Profine

Copper (Copper Sulfate):

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Profine (Copper (Copper Sulfate)) reviews

Water-Resistant Protection Without Bandaging

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

NOTE: Profine (Copper (Copper Sulfate))^® 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:

Profine (Copper (Copper Sulfate)) 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
• Profine (Folic Acid) reviews

INDICATIONS AND USAGE

Profine (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.

PRECAUTIONS

Profine (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 Profine (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

Profine (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.

Profine (Folic Acid) and the BIFERA logo are registered trademarks and the Profine (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:

• Profine (Inositol) reviews

Iron (Ferrous Gluconate):

• 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
• Profine (Iron (Ferrous Gluconate)) reviews

1 INDICATIONS AND USAGE

Profine (Iron (Ferrous Gluconate)) is indicated for the treatment of Profine (Iron (Ferrous Gluconate)) deficiency anemia in patients with chronic kidney disease (CKD).

Profine (Iron (Ferrous Gluconate)) is an Profine (Iron (Ferrous Gluconate)) replacement product indicated for the treatment of Profine (Iron (Ferrous Gluconate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

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

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

Administer Profine (Iron (Ferrous Gluconate)) 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. Profine (Iron (Ferrous Gluconate)) should be administered early during the dialysis session. The usual total treatment course of Profine (Iron (Ferrous Gluconate)) is 1000 mg. Profine (Iron (Ferrous Gluconate)) treatment may be repeated if Profine (Iron (Ferrous Gluconate)) deficiency reoccurs.

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

Administer Profine (Iron (Ferrous Gluconate)) 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 Profine (Iron (Ferrous Gluconate)), 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. Profine (Iron (Ferrous Gluconate)) treatment may be repeated if Profine (Iron (Ferrous Gluconate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Profine (Iron (Ferrous Gluconate)) 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 Profine (Iron (Ferrous Gluconate)) in a maximum of 250 mL of 0.9% NaCl. Profine (Iron (Ferrous Gluconate)) treatment may be repeated if Profine (Iron (Ferrous Gluconate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Profine (Iron (Ferrous Gluconate)) maintenance treatment

The dosing for Profine (Iron (Ferrous Gluconate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Profine (Iron (Ferrous Gluconate)) maintenance treatment: Administer Profine (Iron (Ferrous Gluconate)) 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. Profine (Iron (Ferrous Gluconate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Profine (Iron (Ferrous Gluconate)) maintenance treatment

The dosing for Profine (Iron (Ferrous Gluconate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Profine (Iron (Ferrous Gluconate)) maintenance treatment: Administer Profine (Iron (Ferrous Gluconate)) 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. Profine (Iron (Ferrous Gluconate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Profine (Iron (Ferrous Gluconate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Profine (Iron (Ferrous Gluconate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Profine (Iron (Ferrous Gluconate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Profine (Iron (Ferrous Gluconate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Profine (Iron (Ferrous Gluconate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Profine (Iron (Ferrous Gluconate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Profine (Iron (Ferrous Gluconate))

• Known hypersensitivity to Profine (Iron (Ferrous Gluconate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Profine (Iron (Ferrous Gluconate)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Profine ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Profine (Iron (Ferrous Gluconate)) 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 Profine ) 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 Profine (Iron (Ferrous Gluconate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

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

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 Profine (Iron (Ferrous Gluconate)) maintenance treatment with Profine (Iron (Ferrous Gluconate)) 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 Profine (Iron (Ferrous Gluconate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Profine (Iron (Ferrous Gluconate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Profine (Iron (Ferrous Gluconate)) 2.0 mg/kg.

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

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

Profine (Iron (Ferrous Gluconate)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

Clinical studies of Profine (Iron (Ferrous Gluconate)) 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 Profine (Iron (Ferrous Gluconate)), 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 Profine (Iron (Ferrous Gluconate)) in humans. Excessive dosages of Profine (Iron (Ferrous Gluconate)) may lead to accumulation of Profine (Iron (Ferrous Gluconate)) in storage sites potentially leading to hemosiderosis. Do not administer Profine (Iron (Ferrous Gluconate)) to patients with Profine (Iron (Ferrous Gluconate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Profine (Iron (Ferrous Gluconate)) 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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

Profine (Iron (Ferrous Gluconate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Profine (Iron (Ferrous Gluconate)) 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 Profine (Iron (Ferrous Gluconate)) sucrose.

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

Profine (Iron (Ferrous Gluconate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Profine (Iron (Ferrous Gluconate)) (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 Profine ).

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 Profine (Iron (Ferrous Gluconate)) treatment and 24 in the historical control group) with Profine (Iron (Ferrous Gluconate)) deficiency anemia. Eligibility criteria for Profine (Iron (Ferrous Gluconate)) 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.

Profine (Iron (Ferrous Gluconate)) 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 Profine (Iron (Ferrous Gluconate)), who were off intravenous Profine (Iron (Ferrous Gluconate)) 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 Profine (Iron (Ferrous Gluconate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

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

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

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

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

Profine ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Profine (Iron (Ferrous Gluconate)), each 5 mL vial contains 100 mg elemental Profine (Iron (Ferrous Gluconate)), and each 2.5 mL vial contains 50 mg elemental Profine (Iron (Ferrous Gluconate)) (20 mg/mL).

16.2 Stability and Storage

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

Syringe Stability: Profine (Iron (Ferrous Gluconate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Profine (Iron (Ferrous Gluconate)) per mL, or undiluted (20 mg elemental Profine (Iron (Ferrous Gluconate)) 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: Profine (Iron (Ferrous Gluconate)), 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 Profine (Iron (Ferrous Gluconate)) 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 Profine (Iron (Ferrous Gluconate)) 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 Profine (Iron (Ferrous Gluconate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Profine (Iron (Ferrous Gluconate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Manganese (Manganese Sulfate):

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

INDICATIONS AND USAGE

Profine (Manganese (Manganese Sulfate)) 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 Profine (Manganese (Manganese Sulfate)) serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Profine (Manganese (Manganese Sulfate)) 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 Profine (Manganese (Manganese Sulfate)) 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.

Profine ) 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 Profine (Manganese (Manganese Sulfate)) 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 Profine ) 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 Profine (Manganese (Manganese Sulfate)) 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 Profine (Manganese (Manganese Sulfate)) chloride. It is also not known whether Profine (Manganese (Manganese Sulfate)) chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Profine (Manganese (Manganese Sulfate)) 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

Profine (Manganese (Manganese Sulfate)) toxicity in TPN patients has not been reported.

DOSAGE AND ADMINISTRATION

Profine (Manganese (Manganese Sulfate)) 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 Profine (Manganese (Manganese Sulfate)) 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 Profine (Manganese (Manganese Sulfate)) 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

Profine (Manganese (Manganese Sulfate)) 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

Protein Hydrolysate:

• 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
• Profine (Protein Hydrolysate) reviews

1 INDICATIONS AND USAGE

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

1.1 Severe Congenital Profine (Protein Hydrolysate) C Deficiency

Profine (Protein Hydrolysate) is indicated for pediatric and adult patients with severe congenital Profine (Protein Hydrolysate) 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 Profine C activity is feasible. (2.1)

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 Profine (Protein Hydrolysate) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Profine (Protein Hydrolysate) C activity is feasible.

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

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

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 Profine (Protein Hydrolysate) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Profine (Protein Hydrolysate) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of Profine (Protein Hydrolysate), higher peak Profine (Protein Hydrolysate) C activity levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention). Maintenance of trough Profine (Protein Hydrolysate) 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 Profine C Activity Monitoring

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

Reconstitution: Use Aseptic Technique

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

2.5 Administration of Profine [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate).
• Inject air into the vial and then withdraw the reconstituted Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) is administered to a patient.

Administration by Infusion

Administer Profine (Protein Hydrolysate) 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

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

Profine (Protein Hydrolysate), 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

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

Simultaneous administration of Profine (Protein Hydrolysate) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) C deficiency. Determine the platelet count immediately and consider discontinuation of Profine (Protein Hydrolysate).

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 Profine (Protein Hydrolysate) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

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

No inhibiting antibodies to Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate):

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 Profine (Protein Hydrolysate) and tissue plasminogen activator (tPA).

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

8.2 Labor and Delivery

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

8.3 Nursing Mothers

Profine (Protein Hydrolysate) has not been studied for use in nursing mothers. Use Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) 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

Profine (Protein Hydrolysate) [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 Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

Profine 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 Profine (Protein Hydrolysate) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) C is not compatible with life. A severe deficiency of this anticoagulant Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) C deficiency.

The Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate). 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 Profine (Protein Hydrolysate).

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Profine 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.

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

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Profine (Protein Hydrolysate) 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:

Profine (Protein Hydrolysate) 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 Profine in subjects with severe congenital Profine (Protein Hydrolysate) 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.

Of 18 episodes of PF (6 severe, 11 moderate, 1 mild) treated with Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) C deficiency were more effectively treated with Profine (Protein Hydrolysate) 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.

In a secondary efficacy rating, 13 (72.2%) of the 18 episodes of PF treated with Profine (Protein Hydrolysate) 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.

Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) treatment, as shown in Table 6.

Changes in the extent of venous thrombus were also measured for the 5 thromboembolic episodes. Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) were free of complications of PF or thromboembolic events, as shown in Table 7.

No episodes of PF occurred in four subjects ranging from 42 to 338 days of long-term prophylactic treatment with Profine (Protein Hydrolysate), as shown in Table 8. When not on prophylactic treatment and receiving Profine (Protein Hydrolysate) 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.

14.2 Retrospective Analysis

A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital Profine (Protein Hydrolysate) C deficiency who were treated with Profine (Protein Hydrolysate) 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

Profine (Protein Hydrolysate) 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 Profine (Protein Hydrolysate) C corresponds to the amidolytically measured activity of Profine (Protein Hydrolysate) 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).

Profine (Protein Hydrolysate) is available in single-dose vials that contain the following nominal product strengths:

NDC 0944-4177-05

Profine (Protein Hydrolysate) C

Concentrate (Human)

Profine (Protein Hydrolysate)

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

Profine (Protein Hydrolysate) C Concentrate

(Human)

Profine (Protein Hydrolysate)

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

Profine (Protein Hydrolysate) C

Concentrate (Human)

Profine (Protein Hydrolysate)

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

Profine (Protein Hydrolysate) C Concentrate (Human)

Profine (Protein Hydrolysate)

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 (Selenium Dioxide Monohydrate):

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Profine (Selenium (Selenium Dioxide Monohydrate)) reviews

Rx Only

TRACE ELEMENT ADDITIVE FOR IV USE AFTER DILUTION

DESCRIPTION

Profine (Selenium (Selenium Dioxide Monohydrate)) 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 Profine (Selenium (Selenium Dioxide Monohydrate)) 40 mcg/mL) and Water for Injection q.s. pH may be adjusted with nitric acid to 1.8 to 2.4.

CLINICAL PHARMACOLOGY

Profine (Selenium (Selenium Dioxide Monohydrate)) 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 Profine (Selenium (Selenium Dioxide Monohydrate)) deficiency symptoms which include muscle pain and tenderness. The symptoms have been reported to respond to supplementation of TPN solutions with Profine (Selenium (Selenium Dioxide Monohydrate)).

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

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

Plasma Profine (Selenium (Selenium Dioxide Monohydrate)) levels of 0.3 and 0.9 mcg/100 mL have been reported to produce deficiency symptoms in humans.

Profine (Selenium (Selenium Dioxide Monohydrate)) 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 Profine (Selenium (Selenium Dioxide Monohydrate)) used in supplementation. Ancillary routes of elimination are lungs and skin.

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

Profine (Selenium (Selenium Dioxide Monohydrate)) Injection should not be given undiluted by direct injection into a peripheral vein because of the potential for infusion phlebitis.

WARNINGS

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

Profine (Selenium (Selenium Dioxide Monohydrate)) 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 Profine ) is eliminated in urine and feces, Profine (Selenium (Selenium Dioxide Monohydrate)) 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 Profine (Selenium (Selenium Dioxide Monohydrate)) plasma level determinations are suggested as a guideline.

In animals, Profine (Selenium (Selenium Dioxide Monohydrate)) 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: Profine (Selenium (Selenium Dioxide Monohydrate)) 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. Profine (Selenium (Selenium Dioxide Monohydrate)) Injection should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

Presence of Profine (Selenium (Selenium Dioxide Monohydrate)) in placenta and umbilical cord blood has been reported in humans.

ADVERSE REACTIONS

The amount of Profine (Selenium (Selenium Dioxide Monohydrate)) present in Profine (Selenium (Selenium Dioxide Monohydrate)) Injection is small. Symptoms of toxicity from Profine (Selenium (Selenium Dioxide Monohydrate)) are unlikely to occur at the recommended dosage level.

OVERDOSAGE

Chronic toxicity in humans resulting from exposure to Profine (Selenium (Selenium Dioxide Monohydrate)) in industrial environments, intake of foods grown in seleniferous soils, use of selenium-contaminated water, and application of cosmetics containing Profine (Selenium (Selenium Dioxide Monohydrate)) 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 Profine (Selenium (Selenium Dioxide Monohydrate)) 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 Profine (Selenium (Selenium Dioxide Monohydrate)) 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

Profine (Selenium (Selenium Dioxide Monohydrate)) 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, Profine (Selenium (Selenium Dioxide Monohydrate)) deficiency states resulting from long-term TPN support, Profine (Selenium (Selenium Dioxide Monohydrate)) 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 Profine (Selenium (Selenium Dioxide Monohydrate)) Injection to the TPN solution under laminar flow hood is recommended. Profine (Selenium (Selenium Dioxide Monohydrate)) is physically compatible with the electrolytes and other trace elements usually present in amino-acid/dextrose solution used for TPN. Frequent monitoring of plasma Profine (Selenium (Selenium Dioxide Monohydrate)) levels is suggested as a guideline for subsequent administration. The normal whole blood range for Profine (Selenium (Selenium Dioxide Monohydrate)) 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

Profine (Selenium (Selenium Dioxide Monohydrate)) Injection containing selenious acid 65.4 mcg/mL (equivalent to elemental Profine (Selenium (Selenium Dioxide Monohydrate)) 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

Profine (Selenium (Selenium Dioxide Monohydrate)) INJECTION

Profine (Selenium (Selenium Dioxide Monohydrate)) 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

Profine (Selenium (Selenium Dioxide Monohydrate)) INJECTION

Profine (Selenium (Selenium Dioxide Monohydrate)) 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

Vitamin A:

• Dosage and administration
• Warning
• Clinical pharmacology
• Dietary supplementation
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Profine (Vitamin A) reviews

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

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

Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, Profine (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.

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

The reaction may be expressed by the equation:

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

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

DIETARY SUPPLEMENTATION

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

WARNINGS

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

PRECAUTIONS

The suggested dose of Profine (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Profine (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

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

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

Profine (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 Profine prescribed?
• Dosage and administration
• Profine (Vitamin B12) side effects, adverse reactions
• Profine contraindications
• Profine using during pregnancy and breastfeeding
• Special instructions
• Profine (Vitamin B12) drug interactions
• Profine (Vitamin B12) reviews

Pharmacological action

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

Dosage and administration

Profine is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Profine (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 Profine (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 Profine (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.

Profine (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

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

Allergic reactions: rarely - urticaria.

Profine contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Profine 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 Profine 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.

Profine (Vitamin B12) drug interactions

In an application of Profine (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 Profine (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 Profine prescribed?
• Dosage and administration
• Profine (Vitamin C) side effects, adverse reactions
• Profine contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Profine drug interactions
• Profine in case of emergency / overdose
• Profine (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. Profine (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. Profine (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 Profine prescribed?

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

Profine (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.

Profine 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

Profine (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.

Profine (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.

Profine 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 Profine (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.

Profine (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.

Profine in case of emergency / overdose

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

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

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

Zinc Sulfate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Profine (Zinc Sulfate) reviews

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Profine (Zinc Sulfate) 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 Profine (Zinc Sulfate) 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 Profine (Zinc Sulfate) from a bolus injection. Administration of Profine (Zinc Sulfate) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Profine (Zinc Sulfate) are suggested as a guideline for subsequent Profine (Zinc Sulfate) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

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

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

Calcium supplements may confer a protective effect against Profine (Zinc Sulfate) toxicity.

DOSAGE AND ADMINISTRATION

Profine (Zinc Sulfate) 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 Profine (Zinc Sulfate) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Profine (Zinc Sulfate).

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

Profine (Zinc Sulfate) 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

Profine (Zinc Sulfate)

1 mg/mL

Profine (Zinc Sulfate) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA