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:
Acute episode/short-term prophylaxis:
Initial dose: IV: 100 to 120 units/kg/dose (for determination of recovery and half-life); followed by subsequent 3 doses: 60 to 80 units/kg/dose every 6 hours adjusted to maintain peak protein C activity of 100%.
Maintenance dose: IV: 45 to 60 units/kg/dose every 6 or 12 hours adjusted to maintain recommended maintenance trough protein C activity levels >25%. Continue until desired anticoagulation achieved.
Long-term prophylaxis: Maintenance dose: IV: 45 to 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; optimal dose not established: IV: Usual dose (median): 100 units/kg/day divided every 4 to 6 hours; reported range: 28 to 375 units/kg/day (Veldman 2010).
Dosing based on a retrospective review of 94 pediatric patients (0 to 18 years including 8 newborns) reported a median dose of 100 units/kg/day divided every 4 to 6 hours was used in the majority of patients (78 of the 94 patients); the remaining patients received an initial bolus with the remainder of daily dose administered as a continuous IV infusion (dosing specifics were not provided); median treatment duration of 33 hours (range: 1 to 645 hours); daily dose range: 28 to 375 units/kg/day (Veldman 2010).
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: Infants, Children, and Adolescents:
Acute episode/short-term prophylaxis:
Initial dose: IV: 100 to 120 units/kg/dose (for determination of recovery and half-life) followed by subsequent 3 doses: 60 to 80 units/kg/dose every 6 hours adjusted to maintain peak protein C activity of 100%.
Maintenance dose: IV: 45 to 60 units/kg/dose every 6 or 12 hours adjusted to maintain recommended maintenance trough protein C activity levels >25%. Continue until desired anticoagulation achieved.
Long-term prophylaxis: Maintenance dose: IV: 45 to 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; optimal dose not established; role in management is not defined (Fuhrman 2017):
Infants, Children, and Adolescents: IV: 100 to 150 units/kg/dose every 6 hours for 72 hours, followed by 50 to 150 units/kg/dose every 12 hours (de Kleijn 2003; Fourier 2003). Other protocols have reported a daily dose of 100 units/kg/day with doses divided every 4 to 6 hours or as a continuous infusion (Veldman 2010) and others used a loading dose (100 units/kg/dose) followed by a continuous infusion (initial rate: 10 units/kg/hour) with titration of rate based upon protein C levels (target: 80 to 120 units/mL) (White 2000). Duration of therapy variable (1 to 24 days) (Veldman 2010); activated protein C levels and clinical response should be closely monitored.
Dosing based on placebo-controlled trials and retrospective reviews. In a phase II, double-blind, placebo-controlled, dose-finding study of 40 pediatric patients (median age: 2.3 years [range: 2.4 months to 16.1 years]), a dose of 100 to 150 units/kg/dose every 6 hours for 72 hours followed by 50 to 150 units/kg/dose every 12 hours until target symptom/sign resolution or treatment duration reaches 7 days was used; results showed dose-related increases in plasma activated protein C and resolution of coagulation imbalances (de Kleijn 2003). A retrospective review of 94 pediatric patients (newborn to 18 years) reported a median dose of 100 units/kg/day divided every 4 to 6 hours (daily dose range: 28 to 375 units/kg/day) in the majority of patients (78 of the 94 patients); the remaining patients received an initial bolus with the remainder of daily dose administered as a continuous IV infusion (dosing specifics were not provided); median treatment duration of 33 hours (range: 1 to 645 hours) (Veldman 2010). An open-label, prospective study of 36 patients (3 months to 72 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 to 120 units/mL (White 2000).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); monitor closely for sodium overload.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
(For additional information see "Protein C, concentrate from human plasma: Drug information")
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 a vitamin K antagonist, continue protein C replacement until stable anticoagulation is obtained. Initiate the vitamin K antagonist at a low dose and adjust incrementally, rather than using a loading dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); monitor closely for sodium overload.
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
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]
No
Parenteral: Administer by IV injection; infusion must be completed within 3 hours of solution preparation.
Neonates, Infants, and Children <10 kg: Rate should not exceed 0.2 mL/kg/minute
Children ≥10 kg and Adolescents: Rate should not exceed 2 mL/minute
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.
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.
Replacement therapy for severe congenital protein C deficiency for the prevention and/or treatment of venous thromboembolism and purpura fulminans (FDA approved in neonatal, pediatric, and adult patients). Has also been used in patients with purpura fulminans secondary to meningococcemia.
Ceprotin may be confused with aprotinin, Cipro
Protein C concentrate (human) may be confused with activated protein C (human, recombinant) which refers to drotrecogin alfa
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined:
Hematologic & oncologic: Major hemorrhage
Hypersensitivity: Hypersensitivity reaction
<1%, postmarketing, and/or case reports: Diaphoresis, injection site reaction, restlessness
There are no contraindications listed in the manufacturer’s labeling.
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.
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.
None known.
Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Alemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Risk X: Avoid combination
Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Risk C: 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. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Risk C: 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. Risk C: Monitor therapy
Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with other anticoagulants prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: 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. Risk X: Avoid combination
Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapy
Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Kanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy
Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination
Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: 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. Risk X: Avoid combination
Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
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. Risk C: 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. Risk X: Avoid combination
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: Monitor for signs and symptoms of bleeding if these agents are combined. For the treatment of acute ischemic stroke, avoidance with anticoagulants is often recommended, see full Lexicomp or drug interaction monograph for details. Risk C: Monitor therapy
Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination
Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
At maximum daily doses, product formulation contains sodium >200 mg.
Protein C Concentrate is derived from purified human plasma.
Protein C activity (chromogenic assay) prior to and during therapy (if acute thrombotic event, check protein C activity immediately before next injection); signs and symptoms of bleeding; hemoglobin/hematocrit, PT/INR, platelet count
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).
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.
Note: Limited data suggests that infants and very young children may have a faster clearance, lower AUC and maximum serum concentration, larger volume of distribution, and shorter half-life than older subjects.
Onset of action: 30 minutes
Distribution: Vd: Median: 0.074L/kg (range: 0.044 to 0.165 L/kg)
Metabolism: Activated protein C (APC) inactivated by plasma protease inhibitors
Half-life elimination: Median: 9.8 hours; range: 4.9 to 14.7 hours
Time to peak, plasma: Tmax: 0.5 hours; range: 0.17 to 1.33 hours
Conversion to vitamin K antagonist therapy may cause a transient hypercoagulable state during therapy initiation due to shorter half-life of protein C than other vitamin K-dependent clotting factors. For patients requiring conversion to oral vitamin K antagonists, it is recommended to continue protein C therapy during oral anticoagulant initiation until anticoagulation stabilized. It is also advised to begin with a low dose of oral anticoagulant instead of a loading dose.
Prescribers should register their patients to assist in the collection and assessment of protein C concentration deficiency, treatment, safety, and outcomes of subjects. More information may be found at the following website: http://clinicaltrials.gov/ct2/show/NCT01127529.
Solution (reconstituted) (Ceprotin Intravenous)
500 unit (Price provided is per AHF Unit): $1.80
1000 unit (Price provided is per AHF Unit): $1.80
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.