Introduction

Anticoagulant; a vitamin K-dependent serine protease precursor prepared from pooled human plasma.

Uses for Protein C Concentrate

Congenital Protein C Deficiency

Replacement therapy in patients with severe congenital protein C deficiency for prevention and treatment of venous thrombosis and purpura fulminans (designated an orphan drug by FDA for this use).

Protein C Concentrate Dosage and Administration

General

• Dosage and duration of therapy is dependent on the severity of protein C deficiency, the plasma protein C concentration, and the patient’s age and clinical condition.

• Individualize dosage based on measured protein C activity, expressed as a percentage of normal plasma protein C concentrations, and adjust according to the pharmacokinetic profile for each individual patient.

• Determine plasma protein C concentrations before and during therapy using a chromogenic assay to measure protein C activity.

• During acute thrombotic episodes, measure protein C activity immediately before administration until the patient is stabilized and continue monitoring afterward. The magnitude of increase in plasma protein C activity may be substantially reduced during acute episodes.

• Monitor coagulation parameters; however, correlation between levels of protein C activity and coagulation parameters not yet established.

Administration

IV Administration

Administer by IV injection.

Initiate therapy under supervision of a clinician experienced in replacement therapy with coagulation factors/inhibitors and where monitoring of protein C activity is feasible.

Protein C (human) may be self-administered if clinician determines that the patient and/or caregiver is competent to safely administer the drug after appropriate training.

Reconstitution

Prior to reconstitution, allow lyophilized powder and manufacturer-supplied diluent to warm to room temperature.

Reconstitute lyophilized powder with diluent provided by manufacturer. Use strict aseptic technique since drug contains no preservative.

Reconstitute appropriate number of vials based on the indicated dosage. Vials contain approximately 500 or 1000 IU protein C (human); actual potency is labeled on each vial.

Reconstitute single-use vials of lyophilized powder by adding 5 or 10 mL of sterile water for injection to vial containing approximately 500 or 1000 units of protein C (human), respectively, using transfer needle provided by manufacturer; resulting solution contains approximately 100 units of protein C (human) per mL. Swirl vial gently until powder is completely dissolved.

Withdraw reconstituted solution from vial(s) using filter needle provided by manufacturer. Before administration, replace filter needle with a suitable needle or infusion set with winged adapter. Filter needle provided by manufacturer is intended to filter contents of a single vial.

Administer at room temperature within 3 hours of reconstitution.

Rate of Administration

Patients weighing <10 kg: Inject at a maximum rate of 0.2 mL/kg per minute.

Patients weighing ≥10 kg: Inject at a maximum rate of 2 mL/minute.

Dosage

Potency of protein C (human) is determined by chromogenic assay and is expressed in international units (IU, units) as tested against the activity of the WHO reference standard.

One unit is approximately equivalent to the protein C activity (as measured by an amidolytic assay) present in 1 mL of plasma. The number of units of protein C is indicated on the label of each vial.

Pediatric Patients

Congenital Protein C Deficiency

Treatment of Acute Episodes of Venous Thrombosis and Purpura Fulminans

Initially, 100–120 units/kg, followed by 60–80 units/kg every 6 hours for 3 doses and a subsequent maintenance dosage of 45–60 units/kg every 6 or 12 hours.

Adjust dosage according to measured plasma protein C activity; initially maintain peak plasma protein C activity at 100% of normal. Following resolution of the acute event, maintain trough plasma protein C activity at a level above 25% of normal for the duration of treatment.

In patients initiating oral anticoagulant therapy, continue protein C replacement therapy until adequate anticoagulation is achieved. (See Specific Drugs under Interactions.)

Prophylaxis of Thrombotic Events

Short-term prophylaxis: Initially, 100–120 units/kg, followed by 60–80 units/kg every 6 hours for 3 doses and a subsequent maintenance dosage of 45–60 units/kg every 6 or 12 hours.

Long-term prophylaxis (maintenance dosage): 45–60 units/kg every 12 hours; adjust dosage to maintain trough plasma protein C activity above 25% of normal. An increase in peak plasma protein C activity may be appropriate during periods of increased thrombotic risk (e.g., infection, trauma, surgery).

Adjust dosage according to measured plasma protein C activity; initially maintain peak plasma protein C activity at 100% of normal. Following resolution of the acute event, maintain trough plasma protein C activity at a level above 25% of normal for the duration of treatment.

In patients initiating oral anticoagulant therapy, continue protein C replacement therapy until adequate anticoagulation is achieved. (See Specific Drugs under Interactions.)

Adults

Congenital Protein C Deficiency

Treatment of Acute Episodes of Venous Thrombosis and Purpura Fulminans

Initially, 100–120 units/kg, followed by 60–80 units/kg every 6 hours for 3 doses and a subsequent maintenance dosage of 45–60 units/kg every 6 or 12 hours.

Adjust dosage according to measured plasma protein C activity; initially maintain peak plasma protein C activity at 100% of normal. Following resolution of the acute event, maintain trough plasma protein C activity at a level above 25% of normal for the duration of treatment.

In patients initiating oral anticoagulant therapy, continue protein C replacement therapy until adequate anticoagulation is achieved. (See Specific Drugs under Interactions.)

Prophylaxis of Thrombotic Events

Short-term prophylaxis: Initially, 100–120 units/kg, followed by 60–80 units/kg every 6 hours for 3 doses and a subsequent maintenance dosage of 45–60 units/kg every 6 or 12 hours.

Long-term prophylaxis (maintenance dosage): 45–60 units/kg every 12 hours; adjust dosage to maintain trough plasma protein C activity above 25% of normal. An increase in peak plasma protein C activity may be appropriate during periods of increased thrombotic risk (e.g., infection, trauma, surgery).

Adjust dosage according to measured plasma protein C activity; initially maintain peak plasma protein C activity at 100% of normal. Following resolution of the acute event, maintain trough plasma protein C activity at a level above 25% of normal for the duration of treatment.

In patients initiating oral anticoagulant therapy, continue protein C replacement therapy until adequate anticoagulation is achieved. (See Specific Drugs under Interactions.)

Prescribing Limits

Pediatric Patients

Congenital Protein C Deficiency

IV

Patients weighing <10 kg: Inject at a maximum rate of 0.2 mL/kg per minute.

Patients weighing ≥10 kg: Inject at a maximum rate of 2 mL/minute.

Adults

Congenital Protein C Deficiency

IV

Inject at a maximum rate of 2 mL/minute.

Special Populations

No special population dosage recommendations at this time.

Contraindications

• No known contraindications.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reaction

Possible hypersensitivity reactions, including anaphylaxis. If hypersensitivity reaction occurs, discontinue immediately and institute appropriate therapy as indicated.

Possible allergic reactions to trace amounts of murine (mouse) protein and/or heparin.

Antibody Formation

Inhibiting antibodies to protein C (human) not observed in clinical studies; however, the potential for developing antibodies cannot be ruled out.

Risk of Transmissible Agents in Plasma-derived Preparations

Potential vehicle for transmission of human viruses (i.e., HIV, hepatitis A [HAV], hepatitis B [HBV], hepatitis C [HCV], parvovirus B19) and other infectious agents.

Improved donor screening, viral-inactivating procedures (e.g., solvent/detergent, heat treatment), and/or immunoaffinity chromatography procedures have reduced but not completely eliminated risk of pathogen transmission with plasma-derived protein C (human) preparations. Some viruses (e.g., human parvovirus B19, HAV) are difficult to remove or inactivate.

Human parvovirus B19 infection is most serious in pregnant women (fetal infection) or immunocompromised patients.

Consider vaccination (against HAV and HBV infection) for patients who routinely or repeatedly receive protein C (human).

Theoretical possibility of transmitting causative agent of Creutzfeldt-Jakob disease (CJD).

Report suspected infections to the manufacturer at 866-888-2472.

Bleeding

Severe bleeding reported; may be associated with concomitant use of anticoagulants. (See Specific Drugs under Interactions.)

Heparin-induced Thrombocytopenia

Possible heparin-induced thrombocytopenia (HIT) due to trace amounts of heparin contained in protein C (human) preparations.

If HIT occurs, immediately determine platelet count and consider discontinuance of protein C (human).

Sodium Content

The quantity of sodium in the maximum daily dosage of protein C (human) exceeds 200 mg.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether protein C (human) is distributed into milk in humans.

Pediatric Use

Safety and efficacy established in children ≥2 days of age.

Pharmacokinetics not established in pediatric patients. However, systemic exposure may be reduced in very young children compared with older individuals; consider this fact when selecting a dosage regimen for children. (See Pediatric Patients under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Geriatric Use

Experience in patients ≥65 years of age is insufficient to determine whether they respond differently than younger adults.

Hepatic Impairment

Safety and efficacy not established in patients with hepatic impairment.

Renal Impairment

Safety and efficacy not established in patients with renal impairment.

Monitor closely for sodium overload. (See Sodium Content under Cautions.)

Common Adverse Effects

Hypersensitivity reactions (e.g., itching, rash), lightheadedness.

General

• Dosage and duration of therapy is dependent on the severity of protein C deficiency, the plasma protein C concentration, and the patient’s age and clinical condition.

• Individualize dosage based on measured protein C activity, expressed as a percentage of normal plasma protein C concentrations, and adjust according to the pharmacokinetic profile for each individual patient.

• Determine plasma protein C concentrations before and during therapy using a chromogenic assay to measure protein C activity.

• During acute thrombotic episodes, measure protein C activity immediately before administration until the patient is stabilized and continue monitoring afterward. The magnitude of increase in plasma protein C activity may be substantially reduced during acute episodes.

• Monitor coagulation parameters; however, correlation between levels of protein C activity and coagulation parameters not yet established.

Administration

IV Administration

Administer by IV injection.

Initiate therapy under supervision of a clinician experienced in replacement therapy with coagulation factors/inhibitors and where monitoring of protein C activity is feasible.

Protein C (human) may be self-administered if clinician determines that the patient and/or caregiver is competent to safely administer the drug after appropriate training.

Reconstitution

Prior to reconstitution, allow lyophilized powder and manufacturer-supplied diluent to warm to room temperature.

Reconstitute lyophilized powder with diluent provided by manufacturer. Use strict aseptic technique since drug contains no preservative.

Reconstitute appropriate number of vials based on the indicated dosage. Vials contain approximately 500 or 1000 IU protein C (human); actual potency is labeled on each vial.

Reconstitute single-use vials of lyophilized powder by adding 5 or 10 mL of sterile water for injection to vial containing approximately 500 or 1000 units of protein C (human), respectively, using transfer needle provided by manufacturer; resulting solution contains approximately 100 units of protein C (human) per mL. Swirl vial gently until powder is completely dissolved.

Withdraw reconstituted solution from vial(s) using filter needle provided by manufacturer. Before administration, replace filter needle with a suitable needle or infusion set with winged adapter. Filter needle provided by manufacturer is intended to filter contents of a single vial.

Administer at room temperature within 3 hours of reconstitution.

Rate of Administration

Patients weighing <10 kg: Inject at a maximum rate of 0.2 mL/kg per minute.

Patients weighing ≥10 kg: Inject at a maximum rate of 2 mL/minute.

Dosage

Potency of protein C (human) is determined by chromogenic assay and is expressed in international units (IU, units) as tested against the activity of the WHO reference standard.

One unit is approximately equivalent to the protein C activity (as measured by an amidolytic assay) present in 1 mL of plasma. The number of units of protein C is indicated on the label of each vial.

Pediatric Patients

Congenital Protein C Deficiency

Treatment of Acute Episodes of Venous Thrombosis and Purpura Fulminans

Initially, 100–120 units/kg, followed by 60–80 units/kg every 6 hours for 3 doses and a subsequent maintenance dosage of 45–60 units/kg every 6 or 12 hours.

Adjust dosage according to measured plasma protein C activity; initially maintain peak plasma protein C activity at 100% of normal. Following resolution of the acute event, maintain trough plasma protein C activity at a level above 25% of normal for the duration of treatment.

In patients initiating oral anticoagulant therapy, continue protein C replacement therapy until adequate anticoagulation is achieved. (See Specific Drugs under Interactions.)

Prophylaxis of Thrombotic Events

Short-term prophylaxis: Initially, 100–120 units/kg, followed by 60–80 units/kg every 6 hours for 3 doses and a subsequent maintenance dosage of 45–60 units/kg every 6 or 12 hours.

Long-term prophylaxis (maintenance dosage): 45–60 units/kg every 12 hours; adjust dosage to maintain trough plasma protein C activity above 25% of normal. An increase in peak plasma protein C activity may be appropriate during periods of increased thrombotic risk (e.g., infection, trauma, surgery).

Adjust dosage according to measured plasma protein C activity; initially maintain peak plasma protein C activity at 100% of normal. Following resolution of the acute event, maintain trough plasma protein C activity at a level above 25% of normal for the duration of treatment.

In patients initiating oral anticoagulant therapy, continue protein C replacement therapy until adequate anticoagulation is achieved. (See Specific Drugs under Interactions.)

Adults

Congenital Protein C Deficiency

Treatment of Acute Episodes of Venous Thrombosis and Purpura Fulminans

Initially, 100–120 units/kg, followed by 60–80 units/kg every 6 hours for 3 doses and a subsequent maintenance dosage of 45–60 units/kg every 6 or 12 hours.

Adjust dosage according to measured plasma protein C activity; initially maintain peak plasma protein C activity at 100% of normal. Following resolution of the acute event, maintain trough plasma protein C activity at a level above 25% of normal for the duration of treatment.

In patients initiating oral anticoagulant therapy, continue protein C replacement therapy until adequate anticoagulation is achieved. (See Specific Drugs under Interactions.)

Prophylaxis of Thrombotic Events

Short-term prophylaxis: Initially, 100–120 units/kg, followed by 60–80 units/kg every 6 hours for 3 doses and a subsequent maintenance dosage of 45–60 units/kg every 6 or 12 hours.

Long-term prophylaxis (maintenance dosage): 45–60 units/kg every 12 hours; adjust dosage to maintain trough plasma protein C activity above 25% of normal. An increase in peak plasma protein C activity may be appropriate during periods of increased thrombotic risk (e.g., infection, trauma, surgery).

Adjust dosage according to measured plasma protein C activity; initially maintain peak plasma protein C activity at 100% of normal. Following resolution of the acute event, maintain trough plasma protein C activity at a level above 25% of normal for the duration of treatment.

In patients initiating oral anticoagulant therapy, continue protein C replacement therapy until adequate anticoagulation is achieved. (See Specific Drugs under Interactions.)

Prescribing Limits

Pediatric Patients

Congenital Protein C Deficiency

IV

Patients weighing <10 kg: Inject at a maximum rate of 0.2 mL/kg per minute.

Patients weighing ≥10 kg: Inject at a maximum rate of 2 mL/minute.

Adults

Congenital Protein C Deficiency

IV

Inject at a maximum rate of 2 mL/minute.

Special Populations

No special population dosage recommendations at this time.

No formal drug interaction studies performed to date.

Specific Drugs