DRUGS & SUPPLEMENTS

Protimin Drops

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Protimin Drops uses

Protimin Drops consists of Copper (Copper Sulfate), Folic Acid, Iron (Ferric Ammonium Citrate), Manganese (Manganese Sulfate), Protein Hydrolysate.

Copper (Copper Sulfate):



Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Protimin Drops (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 Protimin Drops (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 Protimin Drops (Copper (Copper Sulfate))® onto hair since contact with Protimin Drops (Copper (Copper Sulfate))® may cause some hair loss. Do not contaminate feed.

NOTE: Protimin Drops (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:

Protimin Drops (Copper (Copper Sulfate)) Naphthenate..........37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients.........................62.5% w/w

Total......................................... 100.0%

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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

Protimin Drops (Folic Acid)® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.

CONTRAINDICATIONS

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

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

PRECAUTIONS

Protimin Drops (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 Protimin Drops (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

Protimin Drops (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.

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

MEDA PHARMACEUTICALS mark and logo are trademarks of Meda AB.

IN-6885-02 Rev 6/2014

Iron (Ferric Ammonium Citrate):


1 INDICATIONS AND USAGE

Protimin Drops (Iron (Ferric Ammonium Citrate)) is indicated for the treatment of Protimin Drops (Iron (Ferric Ammonium Citrate)) deficiency anemia in patients with chronic kidney disease (CKD).

Protimin Drops (Iron (Ferric Ammonium Citrate)) is an Protimin Drops (Iron (Ferric Ammonium Citrate)) replacement product indicated for the treatment of Protimin Drops (Iron (Ferric Ammonium Citrate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Protimin Drops ) must only be administered intravenously either by slow injection or by infusion. The dosage of Protimin Drops (Iron (Ferric Ammonium Citrate)) is expressed in mg of elemental Protimin Drops (Iron (Ferric Ammonium Citrate)). Each mL contains 20 mg of elemental Protimin Drops (Iron (Ferric Ammonium Citrate)).

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

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

Administer Protimin Drops (Iron (Ferric Ammonium Citrate)) 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. Protimin Drops (Iron (Ferric Ammonium Citrate)) should be administered early during the dialysis session. The usual total treatment course of Protimin Drops (Iron (Ferric Ammonium Citrate)) is 1000 mg. Protimin Drops (Iron (Ferric Ammonium Citrate)) treatment may be repeated if Protimin Drops (Iron (Ferric Ammonium Citrate)) deficiency reoccurs.

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

Administer Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)), 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. Protimin Drops (Iron (Ferric Ammonium Citrate)) treatment may be repeated if Protimin Drops (Iron (Ferric Ammonium Citrate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)) in a maximum of 250 mL of 0.9% NaCl. Protimin Drops (Iron (Ferric Ammonium Citrate)) treatment may be repeated if Protimin Drops (Iron (Ferric Ammonium Citrate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Protimin Drops (Iron (Ferric Ammonium Citrate)) maintenance treatment

The dosing for Protimin Drops (Iron (Ferric Ammonium Citrate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Protimin Drops (Iron (Ferric Ammonium Citrate)) maintenance treatment: Administer Protimin Drops (Iron (Ferric Ammonium Citrate)) 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. Protimin Drops (Iron (Ferric Ammonium Citrate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Protimin Drops (Iron (Ferric Ammonium Citrate)) maintenance treatment

The dosing for Protimin Drops (Iron (Ferric Ammonium Citrate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Protimin Drops (Iron (Ferric Ammonium Citrate)) maintenance treatment: Administer Protimin Drops (Iron (Ferric Ammonium Citrate)) 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. Protimin Drops (Iron (Ferric Ammonium Citrate)) treatment may be repeated if necessary.

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3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Protimin Drops (Iron (Ferric Ammonium Citrate))
  • Known hypersensitivity to Protimin Drops (Iron (Ferric Ammonium Citrate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

Protimin Drops ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Protimin Drops (Iron (Ferric Ammonium Citrate)). Hypotension following administration of Protimin Drops (Iron (Ferric Ammonium Citrate)) may be related to the rate of administration and/or total dose administered .

5.3 Protimin Drops (Iron (Ferric Ammonium Citrate)) Overload

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

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6 ADVERSE REACTIONS

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

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


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

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

respiratory tract infections, Pharyngitis

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

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

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 Protimin Drops (Iron (Ferric Ammonium Citrate)) maintenance treatment with Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Protimin Drops (Iron (Ferric Ammonium Citrate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Protimin Drops (Iron (Ferric Ammonium Citrate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Protimin Drops (Iron (Ferric Ammonium Citrate)) 0.5 mg/kg group, 10 (21%) patients in the Protimin Drops (Iron (Ferric Ammonium Citrate)) 1.0 mg/kg group, and 10 (21%) patients in the Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)). 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 Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)) injection. Reactions have occurred following the first dose or subsequent doses of Protimin Drops (Iron (Ferric Ammonium Citrate)). 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.

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7 DRUG INTERACTIONS

Drug interactions involving Protimin Drops (Iron (Ferric Ammonium Citrate)) have not been studied. However, Protimin Drops (Iron (Ferric Ammonium Citrate)) may reduce the absorption of concomitantly administered oral Protimin Drops (Iron (Ferric Ammonium Citrate)) 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, Protimin Drops ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) (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 Protimin Drops (Iron (Ferric Ammonium Citrate)) sucrose. Because animal reproductive studies are not always predictive of human response, Protimin Drops (Iron (Ferric Ammonium Citrate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Protimin Drops ) for Protimin Drops (Iron (Ferric Ammonium Citrate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Protimin Drops (Iron (Ferric Ammonium Citrate)) for Protimin Drops (Iron (Ferric Ammonium Citrate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Protimin Drops (Iron (Ferric Ammonium Citrate)) 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)]

Protimin Drops (Iron (Ferric Ammonium Citrate)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

Clinical studies of Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)), 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 Protimin Drops (Iron (Ferric Ammonium Citrate)) in humans. Excessive dosages of Protimin Drops (Iron (Ferric Ammonium Citrate)) may lead to accumulation of Protimin Drops (Iron (Ferric Ammonium Citrate)) in storage sites potentially leading to hemosiderosis. Do not administer Protimin Drops (Iron (Ferric Ammonium Citrate)) to patients with Protimin Drops (Iron (Ferric Ammonium Citrate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Protimin Drops (Iron (Ferric Ammonium Citrate)) 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

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

Each mL contains 20 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) as Protimin Drops (Iron (Ferric Ammonium Citrate)) sucrose in water for injection. Protimin Drops (Iron (Ferric Ammonium Citrate)) is available in 10 mL single-use vials (200 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) per 10 mL), 5 mL single-use vials (100 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) 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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

Protimin Drops (Iron (Ferric Ammonium Citrate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)) sucrose.

Protimin Drops (Iron (Ferric Ammonium Citrate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Protimin Drops (Iron (Ferric Ammonium Citrate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Protimin Drops (Iron (Ferric Ammonium Citrate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) (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 Protimin Drops ).

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 Protimin Drops (Iron (Ferric Ammonium Citrate)) treatment and 24 in the historical control group) with Protimin Drops (Iron (Ferric Ammonium Citrate)) deficiency anemia. Eligibility criteria for Protimin Drops (Iron (Ferric Ammonium Citrate)) 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.

Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)), who were off intravenous Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


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


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Protimin Drops (Iron (Ferric Ammonium Citrate)) (n=69 Historical Control (n=18) Protimin Drops (Iron (Ferric Ammonium Citrate))

(n=73)

Historical Control

(n=18)

Protimin Drops (Iron (Ferric Ammonium Citrate))

(n=71)

Historical

Control

(n=15)

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

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

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

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

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

Protimin Drops ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)), each 5 mL vial contains 100 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)), and each 2.5 mL vial contains 50 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) (20 mg/mL).

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

16.2 Stability and Storage

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

Syringe Stability: Protimin Drops (Iron (Ferric Ammonium Citrate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) per mL, or undiluted (20 mg elemental Protimin Drops (Iron (Ferric Ammonium Citrate)) 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: Protimin Drops (Iron (Ferric Ammonium Citrate)), 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 Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)) 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 Protimin Drops (Iron (Ferric Ammonium Citrate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Protimin Drops (Iron (Ferric Ammonium Citrate)) 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

Protimin Drops (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 Protimin Drops (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 Protimin Drops (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 Protimin Drops (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.

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

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

DOSAGE AND ADMINISTRATION

Protimin Drops (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 Protimin Drops (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 Protimin Drops (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

Protimin Drops (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:


1 INDICATIONS AND USAGE

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

1.1 Severe Congenital Protimin Drops (Protein Hydrolysate) C Deficiency

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


Protimin Drops (Protein Hydrolysate) Dosing Schedule for Acute Episodes, Short-term Prophyaxis and Long-term Prophylaxis Dosing is based upon a pivotal clinical trial of 15 patients


Initial Dose The dose regimen should be adjusted according to the pharmacokinetic profile for each individual. (2.1, 2.2)


Subsequent # Doses


Maintenance Dose


Acute Episodes, Short-term ProphyaxisProtimin Drops (Protein Hydrolysate) should be continued until desired anticoagulation is achieved.


100-120 IU/kg


60-80 IU/kg

Q 6 hours


45-60 IU/kg

Q 6 or Q 12 hours


Long-term Prophylaxis


NA


NA


45-60 IU/kg

Q 12 hours


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

2.1 General

For intravenous administration only.

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

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

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

NA = Not applicable; Q = every.

Initial Dose The dose regimen should be adjusted according to the pharmacokinetic profile for each individual. (2.1, 2.2)


Subsequent 3

Doses


Maintenance

Dose


Acute Episode /

Short-term ProphylaxisProtimin Drops (Protein Hydrolysate) should be continued until desired anticoagulation is achieved.


100-120 IU/kg


60 - 80 IU/kg

Q 6 hours


45 - 60 IU/kg

Q 6 or 12 hours


Long-term Prophylaxis


NA


NA


45 - 60 IU/kg

Q 12 hours


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

In patients receiving prophylactic administration of Protimin Drops (Protein Hydrolysate), higher peak Protimin Drops (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 Protimin Drops (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 Protimin Drops C Activity Monitoring

The measurement of Protimin Drops (Protein Hydrolysate) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Protimin Drops (Protein Hydrolysate) C before and during treatment with Protimin Drops (Protein Hydrolysate). The half-life of Protimin Drops (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 Protimin Drops (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 Protimin Drops (Protein Hydrolysate) C levels to maintain the trough Protimin Drops (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 Protimin Drops (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 Protimin Drops C, itself a vitamin K-dependent plasma Protimin Drops (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 Protimin Drops (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 Protimin Drops (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 Protimin Drops (Protein Hydrolysate) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

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

2.5 Administration of Protimin Drops [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

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

Administration by Infusion

Administer Protimin Drops (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

Protimin Drops (Protein Hydrolysate) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Protimin Drops (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 Protimin Drops (Protein Hydrolysate) C at a concentration of 100 IU/mL.

Protimin Drops (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

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

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

5.4 Heparin-induced Thrombocytopenia

Protimin Drops (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 Protimin Drops (Protein Hydrolysate) C deficiency. Determine the platelet count immediately and consider discontinuation of Protimin Drops (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 Protimin Drops (Protein Hydrolysate) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

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

No inhibiting antibodies to Protimin Drops (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 Protimin Drops (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 Protimin Drops (Protein Hydrolysate) and tissue plasminogen activator (tPA).

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

8.2 Labor and Delivery

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

8.3 Nursing Mothers

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

Protimin Drops (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 Protimin Drops (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 Protimin Drops (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.

Abbreviations: IEX, Ion Exchange Chromatography; IAX, Immunoaffinity Chromatography; HIV-1, Human Immunodeficiency Virus Type I; TBEV, Tick-Borne Encephalitis Virus (model for hepatitis C virus); BVDV, Bovine Viral Diarrhea Virus (model virus for HCV and other small, enveloped RNA viruses); PRV, Pseudorabies Virus (model virus for enveloped DNA viruses, e.g. HBV, Hepatitis B Virus); HAV, Hepatitis A Virus; MMV, Mice Minute Virus (model for Human Parvovirus B19 and for non enveloped viruses); n.d., not done.

Manufact-uring Step


HIV-1


HCV Model Viruses


PRV


HAV


MMV


BVDV


TBEV


P80 Treatment


>5.1


>4.7


n.d.


2.5Coupled with IEX. I


>3.8


1.4


IAX


5.7


n.d.


4.8


5.4


3.1


3.6


Vapor Heating


4.6


>5.9


n.d.


5.9


>4.2


1.2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

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


PK parameter


N


Median


95% CI for median


Min


Max


Cmax [IU/dL]


21


110


106 to 127


40


141


Tmax [h]


21


0.50


0.50 to 1.05


0.17


1.33


Incremental recovery

[(IU/dL)/(IU/kg)]


21


1.42


1.32 to 1.59


0.50


1.76


Initial half-life [h]


21


7.8


5.4 to 9.3


3.0


36.1


Terminal half-life [h]


21


9.9


7.0 to 12.4


4.4


15.8


Half-life by the non-compartmental approach [h]


21


9.8


7.1 to 11.6


4.9


14.7


AUC0-Infinity [IU*h/dL]


21


1500


1289 to 1897


344


2437


MRT [h]


21


14.1


10.3 to 16.7


7.1


21.3


Clearance [dL/kg/h]


21


0.0533


0.0428 to 0.0792


0.0328


0.2324


Volume of distribution at steady state [dL/kg]


21


0.74


0.70 to 0.89


0.44


1.65


Cmax = Maximum concentration after infusion; T max = Time at maximum concentration;

AUC 0-Infinity = Area under the curve from 0 to infinity; MRT = Mean residence time; and

Incremental recovery = Maximum increase in Protimin Drops (Protein Hydrolysate) C concentration following infusion divided by dose


The Protimin Drops (Protein Hydrolysate) C plasma activity was measured by chromogenic and/or clotting assay. The maximum plasma concentrations (Cmax) 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 Protimin Drops (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 Protimin Drops (Protein Hydrolysate).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Protimin Drops (Protein Hydrolysate) may be different between very young children and adults. The systemic exposure (Cmax and AUC) may be considerably reduced due to a faster clearance, a larger volume of distribution, and/or a shorter half-life of Protimin Drops (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 Protimin Drops (Protein Hydrolysate) C activity levels. See DOSAGE AND ADMINISTRATION: Protimin Drops (Protein Hydrolysate) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Protimin Drops 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.

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

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Protimin Drops (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:

Protimin Drops (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 Protimin Drops in subjects with severe congenital Protimin Drops (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.


Protimin Drops (Protein Hydrolysate) C

Concentrate (Human)


Historical

Controls


Episode Type


Primary Efficacy Rating


N


%


N


%


Purpura Fulminans


Effective


17


94.4


11


52.4


Effective with Complication


1


5.6


7


33.3


Not Effective


0


0.0


3


14.3


Total


18


100


21


100


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




Purpura Fulminans

Skin Necrosis


Other Thrombotic Events


Total




Mild


Moderate


Severe


Total


Total




Rating Category


N


%


N


%


N


%


N


%


N


%


N


%


Excellent


1


5.6


7


38.9


5


27.8


13


72.2


4


80.0


17


73.9


Good


0


0.0


4


22.2


0


0.0


4


22.2


1


20.0


5


21.7


Fair


0


0.0


0


0.0


1


5.6


1


5.6


0


0


1


4.3


Total


1


5.6


11


61.1


6


33.3


18


100.0


5


100.0


23


100.0


N = Number of episodes


In a secondary efficacy rating, 13 (72.2%) of the 18 episodes of PF treated with Protimin Drops (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.

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


Lesion Type


Number of Episodes

(Number of Subjects)


Mean


Median


Minimum


Maximum


Non-necrotic


16 (9 subjects)


4.6


4.0


1


12


Necrotic


7 (5 subjects)


21.1


11.0


5


52


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


Reason for

Treatment


Number of Treatments


Presentation of Purpura Fulminans During Treatment Episodes


Thromboembolic Complications During Treatment Episode


Number of Treatments Free of Complications


N


%


N


%


N


%


Anticoagulation Therapy


3


0


0.0


0


0.0


3


100.0


Surgical Procedure


4


0


0.0


0


0.0


4


100.0


Total


7


0


0.0


0


0.0


7


100.0


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


Summary Statistic


Long-Term Prophylactic Treatment


While On-Demand Total number of episodes while subjects were On-Demand was 13


Time to First Episode After Existing Long Term Prophylaxis


Number of Episodes per Subject


Number of Days Receiving Prophylactic Treatment


Monthly Rate of Episodes


Number of Episodes per Subject


Number of Days Not Receiving Study Drug


Monthly Rate of Episodes


Mean


0


229


0.0


3.3


165


1.91


23.3


Median


0


268


0.0


3.0


159


0.49


24.5


Minimum


0


42


0.0


1.0


19


0.25


12.0


Maximum


0


338


0.0


6.0


323


6.40


32.0

14.2 Retrospective Analysis

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

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

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

NDC 0944-4177-05

Protimin Drops (Protein Hydrolysate) C

Concentrate (Human)

Protimin Drops (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

Protimin Drops (Protein Hydrolysate) C Concentrate

(Human)

Protimin Drops (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

Protimin Drops (Protein Hydrolysate) C

Concentrate (Human)

Protimin Drops (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

Protimin Drops (Protein Hydrolysate) C Concentrate (Human)

Protimin Drops (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

Protimin Drops pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Protimin Drops available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Protimin Drops destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Protimin Drops Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Protimin Drops pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."FOLIC ACID INJECTION, SOLUTION [FRESENIUS KABI USA, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ASCORBIC ACID; BIOTIN; CYANOCOBALAMIN; DEXPANTHENOL; ERGOCALCIFEROL; FOLIC ACID; NIACINAMIDE; PHYTONADIONE; PYRIDOXINE HYDROCHLORIDE; RIBOFLAVIN 5'-PHOSPHATE SODIUM; THIAMINE HYDROCHLORIDE; VITAMIN A; VITAMIN E: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."COPPER: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Protimin Drops?

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

Is Protimin Drops addictive or habit forming?

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

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

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Review

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

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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