Phenyl-Free 1

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
• Phenyl-Free 1 (Calcium) reviews

1 INDICATIONS AND USAGE

Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) acetate capsule.

- Capsule: 667 mg Phenyl-Free 1 (Calcium) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Phenyl-Free 1 acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium), including Phenyl-Free 1 (Calcium) acetate. Avoid the use of Phenyl-Free 1 (Calcium) supplements, including Phenyl-Free 1 (Calcium) based nonprescription antacids, concurrently with Phenyl-Free 1 (Calcium) acetate.

An overdose of Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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, Phenyl-Free 1 (Calcium) acetate has been generally well tolerated.

Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) acetate N=167 N (%)	3 month, open label study of Phenyl-Free 1 (Calcium) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Phenyl-Free 1 (Calcium) acetate N=69
			Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) concentration could reduce the incidence and severity of Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Phenyl-Free 1 acetate is characterized by the potential of Phenyl-Free 1 (Calcium) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Phenyl-Free 1 (Calcium) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Phenyl-Free 1 (Calcium) acetate and most concomitant drugs. When administering an oral medication with Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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:

Phenyl-Free 1 acetate capsules contains Phenyl-Free 1 (Calcium) acetate. Animal reproduction studies have not been conducted with Phenyl-Free 1 (Calcium) acetate, and there are no adequate and well controlled studies of Phenyl-Free 1 (Calcium) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Phenyl-Free 1 (Calcium) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Phenyl-Free 1 (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. Phenyl-Free 1 (Calcium) acetate treatment, as recommended, is not expected to harm a fetus if maternal Phenyl-Free 1 (Calcium) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Phenyl-Free 1 (Calcium) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Phenyl-Free 1 Acetate Capsules contains Phenyl-Free 1 (Calcium) acetate and is excreted in human milk. Human milk feeding by a mother receiving Phenyl-Free 1 (Calcium) acetate is not expected to harm an infant, provided maternal serum Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Phenyl-Free 1 (Calcium) acetate acts as a phosphate binder. Its chemical name is Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Phenyl-Free 1 (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.

Phenyl-Free 1 (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 Phenyl-Free 1 resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Phenyl-Free 1 (Calcium) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Phenyl-Free 1 (Calcium) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) acetate.

14 CLINICAL STUDIES

Effectiveness of Phenyl-Free 1 (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Phenyl-Free 1 (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
Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) acetate is shown in the Table 3.

* ANOVA of Phenyl-Free 1 (Calcium) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Phenyl-Free 1 (Calcium) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Phenyl-Free 1 (Calcium) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with Phenyl-Free 1 (Calcium) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Phenyl-Free 1 (Calcium) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Phenyl-Free 1 (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 Phenyl-Free 1 (Calcium) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Choline:

• Phenyl-Free 1 (Choline) reviews

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

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

This compound is needed for good nerve conduction throughout the CNS (central nervous system) as it is a precursor to acetylcholine (ACh). Phenyl-Free 1 (Choline) is also needed for gallbladder regulation, liver function and lecithin (a key lipid) formation. Phenyl-Free 1 (Choline) also aids in fat and cholesterol metabolism and prevents excessive fat build up in the liver. Phenyl-Free 1 (Choline) has been used to mitigate the effects of Parkinsonism and tardive dyskinesia. Phenyl-Free 1 (Choline) deficiencies may result in excessive build-up of fat in the liver, high blood pressure, gastric ulcers, kidney and liver dysfunction and stunted growth.

Copper:

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Phenyl-Free 1 (Copper) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Phenyl-Free 1 (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 Phenyl-Free 1 (Copper)^®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Phenyl-Free 1 (Copper)^® onto hair since contact with Phenyl-Free 1 (Copper)^® may cause some hair loss. Do not contaminate feed.

NOTE: Phenyl-Free 1 (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:

Phenyl-Free 1 (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
• Phenyl-Free 1 (Folic Acid) reviews

INDICATIONS AND USAGE

Phenyl-Free 1 (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

Phenyl-Free 1 (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 Phenyl-Free 1 (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

Phenyl-Free 1 (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.

Phenyl-Free 1 (Folic Acid) and the BIFERA logo are registered trademarks and the Phenyl-Free 1 (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

Inositol:

• Phenyl-Free 1 (Inositol) reviews

Niacin is used with a proper diet and exercise program to help lower "bad" cholesterol and fats ( LDL, triglycerides ) and raise "good" cholesterol (HDL) in the blood. It is generally used after non-drug treatments have not been fully successful at lowering cholesterol. Niacin is also known as vitamin B-3 ( nicotinic acid ), one of the B-complex vitamins. It may be used with or without other medications. Lowering "bad" cholesterol/triglycerides and raising "good" cholesterol helps prevent strokes and heart attacks. Lowering fats may also help reduce the risk of pancreas problems ( pancreatitis ) in people at risk. In addition to eating a proper diet (such as a low-cholesterol/low-fat diet), other lifestyle changes that may help this medication work better include exercising, losing weight if overweight, and stopping smoking. Consult your doctor for more details.

Iodine:

• Iodine tincture 7%
• Iodine tincture 7%
• Phenyl-Free 1 (Iodine) reviews

Phenyl-Free 1 Tincture 7%

Directions:

Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Phenyl-Free 1 (Iodine) with a swab.

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

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

Do not apply under bandage.

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

Storage:

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

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

DANGER - Poison

Caution:

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

activated charcoal. A 5% solutions of sodium thiosulfate

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

rate of 10 ml per kilogram of body weight.

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

Avoid contamination of food.

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

Phenyl-Free 1 Tincture 7%

image description

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
• Phenyl-Free 1 (Iron) reviews

1 INDICATIONS AND USAGE

Phenyl-Free 1 (Iron) is indicated for the treatment of Phenyl-Free 1 (Iron) deficiency anemia in patients with chronic kidney disease (CKD).

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

2 DOSAGE AND ADMINISTRATION

Phenyl-Free 1 must only be administered intravenously either by slow injection or by infusion. The dosage of Phenyl-Free 1 (Iron) is expressed in mg of elemental Phenyl-Free 1 (Iron). Each mL contains 20 mg of elemental Phenyl-Free 1 (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 Phenyl-Free 1 (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. Phenyl-Free 1 (Iron) should be administered early during the dialysis session. The usual total treatment course of Phenyl-Free 1 (Iron) is 1000 mg. Phenyl-Free 1 (Iron) treatment may be repeated if Phenyl-Free 1 (Iron) deficiency reoccurs.

