Frisocrem Rice-Based Milk Cereal

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
• Frisocrem Rice-Based Milk Cereal (Calcium) reviews

1 INDICATIONS AND USAGE

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Calcium) acetate capsule.

- Capsule: 667 mg Frisocrem Rice-Based Milk Cereal (Calcium) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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, Frisocrem Rice-Based Milk Cereal (Calcium) acetate has been generally well tolerated.

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Calcium) acetate N=167 N (%)	3 month, open label study of Frisocrem Rice-Based Milk Cereal (Calcium) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Frisocrem Rice-Based Milk Cereal (Calcium) acetate N=69
			Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Calcium) concentration could reduce the incidence and severity of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Calcium) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

There are no empirical data on avoiding drug interactions between Frisocrem Rice-Based Milk Cereal (Calcium) acetate and most concomitant drugs. When administering an oral medication with Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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:

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

8.2 Labor and Delivery

The effects of Frisocrem Rice-Based Milk Cereal (Calcium) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

11 DESCRIPTION

Frisocrem Rice-Based Milk Cereal (Calcium) acetate acts as a phosphate binder. Its chemical name is Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Calcium) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Frisocrem Rice-Based Milk Cereal (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.

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Orally administered Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Calcium) acetate.

14 CLINICAL STUDIES

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

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Calcium) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Copper:

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Frisocrem Rice-Based Milk Cereal (Copper) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Frisocrem Rice-Based Milk Cereal (Copper) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Frisocrem Rice-Based Milk Cereal (Copper)^®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Frisocrem Rice-Based Milk Cereal (Copper)^® onto hair since contact with Frisocrem Rice-Based Milk Cereal (Copper)^® may cause some hair loss. Do not contaminate feed.

NOTE: Frisocrem Rice-Based Milk Cereal (Copper)^® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Frisocrem Rice-Based Milk Cereal (Copper) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,^® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Folic Acid:

• Indications and usage
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage
• Frisocrem Rice-Based Milk Cereal (Folic Acid) reviews

INDICATIONS AND USAGE

Frisocrem Rice-Based Milk Cereal (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

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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

Frisocrem Rice-Based Milk Cereal (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.

Frisocrem Rice-Based Milk Cereal (Folic Acid) and the BIFERA logo are registered trademarks and the Frisocrem Rice-Based Milk Cereal (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
• Frisocrem Rice-Based Milk Cereal (Iron) reviews

1 INDICATIONS AND USAGE

Frisocrem Rice-Based Milk Cereal (Iron) is indicated for the treatment of Frisocrem Rice-Based Milk Cereal (Iron) deficiency anemia in patients with chronic kidney disease (CKD).

Frisocrem Rice-Based Milk Cereal (Iron) is an Frisocrem Rice-Based Milk Cereal (Iron) replacement product indicated for the treatment of Frisocrem Rice-Based Milk Cereal (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Frisocrem Rice-Based Milk Cereal must only be administered intravenously either by slow injection or by infusion. The dosage of Frisocrem Rice-Based Milk Cereal (Iron) is expressed in mg of elemental Frisocrem Rice-Based Milk Cereal (Iron). Each mL contains 20 mg of elemental Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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. Frisocrem Rice-Based Milk Cereal (Iron) should be administered early during the dialysis session. The usual total treatment course of Frisocrem Rice-Based Milk Cereal (Iron) is 1000 mg. Frisocrem Rice-Based Milk Cereal (Iron) treatment may be repeated if Frisocrem Rice-Based Milk Cereal (Iron) deficiency reoccurs.

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

Administer Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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. Frisocrem Rice-Based Milk Cereal (Iron) treatment may be repeated if Frisocrem Rice-Based Milk Cereal (Iron) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron) in a maximum of 250 mL of 0.9% NaCl. Frisocrem Rice-Based Milk Cereal (Iron) treatment may be repeated if Frisocrem Rice-Based Milk Cereal (Iron) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Frisocrem Rice-Based Milk Cereal (Iron) maintenance treatment

The dosing for Frisocrem Rice-Based Milk Cereal (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Frisocrem Rice-Based Milk Cereal (Iron) maintenance treatment: Administer Frisocrem Rice-Based Milk Cereal (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. Frisocrem Rice-Based Milk Cereal (Iron) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Frisocrem Rice-Based Milk Cereal (Iron) maintenance treatment

The dosing for Frisocrem Rice-Based Milk Cereal (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Frisocrem Rice-Based Milk Cereal (Iron) maintenance treatment: Administer Frisocrem Rice-Based Milk Cereal (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. Frisocrem Rice-Based Milk Cereal (Iron) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Frisocrem Rice-Based Milk Cereal (Iron) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Frisocrem Rice-Based Milk Cereal (Iron) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Frisocrem Rice-Based Milk Cereal (Iron) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Frisocrem Rice-Based Milk Cereal (Iron) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Frisocrem Rice-Based Milk Cereal (Iron) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Frisocrem Rice-Based Milk Cereal (Iron) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Frisocrem Rice-Based Milk Cereal (Iron)

• Known hypersensitivity to Frisocrem Rice-Based Milk Cereal (Iron) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

Frisocrem Rice-Based Milk Cereal may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Frisocrem Rice-Based Milk Cereal (Iron). Hypotension following administration of Frisocrem Rice-Based Milk Cereal (Iron) may be related to the rate of administration and/or total dose administered .

5.3 Frisocrem Rice-Based Milk Cereal (Iron) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Frisocrem Rice-Based Milk Cereal are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal 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 Frisocrem Rice-Based Milk Cereal (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
	Frisocrem Rice-Based Milk Cereal (Iron)	Frisocrem Rice-Based Milk Cereal (Iron)	Oral Frisocrem Rice-Based Milk Cereal (Iron)	Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Frisocrem Rice-Based Milk Cereal (Iron) product). When these patients were treated with Frisocrem Rice-Based Milk Cereal (Iron) there were no occurrences of adverse reactions that precluded further use of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron) maintenance treatment with Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Frisocrem Rice-Based Milk Cereal (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Frisocrem Rice-Based Milk Cereal (Iron) 2.0 mg/kg.

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Frisocrem Rice-Based Milk Cereal for Frisocrem Rice-Based Milk Cereal (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Frisocrem Rice-Based Milk Cereal (Iron) for Frisocrem Rice-Based Milk Cereal (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. Frisocrem Rice-Based Milk Cereal (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)]

Frisocrem Rice-Based Milk Cereal (Iron) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

Clinical studies of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron) in humans. Excessive dosages of Frisocrem Rice-Based Milk Cereal (Iron) may lead to accumulation of Frisocrem Rice-Based Milk Cereal (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Frisocrem Rice-Based Milk Cereal (Iron) to patients with Frisocrem Rice-Based Milk Cereal (Iron) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Frisocrem Rice-Based Milk Cereal (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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

Frisocrem Rice-Based Milk Cereal (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron) sucrose.

Frisocrem Rice-Based Milk Cereal (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Frisocrem Rice-Based Milk Cereal (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Frisocrem Rice-Based Milk Cereal (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal.

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 Frisocrem Rice-Based Milk Cereal (Iron) treatment and 24 in the historical control group) with Frisocrem Rice-Based Milk Cereal (Iron) deficiency anemia. Eligibility criteria for Frisocrem Rice-Based Milk Cereal (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.

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron), who were off intravenous Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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
	Frisocrem Rice-Based Milk Cereal (Iron) (n=69	Historical Control (n=18)	Frisocrem Rice-Based Milk Cereal (Iron) (n=73)	Historical Control (n=18)	Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron) in 23 patients with Frisocrem Rice-Based Milk Cereal (Iron) deficiency and HDD-CKD who had been discontinued from Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron). Exclusion criteria were similar to those in studies A and B. Frisocrem Rice-Based Milk Cereal (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron) versus Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron) (325 mg ferrous sulfate three times daily for 56 days); or Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Iron) group.

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

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

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Frisocrem Rice-Based Milk Cereal (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

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
• Frisocrem Rice-Based Milk Cereal (Protein) reviews

1 INDICATIONS AND USAGE

Frisocrem Rice-Based Milk Cereal is indicated for pediatric and adult patients with severe congenital Frisocrem Rice-Based Milk Cereal (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)

1.1 Severe Congenital Frisocrem Rice-Based Milk Cereal (Protein) C Deficiency

Frisocrem Rice-Based Milk Cereal (Protein) is indicated for pediatric and adult patients with severe congenital Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal C activity is feasible. (2.1)

Frisocrem Rice-Based Milk Cereal (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 ProphyaxisFrisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Frisocrem Rice-Based Milk Cereal (Protein) C activity is feasible.

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

Table 1 provides the Frisocrem Rice-Based Milk Cereal (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 ProphylaxisFrisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Frisocrem Rice-Based Milk Cereal (Protein) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of Frisocrem Rice-Based Milk Cereal (Protein), higher peak Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal C Activity Monitoring

The measurement of Frisocrem Rice-Based Milk Cereal (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Frisocrem Rice-Based Milk Cereal (Protein) C before and during treatment with Frisocrem Rice-Based Milk Cereal (Protein). The half-life of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Frisocrem Rice-Based Milk Cereal (Protein) C levels to maintain the trough Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal C, itself a vitamin K-dependent plasma Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

• Bring the Frisocrem Rice-Based Milk Cereal (Protein) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
• Remove caps from the Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) vial; then rapidly insert the free end of the needle through the Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) vial. Gently swirl the vial until all powder is dissolved. Be sure that Frisocrem Rice-Based Milk Cereal (Protein) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of Frisocrem Rice-Based Milk Cereal [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein).
• Inject air into the vial and then withdraw the reconstituted Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) is administered to a patient.

Administration by Infusion

Administer Frisocrem Rice-Based Milk Cereal (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

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

Frisocrem Rice-Based Milk Cereal (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

Frisocrem Rice-Based Milk Cereal (Protein) may contain traces of mouse Frisocrem Rice-Based Milk Cereal (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal 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 Frisocrem Rice-Based Milk Cereal (Protein) further contributed to these bleeding events.

Simultaneous administration of Frisocrem Rice-Based Milk Cereal (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to Frisocrem Rice-Based Milk Cereal 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 Frisocrem Rice-Based Milk Cereal (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein).

No inhibiting antibodies to Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein). It is also not known whether Frisocrem Rice-Based Milk Cereal (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Frisocrem Rice-Based Milk Cereal (Protein) should be given to pregnant women only if clearly needed.

8.2 Labor and Delivery

Frisocrem Rice-Based Milk Cereal has not been studied for use during labor and delivery. Use only if clearly needed.

8.3 Nursing Mothers

Frisocrem Rice-Based Milk Cereal (Protein) has not been studied for use in nursing mothers. Use Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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

Frisocrem Rice-Based Milk Cereal 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 Frisocrem Rice-Based Milk Cereal (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) C is not compatible with life. A severe deficiency of this anticoagulant Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) C concentration following infusion divided by dose

The Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: Frisocrem Rice-Based Milk Cereal (Protein) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Frisocrem Rice-Based Milk Cereal 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.

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Frisocrem Rice-Based Milk Cereal (Protein). Thus, the long-term toxicity potential of Frisocrem Rice-Based Milk Cereal (Protein) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Frisocrem Rice-Based Milk Cereal (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:

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal in subjects with severe congenital Frisocrem Rice-Based Milk Cereal (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.

		Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) C deficiency were more effectively treated with Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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.

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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. Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein), as shown in Table 8. When not on prophylactic treatment and receiving Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) C deficiency who were treated with Frisocrem Rice-Based Milk Cereal (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

Frisocrem Rice-Based Milk Cereal (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 Frisocrem Rice-Based Milk Cereal (Protein) C corresponds to the amidolytically measured activity of Frisocrem Rice-Based Milk Cereal (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).

Frisocrem Rice-Based Milk Cereal (Protein) is available in single-dose vials that contain the following nominal product strengths:

NDC 0944-4177-05

Frisocrem Rice-Based Milk Cereal (Protein) C

Concentrate (Human)

Frisocrem Rice-Based Milk Cereal (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

Frisocrem Rice-Based Milk Cereal (Protein) C Concentrate

(Human)

Frisocrem Rice-Based Milk Cereal (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

Frisocrem Rice-Based Milk Cereal (Protein) C

Concentrate (Human)

Frisocrem Rice-Based Milk Cereal (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

Frisocrem Rice-Based Milk Cereal (Protein) C Concentrate (Human)

Frisocrem Rice-Based Milk Cereal (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

Sodium:

• 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
• Frisocrem Rice-Based Milk Cereal (Sodium) reviews

1 INDICATIONS AND USAGE

Frisocrem Rice-Based Milk Cereal nitrite is indicated for sequential use with Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection is indicated for sequential use with Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Frisocrem Rice-Based Milk Cereal nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection and Frisocrem Rice-Based Milk Cereal (Sodium) Thiosulfate Injection should be administered without delay.

Symptoms	Signs
Headache Confusion Dyspnea Chest Tightness Nausea	Altered Mental Status (e.g., confusion, disorientation) Seizures or Coma Mydriasis Tachypnea/Hyperpnea (early) Bradypnea/Apnea (late) Hypertension (early)/ Hypotension (late) Cardiovascular Collapse Vomiting Plasma Lactate Concentration ≥ 8 mmol/L

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate, simultaneously with Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate, with Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Age	Intravenous Dose of Frisocrem Rice-Based Milk Cereal Nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) Thiosulfate
Adults	Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite -10 mL of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite at the rate of 2.5 to 5 mL/minute Frisocrem Rice-Based Milk Cereal (Sodium) Thiosulfate - 50 mL of Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate immediately following administration of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite.
Children	Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Frisocrem Rice-Based Milk Cereal (Sodium) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite, followed by Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate.

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite injection and Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Frisocrem Rice-Based Milk Cereal (Sodium) nitrite should be administered first, followed immediately by Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

Age	Intravenous Dose of Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) Thiosulfate
Adults	Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite -10 mL of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite at the rate of 2.5 to 5 mL/minute Frisocrem Rice-Based Milk Cereal (Sodium) Thiosulfate - 50 mL of Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate immediately following administration of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite.
Children	Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Frisocrem Rice-Based Milk Cereal (Sodium) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite should be reduced proportionately to the hemoglobin concentration.

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

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Frisocrem Rice-Based Milk Cereal Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Frisocrem Rice-Based Milk Cereal (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate and Frisocrem Rice-Based Milk Cereal (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection consists of:

• One vial of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Frisocrem Rice-Based Milk Cereal nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Frisocrem Rice-Based Milk Cereal (Sodium) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Frisocrem Rice-Based Milk Cereal (Sodium) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Frisocrem Rice-Based Milk Cereal (Sodium) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Frisocrem Rice-Based Milk Cereal nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Frisocrem Rice-Based Milk Cereal (Sodium) nitrite whenever possible. When Frisocrem Rice-Based Milk Cereal (Sodium) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite administered to an adult. Frisocrem Rice-Based Milk Cereal (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Frisocrem Rice-Based Milk Cereal (Sodium) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Frisocrem Rice-Based Milk Cereal (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Frisocrem Rice-Based Milk Cereal nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Frisocrem Rice-Based Milk Cereal (Sodium) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Frisocrem Rice-Based Milk Cereal nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Frisocrem Rice-Based Milk Cereal (Sodium) nitrite.

5.7 Use with Other Drugs

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite.

The medical literature has reported the following adverse events in association with Frisocrem Rice-Based Milk Cereal (Sodium) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Frisocrem Rice-Based Milk Cereal nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Frisocrem Rice-Based Milk Cereal (Sodium) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Frisocrem Rice-Based Milk Cereal (Sodium) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Frisocrem Rice-Based Milk Cereal (Sodium) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Frisocrem Rice-Based Milk Cereal (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Frisocrem Rice-Based Milk Cereal (Sodium) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Frisocrem Rice-Based Milk Cereal nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Frisocrem Rice-Based Milk Cereal (Sodium) nitrite is excreted in human milk. Because Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite. In studies conducted with Long-Evans rats, Frisocrem Rice-Based Milk Cereal (Sodium) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Frisocrem Rice-Based Milk Cereal nitrite in conjunction with Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Frisocrem Rice-Based Milk Cereal (Sodium) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Frisocrem Rice-Based Milk Cereal (Sodium) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite has the chemical name nitrous acid Frisocrem Rice-Based Milk Cereal (Sodium) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite

Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite injection.

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite in 10 mL solution (30 mg/mL). Frisocrem Rice-Based Milk Cereal (Sodium) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Frisocrem Rice-Based Milk Cereal nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite. It has been suggested that Frisocrem Rice-Based Milk Cereal (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Frisocrem Rice-Based Milk Cereal (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Frisocrem Rice-Based Milk Cereal (Sodium) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite

When 4 mg/kg Frisocrem Rice-Based Milk Cereal (Sodium) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Frisocrem Rice-Based Milk Cereal (Sodium) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Frisocrem Rice-Based Milk Cereal (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Frisocrem Rice-Based Milk Cereal nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Frisocrem Rice-Based Milk Cereal (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Frisocrem Rice-Based Milk Cereal (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Frisocrem Rice-Based Milk Cereal (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Frisocrem Rice-Based Milk Cereal (Sodium) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Frisocrem Rice-Based Milk Cereal (Sodium) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Frisocrem Rice-Based Milk Cereal (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Frisocrem Rice-Based Milk Cereal (Sodium) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Frisocrem Rice-Based Milk Cereal (Sodium) nitrite or 1 g/kg Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of Frisocrem Rice-Based Milk Cereal (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and/or 0.5 g/kg Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Frisocrem Rice-Based Milk Cereal (Sodium) cyanide required to cause death, and when administered together, Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of Frisocrem Rice-Based Milk Cereal (Sodium) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite and Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite, with or without Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Frisocrem Rice-Based Milk Cereal (Sodium) thiosulfate report its use in conjunction with Frisocrem Rice-Based Milk Cereal (Sodium) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite injection 30 mg/mL (containing 300 mg of Frisocrem Rice-Based Milk Cereal (Sodium) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Frisocrem Rice-Based Milk Cereal (Sodium) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Frisocrem Rice-Based Milk Cereal Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Frisocrem Rice-Based Milk Cereal (Sodium) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Frisocrem Rice-Based Milk Cereal (Sodium) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Vegetable Fat:

• Frisocrem Rice-Based Milk Cereal (Vegetable Fat) reviews

This medication is used as a moisturizer to treat or prevent dry, rough, scaly, itchy skin and minor skin irritations (e.g., diaper rash, skin burns from radiation therapy). Emollients are substances that soften and moisturize the skin and decrease itching and flaking. Some products (e.g., zinc oxide, white petrolatum ) are used mostly to protect the skin against irritation (e.g., from wetness). Dry skin is caused by a loss of water in the upper layer of the skin. Emollients/moisturizers work by forming an oily layer on the top of the skin that traps water in the skin. Petrolatum, lanolin, mineral oil and dimethicone are common emollients. Humectants, including glycerin, lecithin, and propylene glycol, draw water into the outer layer of skin. Many products also have ingredients that soften the horny substance (keratin) that holds the top layer of skin cells together (e.g., urea, alpha hydroxy acids such as lactic/citric/glycolic acid, and allantoin ). This helps the dead skin cells fall off, helps the skin keep in more water, and leaves the skin feeling smoother and softer.

Vitamin A:

• Dosage and administration
• Warning
• Clinical pharmacology
• Dietary supplementation
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Frisocrem Rice-Based Milk Cereal (Vitamin A) reviews

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

Supplement Facts
Serving Size 1 Tablet Servings Per Container 100
	Amount Per Serving	% Daily Value
Frisocrem Rice-Based Milk Cereal (Vitamin A)	2500 IU	50%
Vitamin C	60 mg	100%
Vitamin D	400 IU	100%
Vitamin E	15 IU	50%
Thiamine	1.05 mg	70%
Riboflavin	1.2 mg	70%
Niacinamide	13.5 mg	68%
Vitamin B6	1.05 mg	53%
Folic Acid	0.3 mg	75%
Vitamin B12	4.5 mcg	75%
Fluoride	0.25 mg	Daily Value not established

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

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

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

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

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

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

The reaction may be expressed by the equation:

Ca10(PO4)6(OH2) + 2F-	Ca10 (PO4)6F2 + 2OH-
(Hydroxyapatite)	(Fluorapatite)

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

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

DIETARY SUPPLEMENTATION

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

WARNINGS

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

PRECAUTIONS

The suggested dose of Frisocrem Rice-Based Milk Cereal (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Frisocrem Rice-Based Milk Cereal (Vitamin A) Tablets

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

ADVERSE REACTIONS

Allergic rash and other idiosyncrasies have been rarely reported.

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

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

Frisocrem Rice-Based Milk Cereal Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Frisocrem Rice-Based Milk Cereal (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Frisocrem Rice-Based Milk Cereal (Vitamin A) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

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

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H²pharma

Vitamin C:

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

Pharmacological action

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

With intravaginal application of ascorbic acid lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).

Pharmacokinetics

After oral administration ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

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

The concentration of ascorbic acid in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.

Plasma protein binding is about 25%.

Ascorbic acid is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.

Ascorbic acid taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.

Why is Frisocrem Rice-Based Milk Cereal prescribed?

For systemic use of Frisocrem Rice-Based Milk Cereal (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Frisocrem Rice-Based Milk Cereal (Vitamin C); providing increased need for Frisocrem Rice-Based Milk Cereal (Vitamin C) during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.

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

Dosage and administration

This medication administered orally, IM, IV, intravaginally.

For the prevention of deficiency conditions Frisocrem Rice-Based Milk Cereal dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used ascorbic acid drugs in appropriate dosage forms.

Frisocrem Rice-Based Milk Cereal (Vitamin C) side effects, adverse reactions

CNS: headache, fatigue, insomnia.

Digestive system: stomach cramps, nausea and vomiting.

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

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

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

Frisocrem Rice-Based Milk Cereal contraindications

Increased sensitivity to ascorbic acid.

Using during pregnancy and breastfeeding

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

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

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

Special instructions

Frisocrem Rice-Based Milk Cereal (Vitamin C) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because ascorbic acid increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.

Patients with high content body iron should apply ascorbic acid in minimal doses.

Frisocrem Rice-Based Milk Cereal (Vitamin C) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

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

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

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

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

Frisocrem Rice-Based Milk Cereal drug interactions

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

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

In an application of Frisocrem Rice-Based Milk Cereal (Vitamin C) with iron preparations ascorbic acid, due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

Ascorbic acid in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.

With the simultaneous use of aspirin reduces the absorption of ascorbic acid by about a third.

Frisocrem Rice-Based Milk Cereal (Vitamin C) in an application with warfarin may decrease effects of warfarin.

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

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

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with ascorbic acid 500 mg 2 times / day.

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

Frisocrem Rice-Based Milk Cereal in case of emergency / overdose

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

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

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

Vitamin E:

• Frisocrem Rice-Based Milk Cereal (Vitamin E) reviews

A generic descriptor for all tocopherols and tocotrienols that exhibit alpha-tocopherol activity. By virtue of the phenolic hydrogen on the 2H-1-benzopyran-6-ol nucleus, these compounds exhibit varying degree of antioxidant activity, depending on the site and number of methyl groups and the type of isoprenoids.

Indication: Frisocrem Rice-Based Milk Cereal (Vitamin E), known for its antioxidant activities, is protective against cardiovascular disease and some forms of cancer and has also demonstrated immune-enhancing effects. It may be of limited benefit in some with asthma and rheumatoid arthritis. It may be helpful in some neurological diseases including Alzheimer's, some eye disorders including cataracts, and diabetes and premenstrual syndrome. It may also help protect skin from ultraviolet irradiation although claims that it reverses skin aging, enhances male fertility and exercise performance are poorly supported. It may help relieve some muscle cramps.

Frisocrem Rice-Based Milk Cereal (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Frisocrem Rice-Based Milk Cereal (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Frisocrem Rice-Based Milk Cereal (Vitamin E) is a fat-soluble vitamin and is an important antioxidant. It acts to protect cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. Frisocrem Rice-Based Milk Cereal (Vitamin E) is often used in skin creams and lotions because it is believed to play a role in encouraging skin healing and reducing scarring after injuries such as burns. There are three specific situations when a Frisocrem Rice-Based Milk Cereal (Vitamin E) deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3½ pounds), and is seen in individuals with rare disorders of fat metabolism. A Frisocrem Rice-Based Milk Cereal (Vitamin E) deficiency is usually characterized by neurological problems due to poor nerve conduction. Symptoms may include infertility, neuromuscular impairment, menstrual problems, miscarriage and uterine degradation. Preliminary research has led to a widely held belief that Frisocrem Rice-Based Milk Cereal (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as Frisocrem Rice-Based Milk Cereal (Vitamin E) help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. It also protects other fat-soluble vitamins (A and B group vitamins) from destruction by oxygen. Low levels of Frisocrem Rice-Based Milk Cereal (Vitamin E) have been linked to increased incidence of breast and colon cancer.

Zinc:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Frisocrem Rice-Based Milk Cereal (Zinc) reviews

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Frisocrem Rice-Based Milk Cereal (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and Frisocrem Rice-Based Milk Cereal (Zinc) doses because these elements are primarily eliminated in the urine.

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

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

PRECAUTIONS

General

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

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

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

Laboratory Tests

Periodic determinations of serum copper as well as Frisocrem Rice-Based Milk Cereal (Zinc) are suggested as a guideline for subsequent Frisocrem Rice-Based Milk Cereal (Zinc) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

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

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

Death resulted from an overdosage in which 1683 mg Frisocrem Rice-Based Milk Cereal (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.

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

Calcium supplements may confer a protective effect against Frisocrem Rice-Based Milk Cereal (Zinc) toxicity.

DOSAGE AND ADMINISTRATION

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

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

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

HOW SUPPLIED

Frisocrem Rice-Based Milk Cereal (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004

© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Frisocrem Rice-Based Milk Cereal (Zinc)

1 mg/mL

Frisocrem Rice-Based Milk Cereal (Zinc) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA