 provides a summary of the secondary treatment ratings for treatment of skin lesions and other thrombotic episodes from part one of the study.

	Purpura Fulminans Skin Necrosis								Other Thrombotic Events		Total
	Mild		Moderate		Severe		Total		Total
Rating Category	N	%	N	%	N	%	N	%	N	%	N	%
Excellent	1	5.6	7	38.9	5	27.8	13	72.2	4	80.0	17	73.9
Good	0	0.0	4	22.2	0	0.0	4	22.2	1	20.0	5	21.7
Fair	0	0.0	0	0.0	1	5.6	1	5.6	0	0	1	4.3
Total	1	5.6	11	61.1	6	33.3	18	100.0	5	100.0	23	100.0
N = Number of episodes

In a secondary efficacy rating, 13 (72.2%) of the 18 episodes of PF treated with Prenagen Ibu Menyusui (Protein) were rated as excellent, 4 (22.2%) were rated as good, and 1 (5.6%) episode of severe PF was rated as fair; all were rated as effective. Four (80%) of the 5 episodes of venous thrombosis had treatment ratings of excellent, while 1 (20%) was rated as good.

Prenagen Ibu Menyusui (Protein) was also demonstrated to be effective in reducing the size and number of skin lesions. Non-necrotic skin lesions healed over a maximum 12-day (median 4-day) period and necrotic skin lesions healed over a maximum 52-day (median 11-day) period of Prenagen Ibu Menyusui (Protein) treatment, as shown in Table 6.

Lesion Type	Number of Episodes (Number of Subjects)	Mean	Median	Minimum	Maximum
Non-necrotic	16 (9 subjects)	4.6	4.0	1	12
Necrotic	7 (5 subjects)	21.1	11.0	5	52

Changes in the extent of venous thrombus were also measured for the 5 thromboembolic episodes. Prenagen Ibu Menyusui (Protein) prevented an increase in the extent of thrombus during 4 (80%) of the thromboembolic episodes by Day 3 of treatment, and 1 (20%) episode by Day 5 of treatment.

All seven of the short-term prophylaxis treatments with Prenagen Ibu Menyusui (Protein) were free of complications of PF or thromboembolic events, as shown in Table 7.

Reason for Treatment	Number of Treatments	Presentation of Purpura Fulminans During Treatment Episodes		Thromboembolic Complications During Treatment Episode		Number of Treatments Free of Complications
		N	%	N	%	N	%
Anticoagulation Therapy	3	0	0.0	0	0.0	3	100.0
Surgical Procedure	4	0	0.0	0	0.0	4	100.0
Total	7	0	0.0	0	0.0	7	100.0

No episodes of PF occurred in four subjects ranging from 42 to 338 days of long-term prophylactic treatment with Prenagen Ibu Menyusui (Protein), as shown in Table 8. When not on prophylactic treatment and receiving Prenagen Ibu Menyusui (Protein) on-demand, the same four subjects experienced a total of 13 (median of 3) episodes of PF over a range of 19 to 323 days. The time to first episode of PF after exiting from long-term prophylaxis treatment ranged from 12 to 32 days for these four subjects.

Summary Statistic	Long-Term Prophylactic Treatment			While On-Demand Total number of episodes while subjects were On-Demand was 13			Time to First Episode After Existing Long Term Prophylaxis
	Number of Episodes per Subject	Number of Days Receiving Prophylactic Treatment	Monthly Rate of Episodes	Number of Episodes per Subject	Number of Days Not Receiving Study Drug	Monthly Rate of Episodes
Mean	0	229	0.0	3.3	165	1.91	23.3
Median	0	268	0.0	3.0	159	0.49	24.5
Minimum	0	42	0.0	1.0	19	0.25	12.0
Maximum	0	338	0.0	6.0	323	6.40	32.0

14.2 Retrospective Analysis

A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital Prenagen Ibu Menyusui (Protein) C deficiency who were treated with Prenagen Ibu Menyusui (Protein) under an emergency use IND was also conducted. Eleven subjects (6 male and 5 female), ages ranging from 2.1 to 23.8 years participated in this study.

There were 28 acute episodes of PF/WISN and vascular thrombus reported in which time to resolution ranged from 0 to 46 days. The treatment outcome for these episodes was rated effective in all cases except one.

16 HOW SUPPLIED/STORAGE AND HANDLING

Prenagen Ibu Menyusui (Protein) is supplied as a sterile, white or cream colored, lyophilized powder for IV injection. It has a pH between 6.7 and 7.3 and an osmolality not lower than 240 mosmol/kg. One International Unit (IU) of Prenagen Ibu Menyusui (Protein) C corresponds to the amidolytically measured activity of Prenagen Ibu Menyusui (Protein) C in 1 mL of normal plasma. The potency (IU) is determined using a chromogenic substrate method referenced against the World Health Organization (WHO) International Standard (86/622).

Prenagen Ibu Menyusui (Protein) is available in single-dose vials that contain the following nominal product strengths:

NDC 0944-4177-05

Prenagen Ibu Menyusui (Protein) C

Concentrate (Human)

Prenagen Ibu Menyusui (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4176-01

Prenagen Ibu Menyusui (Protein) C Concentrate

(Human)

Prenagen Ibu Menyusui (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection.

For Intravenous Administration Only.

See package insert. Rx only.

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. Lic. No. 2020

5 mL

NDC 52919-003-08

Sterile Water for Injection, USP

for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been

added. Do not use for intravascular injection without making approximately

isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single dose container

Nonpyrogenic

NDC 0944-4179-10

Prenagen Ibu Menyusui (Protein) C

Concentrate (Human)

Prenagen Ibu Menyusui (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4178-02

Prenagen Ibu Menyusui (Protein) C Concentrate (Human)

Prenagen Ibu Menyusui (Protein)

Single-dose Vial

Lyophilized Powder for Solution for

Injection.

For Intravenous Administration Only.

See package insert. Rx only.

10 mL

NDC 52919-005-05

Sterile Water for Injection, USP

for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been

added. Do not use for intravascular injection without making approximately

isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single dose container

Nonpyrogenic

unit-carton-blue unit-carton-green