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

Administer Phenyl-Free 1 (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 Phenyl-Free 1 (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. Phenyl-Free 1 (Iron) treatment may be repeated if Phenyl-Free 1 (Iron) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) in a maximum of 250 mL of 0.9% NaCl. Phenyl-Free 1 (Iron) treatment may be repeated if Phenyl-Free 1 (Iron) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Phenyl-Free 1 (Iron) maintenance treatment

The dosing for Phenyl-Free 1 (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Phenyl-Free 1 (Iron) maintenance treatment: Administer Phenyl-Free 1 (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. Phenyl-Free 1 (Iron) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Phenyl-Free 1 (Iron) maintenance treatment

The dosing for Phenyl-Free 1 (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Phenyl-Free 1 (Iron) maintenance treatment: Administer Phenyl-Free 1 (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. Phenyl-Free 1 (Iron) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Phenyl-Free 1 (Iron) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Phenyl-Free 1 (Iron) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Phenyl-Free 1 (Iron) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Phenyl-Free 1 (Iron) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Phenyl-Free 1 (Iron) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Phenyl-Free 1 (Iron) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Phenyl-Free 1 (Iron)

• Known hypersensitivity to Phenyl-Free 1 (Iron) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Phenyl-Free 1 administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Phenyl-Free 1 (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Phenyl-Free 1 (Iron) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Phenyl-Free 1 (Iron). (5.2)
• Phenyl-Free 1 (Iron) Overload: Regularly monitor hematologic responses during Phenyl-Free 1 (Iron) therapy. Do not administer Phenyl-Free 1 (Iron) to patients with Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Phenyl-Free 1 (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Phenyl-Free 1 (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Phenyl-Free 1 (Iron) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Phenyl-Free 1 may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Phenyl-Free 1 (Iron). Hypotension following administration of Phenyl-Free 1 (Iron) may be related to the rate of administration and/or total dose administered .

5.3 Phenyl-Free 1 (Iron) Overload

Excessive therapy with parenteral Phenyl-Free 1 (Iron) can lead to excess storage of Phenyl-Free 1 (Iron) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Phenyl-Free 1 (Iron) require periodic monitoring of hematologic and Phenyl-Free 1 (Iron) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Phenyl-Free 1 (Iron) to patients with evidence of Phenyl-Free 1 (Iron) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Phenyl-Free 1 (Iron) sucrose; do not perform serum Phenyl-Free 1 (Iron) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Phenyl-Free 1 are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Phenyl-Free 1 (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 Phenyl-Free 1 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 Phenyl-Free 1 (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
	Phenyl-Free 1 (Iron)	Phenyl-Free 1 (Iron)	Oral Phenyl-Free 1 (Iron)	Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Phenyl-Free 1 (Iron) product). When these patients were treated with Phenyl-Free 1 (Iron) there were no occurrences of adverse reactions that precluded further use of Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) maintenance treatment with Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Phenyl-Free 1 (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Phenyl-Free 1 (Iron) 2.0 mg/kg.

A total of 5 (11%) subjects in the Phenyl-Free 1 (Iron) 0.5 mg/kg group, 10 (21%) patients in the Phenyl-Free 1 (Iron) 1.0 mg/kg group, and 10 (21%) patients in the Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) injection. Reactions have occurred following the first dose or subsequent doses of Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) have not been studied. However, Phenyl-Free 1 (Iron) may reduce the absorption of concomitantly administered oral Phenyl-Free 1 (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, Phenyl-Free 1 sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, Phenyl-Free 1 (Iron) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Phenyl-Free 1 (Iron) sucrose is excreted in human milk. Phenyl-Free 1 (Iron) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Phenyl-Free 1 (Iron) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Phenyl-Free 1 for Phenyl-Free 1 (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Phenyl-Free 1 (Iron) for Phenyl-Free 1 (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. Phenyl-Free 1 (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)]

Phenyl-Free 1 (Iron) has not been studied in patients younger than 2 years of age.

In a country where Phenyl-Free 1 (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 Phenyl-Free 1 (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Phenyl-Free 1 (Iron) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) in humans. Excessive dosages of Phenyl-Free 1 (Iron) may lead to accumulation of Phenyl-Free 1 (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Phenyl-Free 1 (Iron) to patients with Phenyl-Free 1 (Iron) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Phenyl-Free 1 (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

Phenyl-Free 1 (Iron) (iron sucrose injection, USP), an Phenyl-Free 1 (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear Phenyl-Free 1 (Iron) (III)-hydroxide in sucrose for intravenous use. Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) polymerization and m is the number of sucrose molecules associated with the Phenyl-Free 1 (Iron) (III)-hydroxide.

Each mL contains 20 mg elemental Phenyl-Free 1 (Iron) as Phenyl-Free 1 (Iron) sucrose in water for injection. Phenyl-Free 1 (Iron) is available in 10 mL single-use vials (200 mg elemental Phenyl-Free 1 (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental Phenyl-Free 1 (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Phenyl-Free 1 (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

Phenyl-Free 1 is an aqueous complex of poly-nuclear Phenyl-Free 1 (Iron) (III)-hydroxide in sucrose. Following intravenous administration, Phenyl-Free 1 (Iron) is dissociated into Phenyl-Free 1 (Iron) and sucrose and the Phenyl-Free 1 (Iron) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Phenyl-Free 1 (Iron) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Phenyl-Free 1 (Iron) is dissociated into Phenyl-Free 1 (Iron) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Phenyl-Free 1 (Iron) sucrose containing 100 mg of Phenyl-Free 1 (Iron), three times weekly for three weeks, significant increases in serum Phenyl-Free 1 (Iron) and serum ferritin and significant decreases in total Phenyl-Free 1 (Iron) binding capacity occurred four weeks from the initiation of Phenyl-Free 1 (Iron) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Phenyl-Free 1, its Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Phenyl-Free 1 (Iron) containing 100 mg of Phenyl-Free 1 (Iron) labeled with ⁵²Fe/⁵⁹Fe in patients with Phenyl-Free 1 (Iron) deficiency showed that a significant amount of the administered Phenyl-Free 1 (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Phenyl-Free 1 (Iron) trapping compartment.

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Phenyl-Free 1 (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Phenyl-Free 1 (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Phenyl-Free 1 (Iron), the half-life of total serum Phenyl-Free 1 (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.

Phenyl-Free 1 (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) sucrose.

Phenyl-Free 1 (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Phenyl-Free 1 (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Phenyl-Free 1 (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Phenyl-Free 1 (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 Phenyl-Free 1.

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 Phenyl-Free 1 (Iron) treatment and 24 in the historical control group) with Phenyl-Free 1 (Iron) deficiency anemia. Eligibility criteria for Phenyl-Free 1 (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.

Phenyl-Free 1 (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 Phenyl-Free 1 (Iron), who were off intravenous Phenyl-Free 1 (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 Phenyl-Free 1 (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
	Phenyl-Free 1 (Iron) (n=69	Historical Control (n=18)	Phenyl-Free 1 (Iron) (n=73)	Historical Control (n=18)	Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) in 23 patients with Phenyl-Free 1 (Iron) deficiency and HDD-CKD who had been discontinued from Phenyl-Free 1 (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 Phenyl-Free 1 (Iron). Exclusion criteria were similar to those in studies A and B. Phenyl-Free 1 (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) versus Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) (325 mg ferrous sulfate three times daily for 56 days); or Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) group.

