Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Ceprotin: 500 units (1 ea); 1000 units (1 ea) [contains albumin human, heparin, mouse (murine) and/or hamster protein]
Pharmacology
Mechanism of Action
Converted to activated protein C (APC). APC is a serine protease which inactivates factors Va and VIIIa, limiting thrombotic formation. In vitro data also suggest inhibition of plasminogen activator inhibitor-1 (PAF-1) resulting in profibrinolytic activity, inhibition of macrophage production of tumor necrosis factor, blocking of leukocyte adhesion, and limitation of thrombin-induced inflammatory responses.
Pharmacokinetics/Pharmacodynamics
Distribution
Vd: Median: 0.074L/kg (range: 0.044 to 0.165 L/kg)
Metabolism
Activated protein C (APC) inactivated by plasma protease inhibitors
Onset of Action
30 minutes
Time to Peak
Plasma: Tmax: 0.5 hours; range: 0.17 to 1.33 hours
Half-Life Elimination
Median: 9.8 hours; range: 4.9 to 14.7 hours
Use: Labeled Indications
Severe congenital protein C deficiency: Prevention and treatment of venous thrombosis and purpura fulminans in adults and pediatric patients with severe congenital protein C deficiency.
Contraindications
There are no contraindications listed in the manufacturer’s labeling.
Dosage and Administration
Dosing: Adult
Patient variables (including age, clinical condition, severity of protein C deficiency, and plasma levels of protein C) will influence dosing and duration of therapy. Individualize frequency, duration, and dose based on protein C activity and patient pharmacokinetic profile.
Severe congenital protein C deficiency: IV:
Acute episode/short-term prophylaxis: Initial dose: 100 to 120 units/kg (for determination of recovery and half-life)
Subsequent 3 doses: 60 to 80 units/kg every 6 hours (adjust to maintain peak protein C activity of 100%)
Maintenance dose: 45 to 60 units/kg every 6 or 12 hours (adjust to maintain recommended maintenance trough protein C activity levels >25%)
Long-term prophylaxis: Maintenance dose: 45 to 60 units/kg every 12 hours (recommended maintenance trough protein C activity levels >25%)
Note: Maintain target peak protein C activity of 100% during acute episodes and short-term prophylaxis. After resolution of the acute episode or for long-term prophylaxis, maintain trough levels of protein C activity >25%. Higher peak levels of protein C may be necessary in prophylactic therapy of patients at increased risk for thrombosis (eg, infection, trauma, surgical intervention). If a patient is switched to an oral anticoagulant, continue protein C replacement until stable anticoagulation is obtained. Initiate the oral anticoagulant at a low dose and adjust incrementally, rather than using a standard loading dose.
Dosing: Pediatric
Note: Patient variables (including age, clinical condition, and plasma levels of protein C) will influence dosing and duration of therapy. Individualize dosing based on protein C activity and patient's pharmacokinetic profile.
Severe congenital protein C deficiency: IV: Infants, Children, and Adolescents:
Acute episode/short-term prophylaxis:
Initial dose: 100-120 units/kg/dose (for determination of recovery and half-life) followed by subsequent 3 doses: 60-80 units/kg/dose every 6 hours adjusted to maintain peak protein C activity of 100%
Maintenance dose: 45-60 units/kg/dose every 6 or 12 hours adjusted to maintain recommended maintenance trough protein C activity levels >25%
Long-term prophylaxis: Maintenance dose: 45-60 units/kg/dose every 12 hours (recommended maintenance trough protein C activity levels >25%)
Note: Maintain target peak protein C activity of 100% during acute episodes and short-term prophylaxis. Maintain trough levels of protein C activity >25%. Higher peak levels of protein C may be necessary in prophylactic therapy of patients at increased risk for thrombosis (eg, infection, trauma, surgical intervention).
Purpura fulminans secondary to meningococcemia: Limited data available: Infants >1month, Children, and Adolescents: IV: 100-150 units/kg/dose every 6 hours for 72 hours then 50-150 units/kg/dose every 12 hours until target symptom/sign resolution or treatment duration reaches 7 days. This protocol was used in a Phase II, double-blind, placebo-controlled, dose-finding study of 40 pediatric patients [median age: 2.3 years (range: 2.4 months-16.1 years)] (de Kleinjn, 2003). A retrospective review of 94 pediatric patients (newborn to 18 years) reported a median dose of 100 units/kg/day divided every 4-6 hours or as an initial bolus with the remainder of daily dose administered as a continuous IV infusion (dosing specifics were not provided); median treatment duration of 2 days (range: 1-24 days); daily dose range: 28-375 units/kg/day (Veldman, 2010). An open-label, prospective study of 36 patients (3 months to 76 years) reported an initial dose of 100 units/kg followed by a continuous IV infusion with an initial rate of 10 units/kg/hour adjusted daily to maintain plasma protein C concentration 80-120 units/mL (White, 2000).
Reconstitution
Allow vials of powder and diluent to reach room temperature. Reconstitute 500 units vial with 5 mL and 1000 units vial with 10 mL sterile water for injection (resultant concentration; 100 units/mL). Gently swirl; ensure powder is completely dissolved. Use provided filter needle to withdraw solution from vial; remove filter needle prior to administration.
Administration
IV: Administer by intravenous injection at a rate not to exceed 2 mL/minute. In infants and children <10 kg, administration should not exceed a rate of 0.2 mL/kg/minute. Administration must be completed within 3 hours of solution preparation.
Dietary Considerations
At maximum daily doses, product formulation contains sodium >200 mg.
Storage
Store under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Administer within 3 hours of reconstitution and discard any unused portion.
Drug Interactions
Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination
Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy
Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy
Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy
Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy
Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification
Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Avoid combination
Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification
Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds). Consider therapy modification
Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy
Inotersen: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy
MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Avoid combination
Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy
Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination
Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification
Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy
Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy
Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination
Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy
Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination
Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy
Adverse Reactions
Frequency not defined:
Hematologic & oncologic: Major hemorrhage
Hypersensitivity: Hypersensitivity reaction
<1%, postmarketing, and/or case reports: Diaphoresis, injection site reaction, restlessness
Warnings/Precautions
Concerns related to adverse effects:
- Heparin-induced thrombocytopenia (HIT): Trace amounts of heparin contained within the formulation may lead to HIT; evaluate platelet counts if HIT is suspected.
- Hypersensitivity reactions: May contain trace amounts of mouse protein and/or heparin. Discontinue use in the presence of hypersensitivity/allergic reactions.
Disease-related concerns:
- Renal impairment: Use with caution in patients with renal impairment; monitor patients closely for sodium overload.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special populations:
- Sodium-restricted patients: Use with caution in patients where sodium restriction is necessary.
Dosage form specific issues:
- Human plasma: Product of human plasma; may potentially contain infectious agents which could transmit disease; screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces this risk. Infections thought to be transmitted by this product should be reported to the manufacturer.
Monitoring Parameters
Protein C activity (chromogenic assay) prior to and during therapy; signs and symptoms of bleeding; hemoglobin/hematocrit, PT/INR, platelet count; signs and symptoms of sodium overload in patients with renal impairment.
Pregnancy
Pregnancy Considerations
Protein C Concentrate is derived from purified human plasma.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Have patient report immediately to prescriber shortness of breath, dizziness, passing out, or signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