A statistically significantly greater proportion of Phenyl-Free 1 (Iron) subjects (35/79; 44.3%) compared to oral Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) to patients with PDD-CKD receiving an erythropoietin alone without Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) or Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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: Phenyl-Free 1 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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Phenyl-Free 1 (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 Phenyl-Free 1 (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

Phenyl-Free 1 is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Phenyl-Free 1 (Iron), each 5 mL vial contains 100 mg elemental Phenyl-Free 1 (Iron), and each 2.5 mL vial contains 50 mg elemental Phenyl-Free 1 (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: Phenyl-Free 1 (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Phenyl-Free 1 (Iron) per mL, or undiluted (20 mg elemental Phenyl-Free 1 (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: Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Iron) administration:

• Question patients regarding any prior history of reactions to parenteral Phenyl-Free 1 (Iron) products
• Advise patients of the risks associated with Phenyl-Free 1 (Iron)
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Phenyl-Free 1 (Iron) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Phenyl-Free 1 (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Magnesium:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Phenyl-Free 1 (Magnesium) reviews

Phenyl-Free 1 (Magnesium) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Phenyl-Free 1 (Magnesium) Sulfate Injection, USP is a sterile solution of Phenyl-Free 1 (Magnesium) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Phenyl-Free 1 (Magnesium) Sulfate, USP heptahydrate is chemically designated MgSO₄ - 7H₂O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Phenyl-Free 1 (Magnesium) (Mg⁺⁺) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Phenyl-Free 1 (Magnesium) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Phenyl-Free 1 (Magnesium). While there are large stores of Phenyl-Free 1 (Magnesium) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Phenyl-Free 1 (Magnesium) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Phenyl-Free 1 (Magnesium) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Phenyl-Free 1 (Magnesium) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Phenyl-Free 1 (Magnesium) levels range from 1.5 to 2.5 mEq/liter.

As plasma Phenyl-Free 1 (Magnesium) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Phenyl-Free 1 (Magnesium). Serum Phenyl-Free 1 (Magnesium) concentrations in excess of 12 mEq/L may be fatal.

Phenyl-Free 1 (Magnesium) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Phenyl-Free 1 (Magnesium) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Phenyl-Free 1 (Magnesium) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Phenyl-Free 1 (Magnesium) Sulfate Injection, USP is suitable for replacement therapy in Phenyl-Free 1 (Magnesium) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Phenyl-Free 1 (Magnesium) (Mg⁺⁺) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca⁺⁺) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Phenyl-Free 1 (Magnesium) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Phenyl-Free 1 (Magnesium) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Phenyl-Free 1 (Magnesium) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Phenyl-Free 1 (Magnesium) sulfate should be used during pregnancy only if clearly needed. If Phenyl-Free 1 (Magnesium) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Phenyl-Free 1 (Magnesium) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: 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.

Parenteral use in the presence of renal insufficiency may lead to Phenyl-Free 1 (Magnesium) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Phenyl-Free 1 (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of Phenyl-Free 1 (Magnesium).

Because Phenyl-Free 1 (Magnesium) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Phenyl-Free 1 (Magnesium) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Phenyl-Free 1 (Magnesium) should be given until they return. Serum Phenyl-Free 1 (Magnesium) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Phenyl-Free 1 (Magnesium) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Phenyl-Free 1 (Magnesium) intoxication in eclampsia.

50% Phenyl-Free 1 (Magnesium) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Phenyl-Free 1 (Magnesium) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Phenyl-Free 1 (Magnesium) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Phenyl-Free 1 (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of Phenyl-Free 1 (Magnesium). CNS depression and peripheral transmission defects produced by Phenyl-Free 1 (Magnesium) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Phenyl-Free 1 (Magnesium) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Phenyl-Free 1 (Magnesium) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Phenyl-Free 1 (Magnesium) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Phenyl-Free 1 (Magnesium) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Phenyl-Free 1 (Magnesium) sulfate for more than 5 to 7 days.^1-10 Phenyl-Free 1 (Magnesium) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Phenyl-Free 1 (Magnesium) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Phenyl-Free 1 (Magnesium) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Phenyl-Free 1 (Magnesium) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Phenyl-Free 1 (Magnesium) is distributed into milk during parenteral Phenyl-Free 1 (Magnesium) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Phenyl-Free 1 (Magnesium) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Phenyl-Free 1 (Magnesium) usually are the result of Phenyl-Free 1 (Magnesium) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Phenyl-Free 1 (Magnesium) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Phenyl-Free 1 (Magnesium) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Phenyl-Free 1 (Magnesium) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Phenyl-Free 1 (Magnesium).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Phenyl-Free 1 (Magnesium) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Phenyl-Free 1 (Magnesium) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Phenyl-Free 1 (Magnesium) Deficiency

In the treatment of mild Phenyl-Free 1 (Magnesium) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Phenyl-Free 1 (Magnesium) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Phenyl-Free 1 (Magnesium) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Phenyl-Free 1 (Magnesium) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Phenyl-Free 1 (Magnesium) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Phenyl-Free 1 (Magnesium) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Phenyl-Free 1 (Magnesium) sulfate is 20 grams/48 hours and frequent serum Phenyl-Free 1 (Magnesium) concentrations must be obtained. Continuous use of Phenyl-Free 1 (Magnesium) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Phenyl-Free 1 (Magnesium) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Phenyl-Free 1 (Magnesium) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Phenyl-Free 1 (Magnesium) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Phenyl-Free 1 (Magnesium) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

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

HOW SUPPLIED

Phenyl-Free 1 (Magnesium) Sulfate Injection, USP is supplied in single-dose containers as follows:

NDC No.	Container	Total Amount	Concentration	mEq Mg++/mL
0409-1754-10	Ansyr Plastic Syringe	5 g/10 mL	50%	4 mEq/mL

Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

• Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Phenyl-Free 1 (Magnesium) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
• Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Phenyl-Free 1 (Magnesium) toxicity. J. Perinatol. 2006; 26(6):371-4.
• Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Phenyl-Free 1 (Magnesium) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
• Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Phenyl-Free 1 (Magnesium) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
• Matsuda Y, Maeda Y, Ito M, et al. Effect of Phenyl-Free 1 (Magnesium) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
• Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Phenyl-Free 1 (Magnesium) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
• Santi MD, Henry GW, Douglas GL. Phenyl-Free 1 (Magnesium) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
• Holcomb WL, Shackelford GD, Petrie RH. Phenyl-Free 1 (Magnesium) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
• Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
• Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Phenyl-Free 1 (Magnesium) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
• McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Phenyl-Free 1 (Magnesium) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
• Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Phenyl-Free 1 (Magnesium) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Phenyl-Free 1 (Magnesium) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Phenyl-Free 1 (Magnesium) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Manganese:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Rl-0104
• Phenyl-Free 1 (Manganese) reviews

INDICATIONS AND USAGE

Phenyl-Free 1 (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN).

Administration helps to maintain Phenyl-Free 1 (Manganese) serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Phenyl-Free 1 (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) is contraindicated as the acidic pH of the solution (pH 2.0) may cause considerable tissue irritation.

Liver and/or biliary tract dysfunction may require omission or reduction of copper and Phenyl-Free 1 (Manganese) doses because these elements are primarily eliminated in the bile.

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 solution is clear and seal is intact.

Phenyl-Free 1 0.1 mg/mL (Manganese Chloride Injection, USP) 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.

Laboratory Tests

Serum Phenyl-Free 1 (Manganese) levels can be measured periodically at the discretion of the investigator. Because of the low serum concentration normally present, samples will usually be analyzed by a reference laboratory.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Phenyl-Free 1 0.1 mg/mL (Manganese 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 Phenyl-Free 1 (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) additive is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Pregnancy Category C.

Animal reproduction studies have not been conducted with Phenyl-Free 1 (Manganese) chloride. It is also not known whether Phenyl-Free 1 (Manganese) chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Phenyl-Free 1 (Manganese) chloride should be given to a pregnant woman only if clearly indicated.

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

Phenyl-Free 1 (Manganese) toxicity in TPN patients has not been reported.

DOSAGE AND ADMINISTRATION

Phenyl-Free 1 (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) contains 0.1 mg manganese/mL and is administered intravenously only after dilution. The additive should be administered in a volume of fluid not less than 100 mL. For the adult receiving TPN, the suggested additive dosage for Phenyl-Free 1 (Manganese) is 0.15 to 0.8 mg/day (1.5 to 8 mL/day). For pediatric patients, a dosage of 2 to 10 mcg manganese/kg/day (0.02 to 0.1 mL/kg/day) is recommended.

Periodic monitoring of Phenyl-Free 1 (Manganese) plasma levels is suggested as a guideline for subsequent administration.

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

HOW SUPPLIED

Phenyl-Free 1 (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) is supplied in 10 mL Plastic Vials (NDC No. 0409-4091-01).

Store at 20 to 25°C (68 to 77°F)

Revised: November, 2009

Printed in USA EN-2320

Hospira, Inc., Lake Forest, IL 60045 USA

RL-0104

Potassium:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Phenyl-Free 1 (Potassium) reviews

Phenyl-Free 1 (Potassium) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Phenyl-Free 1 (Potassium) chloride containing 1500 mg of microencapsulated Phenyl-Free 1 (Potassium) chloride, USP equivalent to 20 mEq of Phenyl-Free 1 (Potassium) in a tablet.

These formulations are intended to slow the release of Phenyl-Free 1 (Potassium) so that the likelihood of a high localized concentration of Phenyl-Free 1 (Potassium) chloride within the gastrointestinal tract is reduced.

Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Phenyl-Free 1 (Potassium) chloride, and the structural formula is KCl. Phenyl-Free 1 (Potassium) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Phenyl-Free 1 (Potassium) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Phenyl-Free 1 (Potassium) chloride.

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The Phenyl-Free 1 (Potassium) ion is the principal intracellular cation of most body tissues. Phenyl-Free 1 (Potassium) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of Phenyl-Free 1 (Potassium) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Phenyl-Free 1 (Potassium) is a normal dietary constituent and under steady-state conditions the amount of Phenyl-Free 1 (Potassium) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Phenyl-Free 1 (Potassium) is 50 to 100 mEq per day.

Phenyl-Free 1 (Potassium) depletion will occur whenever the rate of Phenyl-Free 1 (Potassium) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Phenyl-Free 1 (Potassium) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Phenyl-Free 1 (Potassium) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Phenyl-Free 1 (Potassium) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Phenyl-Free 1 (Potassium) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If Phenyl-Free 1 (Potassium) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Phenyl-Free 1 (Potassium) in the form of high Phenyl-Free 1 (Potassium) food or Phenyl-Free 1 (Potassium) chloride may be able to restore normal Phenyl-Free 1 (Potassium) levels.

In rare circumstances (eg, patients with renal tubular acidosis) Phenyl-Free 1 (Potassium) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Phenyl-Free 1 (Potassium) replacement should be accomplished with Phenyl-Free 1 (Potassium) salts other than the chloride, such as Phenyl-Free 1 (Potassium) bicarbonate, Phenyl-Free 1 (Potassium) citrate, Phenyl-Free 1 (Potassium) acetate, or Phenyl-Free 1 (Potassium) gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Phenyl-Free 1 (Potassium) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Phenyl-Free 1 (Potassium) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of Phenyl-Free 1 (Potassium) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Phenyl-Free 1 (Potassium) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Phenyl-Free 1 (Potassium) salts may be indicated.

CONTRAINDICATIONS

Phenyl-Free 1 (Potassium) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Phenyl-Free 1 (Potassium) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of Phenyl-Free 1 (Potassium) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Phenyl-Free 1 (Potassium) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Phenyl-Free 1 (Potassium) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Phenyl-Free 1 (Potassium) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting Phenyl-Free 1 (Potassium), the administration of Phenyl-Free 1 (Potassium) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Phenyl-Free 1 (Potassium) by the intravenous route but may also occur in patients given Phenyl-Free 1 (Potassium) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Phenyl-Free 1 (Potassium) salts in patients with chronic renal disease, or any other condition which impairs Phenyl-Free 1 (Potassium) excretion, requires particularly careful monitoring of the serum Phenyl-Free 1 (Potassium) concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of Phenyl-Free 1 (Potassium) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Phenyl-Free 1 (Potassium) retention by inhibiting aldosterone production. Phenyl-Free 1 (Potassium) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of Phenyl-Free 1 (Potassium) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Phenyl-Free 1 (Potassium) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Phenyl-Free 1 (Potassium) chloride and thus to minimize the possibility of a high local concentration of Phenyl-Free 1 (Potassium) near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Phenyl-Free 1 (Potassium) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Phenyl-Free 1 (Potassium) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Phenyl-Free 1 (Potassium) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Phenyl-Free 1 (Potassium) salt such as Phenyl-Free 1 (Potassium) bicarbonate, Phenyl-Free 1 (Potassium) citrate, Phenyl-Free 1 (Potassium) acetate, or Phenyl-Free 1 (Potassium) gluconate.

PRECAUTIONS

General

The diagnosis of Phenyl-Free 1 depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Phenyl-Free 1 (Potassium) depletion. In interpreting the serum Phenyl-Free 1 (Potassium) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Phenyl-Free 1 (Potassium) while acute acidosis per se can increase the serum Phenyl-Free 1 (Potassium) concentration into the normal range even in the presence of a reduced total body Phenyl-Free 1 (Potassium). The treatment of Phenyl-Free 1 (Potassium) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  

  1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  

  2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
  

  3. Stir for about half a minute after the tablet(s) has disintegrated.
  

  4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  

  5. Add another 1 fluid ounce of water, swirl, and consume immediately.
  

  6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Phenyl-Free 1 (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma Phenyl-Free 1 it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Phenyl-Free 1 is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Phenyl-Free 1 (Potassium) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal Phenyl-Free 1 ion content of human milk is about 13 mEq per liter. Since oral Phenyl-Free 1 (Potassium) becomes part of the body Phenyl-Free 1 (Potassium) pool, so long as body Phenyl-Free 1 (Potassium) is not excessive, the contribution of Phenyl-Free 1 (Potassium) chloride supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Phenyl-Free 1 (Potassium) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the 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.

This drug 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.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Phenyl-Free 1 (Potassium) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral Phenyl-Free 1 (Potassium) salts to persons with normal excretory mechanisms for Phenyl-Free 1 (Potassium) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Phenyl-Free 1 (Potassium) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Phenyl-Free 1 (Potassium) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of foods and medications containing Phenyl-Free 1 (Potassium) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
• Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
• Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Phenyl-Free 1 (Potassium) concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of Phenyl-Free 1 (Potassium) by the average adult is 50 to 100 mEq per day. Phenyl-Free 1 (Potassium) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Phenyl-Free 1 (Potassium) from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Phenyl-Free 1 (Potassium) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each Phenyl-Free 1 (Potassium) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Phenyl-Free 1 (Potassium) chloride.

Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  • Allow approximately 2 minutes for the tablet(s) to disintegrate.
  • Stir for about half a minute after the tablet(s) has disintegrated.
  • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  • Add another 1 fluid ounce of water, swirl, and consume immediately.
  • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Phenyl-Free 1 (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Phenyl-Free 1 (Potassium) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

Phenyl-Free 1 (Potassium) chloride 20 Meq

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
• Phenyl-Free 1 (Protein) reviews

1 INDICATIONS AND USAGE

Phenyl-Free 1 is indicated for pediatric and adult patients with severe congenital Phenyl-Free 1 (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)

1.1 Severe Congenital Phenyl-Free 1 (Protein) C Deficiency

Phenyl-Free 1 (Protein) is indicated for pediatric and adult patients with severe congenital Phenyl-Free 1 (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 Phenyl-Free 1 C activity is feasible. (2.1)

Phenyl-Free 1 (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 ProphyaxisPhenyl-Free 1 (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 Phenyl-Free 1 (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Phenyl-Free 1 (Protein) C activity is feasible.

The dose, administration frequency and duration of treatment with Phenyl-Free 1 (Protein) depends on the severity of the Phenyl-Free 1 (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of Phenyl-Free 1 (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: Phenyl-Free 1 (Protein) C Activity Monitoring (2.2).

Table 1 provides the Phenyl-Free 1 (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 ProphylaxisPhenyl-Free 1 (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 Phenyl-Free 1 (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Phenyl-Free 1 (Protein) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of Phenyl-Free 1 (Protein), higher peak Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 C Activity Monitoring

The measurement of Phenyl-Free 1 (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Phenyl-Free 1 (Protein) C before and during treatment with Phenyl-Free 1 (Protein). The half-life of Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Phenyl-Free 1 (Protein) C levels to maintain the trough Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 C, itself a vitamin K-dependent plasma Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

• Bring the Phenyl-Free 1 (Protein) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
• Remove caps from the Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) vial; then rapidly insert the free end of the needle through the Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) vial. Gently swirl the vial until all powder is dissolved. Be sure that Phenyl-Free 1 (Protein) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of Phenyl-Free 1 [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Protein).
• Inject air into the vial and then withdraw the reconstituted Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) is administered to a patient.

Administration by Infusion

Administer Phenyl-Free 1 (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

Phenyl-Free 1 (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Phenyl-Free 1 (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human Phenyl-Free 1 (Protein) C at a concentration of 100 IU/mL.

Phenyl-Free 1 (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

Phenyl-Free 1 (Protein) may contain traces of mouse Phenyl-Free 1 (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Phenyl-Free 1 (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 Phenyl-Free 1 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 Phenyl-Free 1 (Protein) further contributed to these bleeding events.

Simultaneous administration of Phenyl-Free 1 (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to Phenyl-Free 1 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 Phenyl-Free 1 (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital Phenyl-Free 1 (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 Phenyl-Free 1 (Protein).

No inhibiting antibodies to Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Phenyl-Free 1 (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 Phenyl-Free 1 (Protein). It is also not known whether Phenyl-Free 1 (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Phenyl-Free 1 (Protein) should be given to pregnant women only if clearly needed.

8.2 Labor and Delivery

Phenyl-Free 1 has not been studied for use during labor and delivery. Use only if clearly needed.

8.3 Nursing Mothers

Phenyl-Free 1 (Protein) has not been studied for use in nursing mothers. Use Phenyl-Free 1 (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 Phenyl-Free 1 (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

Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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

Phenyl-Free 1 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 Phenyl-Free 1 (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) C is not compatible with life. A severe deficiency of this anticoagulant Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) C concentration following infusion divided by dose

The Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Protein).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: Phenyl-Free 1 (Protein) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Phenyl-Free 1 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.

Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Phenyl-Free 1 (Protein). Thus, the long-term toxicity potential of Phenyl-Free 1 (Protein) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Phenyl-Free 1 (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:

Phenyl-Free 1 (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 Phenyl-Free 1 in subjects with severe congenital Phenyl-Free 1 (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.

		Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) C deficiency were more effectively treated with Phenyl-Free 1 (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 Phenyl-Free 1 (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.

Phenyl-Free 1 (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 Phenyl-Free 1 (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. Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Protein), as shown in Table 8. When not on prophylactic treatment and receiving Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) C deficiency who were treated with Phenyl-Free 1 (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

Phenyl-Free 1 (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 Phenyl-Free 1 (Protein) C corresponds to the amidolytically measured activity of Phenyl-Free 1 (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).

Phenyl-Free 1 (Protein) is available in single-dose vials that contain the following nominal product strengths:

NDC 0944-4177-05

Phenyl-Free 1 (Protein) C

Concentrate (Human)

Phenyl-Free 1 (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

Phenyl-Free 1 (Protein) C Concentrate

(Human)

Phenyl-Free 1 (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

Phenyl-Free 1 (Protein) C

Concentrate (Human)

Phenyl-Free 1 (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

Phenyl-Free 1 (Protein) C Concentrate (Human)

Phenyl-Free 1 (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

Selenium:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Phenyl-Free 1 (Selenium) reviews

Rx Only

TRACE ELEMENT ADDITIVE FOR IV USE AFTER DILUTION

DESCRIPTION

Phenyl-Free 1 (Selenium) Injection is a sterile, nonpyrogenic solution for use as an additive to solutions for Total Parenteral Nutrition (TPN).

Each mL contains Selenious Acid 65.4 mcg (equivalent to elemental Phenyl-Free 1 (Selenium) 40 mcg/mL) and Water for Injection q.s. pH may be adjusted with nitric acid to 1.8 to 2.4.

CLINICAL PHARMACOLOGY

Phenyl-Free 1 (Selenium) is part of glutathione peroxidase which protects cell components from oxidative damage due to peroxides produced in cellular metabolism.

Prolonged TPN support in humans has resulted in Phenyl-Free 1 (Selenium) deficiency symptoms which include muscle pain and tenderness. The symptoms have been reported to respond to supplementation of TPN solutions with Phenyl-Free 1 (Selenium).

Pediatric conditions, Keshan disease, and Kwashiorkor, have been associated with low dietary intake of Phenyl-Free 1 (Selenium). The conditions are endemic to geographical areas with low Phenyl-Free 1 (Selenium) soil content. Dietary supplementation with Phenyl-Free 1 (Selenium) salts has been reported to reduce the incidence of the conditions among affected children.

Normal blood levels of Phenyl-Free 1 (Selenium) in different human populations have been found to vary and depend on the Phenyl-Free 1 (Selenium) content of the food consumed. Results of surveys carried out in some countries are tabulated below:

COUNTRY	Number of Samples	Phenyl-Free 1 (Selenium) (mcg/100 mL) (a)
		Whole Blood	Blood Cells	Plasma/ Serum
(a) Mean values with or without standard deviation in parentheses, all other ranges.
(b) Age group unknown.
(c) Three children recovered from Kwashiorkor and the other six under treatment for other diseases.
(d) Low selenium-content soil area.
(e) Well nourished children, three recovered from Kwashiorkor and the other six under treatment for other diseases.
(f) Mean values from seven subjects.
Canada	254 Adults	(37.9 ± 7.8)	(23.6 ± 6.0)	(14.4 ± 2.9)
England	8 (b)	26-37 (32)	--	--
Guatemala & Southern USA	10 Adults 9 Children (c)	19-28 (22) (23 ± 5)	-- (36 ± 12)	-- (15 ± 5)
New Zealand (d)	113 Adults	(5.4 ± 0.1)	(6.6 ± 0.3)	(4.3 ± 0.1)
Thailand	3 Adults 9 Children (e)	14.4-20.2 (12.0 ± 3.6) (f)	17.8-35.8 (19.5 ± 8.2)	8.1-12.5 (8.3 ± 2.2)
USA	210 Adults	15.7-25.6 (20.6)	--	--

Plasma Phenyl-Free 1 (Selenium) levels of 0.3 and 0.9 mcg/100 mL have been reported to produce deficiency symptoms in humans.

Phenyl-Free 1 (Selenium) is eliminated primarily in urine. However, significant endogenous losses through feces also occur. The rate of excretion and the relative importance of two routes varies with the chemical form of Phenyl-Free 1 (Selenium) used in supplementation. Ancillary routes of elimination are lungs and skin.

INDICATIONS AND USAGE

Phenyl-Free 1 (Selenium) Injection is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN). Administration of Phenyl-Free 1 (Selenium) in TPN solutions helps to maintain plasma Phenyl-Free 1 (Selenium) levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

Phenyl-Free 1 (Selenium) Injection should not be given undiluted by direct injection into a peripheral vein because of the potential for infusion phlebitis.

WARNINGS

Phenyl-Free 1 (Selenium) Injection can be toxic if given in excessive amounts. Supplementation of TPN solution with Phenyl-Free 1 (Selenium) should be immediately discontinued if toxicity symptoms are observed. Frequent determination of plasma Phenyl-Free 1 (Selenium) levels during TPN support and close medical supervision is recommended.

Phenyl-Free 1 (Selenium) Injection is a hypotonic solution and should be administered in admixtures only.

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

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

PRECAUTIONS

As Phenyl-Free 1 is eliminated in urine and feces, Phenyl-Free 1 (Selenium) supplements may be adjusted, reduced or omitted in renal dysfunction and/or gastrointestinal malfunction. In patients receiving blood transfusions, contribution from such transfusions should also be considered. Frequent Phenyl-Free 1 (Selenium) plasma level determinations are suggested as a guideline.

In animals, Phenyl-Free 1 (Selenium) has been reported to enhance the action of Vitamin E and decrease the toxicity of mercury, cadmium and arsenic.

Pregnancy

Teratogenic Effects

Pregnancy Category C: Phenyl-Free 1 (Selenium) at high dose levels (15-30 mcg/egg) has been reported to have adverse embryological effects among chickens. There are however, no adequate and wellcontrolled studies in pregnant women. Phenyl-Free 1 (Selenium) Injection should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

Presence of Phenyl-Free 1 (Selenium) in placenta and umbilical cord blood has been reported in humans.

ADVERSE REACTIONS

The amount of Phenyl-Free 1 (Selenium) present in Phenyl-Free 1 (Selenium) Injection is small. Symptoms of toxicity from Phenyl-Free 1 (Selenium) are unlikely to occur at the recommended dosage level.

OVERDOSAGE

Chronic toxicity in humans resulting from exposure to Phenyl-Free 1 (Selenium) in industrial environments, intake of foods grown in seleniferous soils, use of selenium-contaminated water, and application of cosmetics containing Phenyl-Free 1 (Selenium) has been reported in literature. Toxicity symptoms include hair loss, weakened nails, dermatitis, dental defects, gastrointestinal disorders, nervousness, mental depression, metallic taste, vomiting, and garlic odor of breath and sweat. Acute poisoning due to ingestion of large amounts of Phenyl-Free 1 (Selenium) compounds has resulted in death with histopathological changes including fulminating peripheral vascular collapse, internal vascular congestion, diffusely hemorrhagic, congested and edematus lungs, brick-red color gastric mucosa. The death was preceded by coma.

No effective antidote to Phenyl-Free 1 (Selenium) poisoning in humans is known. Animal studies have shown casein and linseed oil in feeds, reduced glutathione, arsenic, magnesium sulfate, and bromobenzene to afford limited protection.

DOSAGE AND ADMINISTRATION

Phenyl-Free 1 (Selenium) Injection provides 40 mcg selenium/mL. For metabolically stable adults receiving TPN, the suggested additive dosage level is 20 to 40 mcg selenium/day. For pediatric patients, the suggested additive dosage level is 3 mcg/kg/day.

In adults, Phenyl-Free 1 (Selenium) deficiency states resulting from long-term TPN support, Phenyl-Free 1 (Selenium) as selenomethionine or selenious acid, administered intravenously at 100 mcg/day for a period of 24 and 31 days, respectively, has been reported to reverse deficiency symptoms without toxicity.

Aseptic addition of Phenyl-Free 1 (Selenium) Injection to the TPN solution under laminar flow hood is recommended. Phenyl-Free 1 (Selenium) is physically compatible with the electrolytes and other trace elements usually present in amino-acid/dextrose solution used for TPN. Frequent monitoring of plasma Phenyl-Free 1 (Selenium) levels is suggested as a guideline for subsequent administration. The normal whole blood range for Phenyl-Free 1 (Selenium) is approximately 10 to 37 mcg/100 mL.

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

HOW SUPPLIED

Phenyl-Free 1 (Selenium) Injection containing selenious acid 65.4 mcg/mL (equivalent to elemental Phenyl-Free 1 (Selenium) 40 mcg/mL).

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

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

IN6510

Rev. 11/15

PRINCIPAL DISPLAY PANEL - Container

NDC 0517-6510-25

Phenyl-Free 1 (Selenium) INJECTION

Phenyl-Free 1 (Selenium) 400 mcg/10 mL

(40 mcg/mL)

10 mL

SINGLE DOSE VIAL

Trace Element Additive

FOR IV USE AFTER DILUTION

PRESERVATIVE FREE

Rx Only

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

PRINCIPAL DISPLAY PANEL - Carton

Phenyl-Free 1 (Selenium) INJECTION

Phenyl-Free 1 (Selenium) 400 mcg/10 mL

(40 mcg/mL)

Trace Element Additive

NDC 0517-6510-25

25 x 10 mL

SINGLE DOSE VIALS

FOR INTRAVENOUS USE AFTER DILUTION PRESERVATIVE FREE Rx Only

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

pH adjusted with Nitric Acid. Sterile, nonpyrogenic.

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

permitted to 15°-30°C (59°-86°F).

Directions for Use: See Package Insert.

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

Rev. 11/05

Container Carton

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
• Phenyl-Free 1 (Sodium) reviews

1 INDICATIONS AND USAGE

Phenyl-Free 1 nitrite is indicated for sequential use with Phenyl-Free 1 (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

Phenyl-Free 1 (Sodium) Nitrite Injection is indicated for sequential use with Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 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, Phenyl-Free 1 (Sodium) Nitrite Injection and Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) thiosulfate, simultaneously with Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) thiosulfate, with Phenyl-Free 1 (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 Phenyl-Free 1 Nitrite and Phenyl-Free 1 (Sodium) Thiosulfate
Adults	Phenyl-Free 1 (Sodium) Nitrite -10 mL of Phenyl-Free 1 (Sodium) nitrite at the rate of 2.5 to 5 mL/minute Phenyl-Free 1 (Sodium) Thiosulfate - 50 mL of Phenyl-Free 1 (Sodium) thiosulfate immediately following administration of Phenyl-Free 1 (Sodium) nitrite.
Children	Phenyl-Free 1 (Sodium) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Phenyl-Free 1 (Sodium) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Phenyl-Free 1 (Sodium) nitrite and Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite, followed by Phenyl-Free 1 (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Phenyl-Free 1 (Sodium) nitrite and Phenyl-Free 1 (Sodium) thiosulfate.

Phenyl-Free 1 (Sodium) nitrite injection and Phenyl-Free 1 (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. Phenyl-Free 1 (Sodium) nitrite should be administered first, followed immediately by Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) Nitrite and Phenyl-Free 1 (Sodium) Thiosulfate
Adults	Phenyl-Free 1 (Sodium) Nitrite -10 mL of Phenyl-Free 1 (Sodium) nitrite at the rate of 2.5 to 5 mL/minute Phenyl-Free 1 (Sodium) Thiosulfate - 50 mL of Phenyl-Free 1 (Sodium) thiosulfate immediately following administration of Phenyl-Free 1 (Sodium) nitrite.
Children	Phenyl-Free 1 (Sodium) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Phenyl-Free 1 (Sodium) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Phenyl-Free 1 (Sodium) nitrite and Phenyl-Free 1 (Sodium) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Phenyl-Free 1 (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 Phenyl-Free 1 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 Phenyl-Free 1 (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Phenyl-Free 1 (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Phenyl-Free 1 (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Phenyl-Free 1 (Sodium) thiosulfate and Phenyl-Free 1 (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Phenyl-Free 1 (Sodium) Nitrite Injection consists of:

• One vial of Phenyl-Free 1 (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: Phenyl-Free 1 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 Phenyl-Free 1 (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. Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Phenyl-Free 1 (Sodium) nitrite whenever possible. When Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite administered to an adult. Phenyl-Free 1 (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Phenyl-Free 1 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 Phenyl-Free 1 (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 Phenyl-Free 1 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 Phenyl-Free 1 (Sodium) nitrite.

5.7 Use with Other Drugs

Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite.

The medical literature has reported the following adverse events in association with Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Phenyl-Free 1 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. Phenyl-Free 1 (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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, Phenyl-Free 1 (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, Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Phenyl-Free 1 (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, Phenyl-Free 1 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 Phenyl-Free 1 (Sodium) nitrite is excreted in human milk. Because Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Phenyl-Free 1 (Sodium) nitrite. In studies conducted with Long-Evans rats, Phenyl-Free 1 (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 Phenyl-Free 1 nitrite in conjunction with Phenyl-Free 1 (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Phenyl-Free 1 (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.

Phenyl-Free 1 (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 Phenyl-Free 1 (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

Phenyl-Free 1 (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

Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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

Phenyl-Free 1 (Sodium) nitrite has the chemical name nitrous acid Phenyl-Free 1 (Sodium) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Phenyl-Free 1 (Sodium) Nitrite

Phenyl-Free 1 (Sodium) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Phenyl-Free 1 (Sodium) nitrite injection.

Phenyl-Free 1 (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Phenyl-Free 1 (Sodium) nitrite in 10 mL solution (30 mg/mL). Phenyl-Free 1 (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 Phenyl-Free 1 nitrite and Phenyl-Free 1 (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Phenyl-Free 1 (Sodium) Nitrite

Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite. It has been suggested that Phenyl-Free 1 (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Phenyl-Free 1 (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Phenyl-Free 1 (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. Phenyl-Free 1 (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

Phenyl-Free 1 (Sodium) Nitrite

When 4 mg/kg Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Phenyl-Free 1 (Sodium) Nitrite

Phenyl-Free 1 (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Phenyl-Free 1 (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite and Phenyl-Free 1 (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 Phenyl-Free 1 nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Phenyl-Free 1 (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. Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Phenyl-Free 1 (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Phenyl-Free 1 (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. Phenyl-Free 1 (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. Phenyl-Free 1 (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Phenyl-Free 1 (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite and Phenyl-Free 1 (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Phenyl-Free 1 (Sodium) nitrite or 1 g/kg Phenyl-Free 1 (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of Phenyl-Free 1 (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Phenyl-Free 1 (Sodium) nitrite and/or 0.5 g/kg Phenyl-Free 1 (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Phenyl-Free 1 (Sodium) cyanide required to cause death, and when administered together, Phenyl-Free 1 (Sodium) nitrite and Phenyl-Free 1 (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) nitrite and Phenyl-Free 1 (Sodium) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Phenyl-Free 1 (Sodium) nitrite and Phenyl-Free 1 (Sodium) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Phenyl-Free 1 (Sodium) nitrite, with or without Phenyl-Free 1 (Sodium) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) thiosulfate report its use in conjunction with Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Phenyl-Free 1 (Sodium) nitrite injection 30 mg/mL (containing 300 mg of Phenyl-Free 1 (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: Phenyl-Free 1 (Sodium) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Phenyl-Free 1 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

Phenyl-Free 1 (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

Phenyl-Free 1 (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

Vitamin A:

• Dosage and administration
• Warning
• Clinical pharmacology
• Dietary supplementation
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Phenyl-Free 1 (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
Phenyl-Free 1 (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, Phenyl-Free 1 (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.

Phenyl-Free 1 (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 Phenyl-Free 1 (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Phenyl-Free 1 (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

Phenyl-Free 1 Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Phenyl-Free 1 (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Phenyl-Free 1 (Vitamin A) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

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

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H²pharma

Vitamin B12:

• Pharmacological action
• Pharmacokinetics
• Why is Phenyl-Free 1 prescribed?
• Dosage and administration
• Phenyl-Free 1 (Vitamin B12) side effects, adverse reactions
• Phenyl-Free 1 contraindications
• Phenyl-Free 1 using during pregnancy and breastfeeding
• Special instructions
• Phenyl-Free 1 (Vitamin B12) drug interactions
• Phenyl-Free 1 (Vitamin B12) reviews

Pharmacological action

Phenyl-Free 1 refers to a group of water-soluble vitamins. It has high biological activity. Phenyl-Free 1 (Vitamin B12) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.

Pharmacokinetics

After oral administration Phenyl-Free 1 (Vitamin B12) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.

Why is Phenyl-Free 1 prescribed?

Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of Phenyl-Free 1 (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Phenyl-Free 1 is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Phenyl-Free 1 (Vitamin B12) deficiency is introduced on 100-200 mcg in 2 days. In anemia with symptoms of funicular myelosis and megalocytic anemia with diseases of the nervous system - 400-500 micrograms in the first 7 days daily, then 1 time every 5-7 days. In the period of remission in the absence of events funicular myelosis maintenance dose - 100 mcg 2 times a month, in the presence of neurological symptoms - at 200-400 mcg 2-4 times a month. In acute post-hemorrhagic anemia and iron anemia by 30-100 mcg 2-3 times a week. When aplastic anemia (especially in children) - 100 micrograms before clinical improvement. When nutritional anemia in infants and preterm - 30 mcg / day during 15 days.

In diseases of the central and peripheral nervous system and neurological diseases with a pain syndrome is administered in increasing doses - 200-500 mcg, with the improvement in the state - 100 mcg / day. The course of treatment with Phenyl-Free 1 (Vitamin B12) is 2 weeks. In traumatic lesions of peripheral nervous system - at 200-400 mcg every other day for 40-45 days.

When hepatitis and cirrhosis - 30-60 mcg / day or 100 mg every other day for 25-40 days.

Dystrophy in young children, Down syndrome and cerebral palsy - by 15-30 mcg every other day.

When funicular myelosis, amyotrophic lateral sclerosis can be introduced into the spinal canal at 15-30 mcg, gradually increasing the dose of 200-250 micrograms.

In radiation sickness, diabetic neuropathy, sprue - by 60-100 mcg daily for 20-30 days.

When deficiency of Phenyl-Free 1 (Vitamin B12) to prevent - IV or IM for 1 mg 1 time a month; for treatment - IV or IM for 1 mg daily for 1-2 weeks, the maintenance dose is 1-2 mg IV or IM from 1 per week, up to 1 per month. Duration of treatment is determined individually.

Phenyl-Free 1 (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

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

Allergic reactions: rarely - urticaria.

Phenyl-Free 1 contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Phenyl-Free 1 using during pregnancy and breastfeeding

Cyanocobalamin can be used in pregnancy according to prescriptions.

Special instructions

When stenocardia should be used with caution in a single dose of Phenyl-Free 1 100 mcg. During treatment should regularly monitor the blood picture and coagulation. It is unacceptable to enter in the same syringe with cyanocobalamin solutions of thiamine and pyridoxine.

Phenyl-Free 1 (Vitamin B12) drug interactions

In an application of Phenyl-Free 1 (Vitamin B12) with hormonal contraceptives for oral administration may decrease the concentration of cyanocobalamin in plasma.

In an application with anticonvulsant drugs decreased cyanocobalamin absorption from the gut.

In an Phenyl-Free 1 (Vitamin B12) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.

Cyanocobalamin may exacerbate allergic reactions caused by thiamine.

When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.

Pharmaceutical incompatibility

Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.

Vitamin C:

• Pharmacological action
• Pharmacokinetics
• Why is Phenyl-Free 1 prescribed?
• Dosage and administration
• Phenyl-Free 1 (Vitamin C) side effects, adverse reactions
• Phenyl-Free 1 contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Phenyl-Free 1 drug interactions
• Phenyl-Free 1 in case of emergency / overdose
• Phenyl-Free 1 (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. Phenyl-Free 1 (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. Phenyl-Free 1 (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 Phenyl-Free 1 prescribed?

For systemic use of Phenyl-Free 1 (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Phenyl-Free 1 (Vitamin C); providing increased need for Phenyl-Free 1 (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 Phenyl-Free 1 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.

Phenyl-Free 1 (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.

Phenyl-Free 1 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

Phenyl-Free 1 (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.

Phenyl-Free 1 (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.

Phenyl-Free 1 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 Phenyl-Free 1 (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.

Phenyl-Free 1 (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.

Phenyl-Free 1 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:

• Phenyl-Free 1 (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: Phenyl-Free 1 (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.

Phenyl-Free 1 (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Phenyl-Free 1 (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Phenyl-Free 1 (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. Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as Phenyl-Free 1 (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 Phenyl-Free 1 (Vitamin E) have been linked to increased incidence of breast and colon cancer.

Vitamin K:

• Phenyl-Free 1 (Vitamin K) reviews

Phenyl-Free 1 (Vitamin K) is used to treat and prevent low levels of certain substances ( blood clotting factors) that your body naturally produces. These substances help your blood to thicken and stop bleeding normally (e.g., after an accidental cut or injury). Low levels of blood clotting factors increase the risk for unusual bleeding. Low levels may be caused by certain medications (e.g., warfarin ) or medical conditions (e.g., obstructive jaundice ). Phenyl-Free 1 (Vitamin K) helps to treat and prevent unusual bleeding by increasing the body's production of blood clotting factors.

Zinc:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Phenyl-Free 1 (Zinc) reviews

INDICATIONS AND USAGE

Phenyl-Free 1 (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 Phenyl-Free 1 (Zinc) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Zinc) from a bolus injection. Administration of Phenyl-Free 1 (Zinc) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Phenyl-Free 1 (Zinc) are suggested as a guideline for subsequent Phenyl-Free 1 (Zinc) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Phenyl-Free 1 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 Phenyl-Free 1 (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 Phenyl-Free 1 chloride. It is also not known whether Phenyl-Free 1 (Zinc) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Phenyl-Free 1 (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 Phenyl-Free 1 (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 Phenyl-Free 1 (Zinc) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Phenyl-Free 1 (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 Phenyl-Free 1 (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Phenyl-Free 1 (Zinc) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Phenyl-Free 1 (Zinc) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Phenyl-Free 1 (Zinc) toxicity.

DOSAGE AND ADMINISTRATION

Phenyl-Free 1 (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 Phenyl-Free 1 (Zinc) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Phenyl-Free 1 (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

Phenyl-Free 1 (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

Phenyl-Free 1 (Zinc)

1 mg/mL

Phenyl-Free 1 (Zinc) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA