Protein C concentrate, human (Ceprotin), is a plasma-derived concentrate of protein C and is the first product approved for the prevention and treatment of venous thrombosis and purpura fulminans in adult and pediatric patients with severe, congenital protein C deficiency. Protein C is a natural anticoagulant that when deficient leaves patients hypercoagulable and at risk for thrombotic events, including deep vein thrombosis and pulmonary embolism. In patients with severe deficiency, more severe thrombotic events, such as purpura fulminans, are possible. Patients with severe protein C deficiency who are undergoing acute thrombotic episodes can also be administered fresh frozen plasma to replace endogenous protein C. However, large volumes of plasma are typically needed, which can lead to fluid overload. Protein C concentrate was approved by the FDA in March 2007.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Administer intravenously.
-Treatment should be initiated under the supervision of a physician experienced in replacement therapy with coagulation factors and/or inhibitors and where monitoring of protein C activity is feasible.
-Allergic reactions are possible. If symptoms of hypersensitivity occur, stop infusion or injection.
-Visually inspect parenteral products for particulate matter and discoloration whenever solution and container permit.
Reconstitution:
-Allow vials of protein C concentrate powder and diluent to reach room temperature. Remove caps from vials and clean stoppers with germicidal solution; allow time to dry prior to use.
-Remove the protective covering from one end of the double-ended transfer needle and insert exposed needle through 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 protein C concentrate vial and then rapidly insert the free end of the needle through the protein C concentrate vial stopper at its center. The vacuum in the vial will draw in the diluent. If this does not happen, do not use the product and contact Baxter (1-888-CEPROTIN).
-Disconnect the 2 vials be removing the needle from the diluent vial stopper. Remove the transfer needle from the protein C concentrate vial.
-Gently swirl the vial until all powder is dissolved. Ensure that all powder is dissolved or active material will be removed by the filter needle.
-The solution should be colorless to slightly yellowish and clear to slightly opalescent and free from visible particles. Do not use if the solution does not meet these criteria.
-Storage: Administer within 3 hours of reconstitution.
Intravenous injection:
-Attach a filter needle to a sterile, disposable syringe and draw back the plunger to allow air into the syringe. Insert the filter needle into the vial of reconstituted protein C concentrate and inject air into the vial. Then, withdraw the protein C concentrate into the syringe. After the dose is withdrawn, discard the filter needle as it should only be used one time.
-Using a suitable needle or infusion set with winged adapter, inject at a rate not to exceed 2 ml/min in patients weighing >= 10 kg or at a rate not to exceed 0.2 ml/kg/min in children weighing < 10 kg.
The safety of protein C concentrate was determined by 121 patients from clinical studies and compassionate use of protein C concentrate; duration of exposure ranged from 1 day to 8 years.
Although antibody formation was not reported during clinical trials or postmarketing use of protein C concentrate, the potential for antibody formation cannot be ruled out.
Hypersensitivity reactions, including pruritus and rash (unspecified), have been reported with protein C concentrate in clinical studies.
Dizziness (reported as lightheadedness) has been reported with protein C concentrate in clinical studies. Restlessness has been reported during postmarketing use of protein C concentrate.
Injection site reaction has been reported with postmarketing use of protein C concentrate.
Hyperhidrosis has been reported during postmarketing use of protein C concentrate.
Several bleeding episodes were observed during clinical trials with protein C concentrate. Concurrent administration of other anticoagulants during treatment may have caused the bleeding episodes; however, it is possible that the administration of protein C concentrate further contributed to the bleeding events. Two cases of moderate hemorrhage were reported in a retrospective study of 94 children who received protein C concentrate.
Protein C concentrate may contain trace amounts of mouse protein and heparin. Allergic reactions to mouse protein or heparin are possible. Protein C concentrate should be used with caution in patients with murine protein hypersensitivity or heparin hypersensitivity. If symptoms of hypersensitivity occur, discontinue protein C concentrate and institute appropriate medical therapy.
As with other products derived from or purified with human blood components, the possibility of transmitting a viral infection, including hepatitis, or Creutzfeldt-Jakob disease (CJD) exists in patients receiving protein C concentrate. Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating and/or reducing viruses has reduced the risk of transmission of infectious agents; however, none of the processes are completely effective. There is also the possibility that unknown infectious agents are present in the pooled product. All infections thought to have been transmitted by protein C concentrate should be reported to the manufacturer.
Because protein C concentrate contains trace amounts of heparin, heparin-induced thrombocytopenia (HIT) is possible. During therapy with protein C concentrate, it may be prudent to monitor platelet concentrations periodically, especially in patients who experience symptoms suggestive of HIT or have a history of HIT. If HIT is suspected, discontinuing protein C concentrate should be considered.
Protein C concentrate contains 8.8 mg/ml of sodium chloride. When using maximum daily doses, the amount of sodium the patient receives may exceed 200 mg. Patients with renal impairment or those on a low sodium diet (e.g., patients with heart failure, hypertension) should be monitored for symptoms of sodium and/or fluid overload.
Protein C concentrate has not been studied in pregnant women, and it is not known if it can cause fetal harm when administered during pregnancy.
According to the manufacturer, it is not known whether or not protein C concentrate is excreted in human milk. Protein C concentrate has not been studied in women who are breast-feeding their infants. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For thrombosis prophylaxis and treatment, including treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE), deep venous thrombosis (DVT) prophylaxis, and pulmonary embolism prophylaxis, in patients with severe congenital protein C deficiency:
Intravenous dosage:
Adults: Dosage regimen dependent on phase of treatment, patient's age and condition, and severity of the protein C deficiency. Initial dose for acute episode/short-term prophylaxis: Loading dose of 100 to 120 International Units/kg/dose IV, followed by 3 doses of 60 to 80 International Units/kg/dose IV every 6 hours. This is followed by a maintenance dose of 45 to 60 International Units/kg/dose IV every 6 or 12 hours. Adjust doses as necessary to maintain target protein C activity (peak at 100% for acute episodes and trough more than 25% after resolution of the acute episode). Long-term prophylaxis: 45 to 60 International Units/kg/dose IV every 12 hours; adjust dose to maintain protein C activity more than 25%. Higher peak protein C concentrations for the prophylaxis of thrombosis may be warranted in situations of increased thrombotic risk (e.g., infection, trauma, surgical intervention).
Neonates, Infants, Children, and Adolescents: Dosage regimen dependent on phase of treatment, patient's age and condition, and severity of the protein C deficiency. Initial dose for acute episode/short-term prophylaxis: Loading dose of 100 to 120 International Units/kg/dose IV, followed by 3 doses of 60 to 80 International Units/kg/dose IV every 6 hours. This is followed by a maintenance dose of 45 to 60 International Units/kg/dose IV every 6 or 12 hours. Adjust doses as necessary to maintain target protein C activity (peak at 100% for acute episodes and trough more than 25% after resolution of the acute episode). Long-term prophylaxis: 45 to 60 International Units/kg/dose IV every 12 hours; adjust dose to maintain protein C activity more than 25%. Higher peak protein C concentrations for the prophylaxis of thrombosis may be warranted in situations of increased thrombotic risk (e.g., infection, trauma, surgical intervention).
Subcutaneous dosage*:
Infants and Children: Although not FDA-approved, the subcutaneous route of administration has been used successfully for long-term management of severe protein C deficiency in pediatric patients unable to use the IV route. Limited data have shown that doses of 250 to 350 International Units/kg/dose subcutaneously every 48 hours have resulted in goal trough protein C concentrations more than 0.25 International Units/mL and successful avoidance of thrombotic recurrence in reported cases (n = 4). A case report using approximately 200 International Units/kg/dose subcutaneously once daily reported trough concentrations of less than 0.25 International Units/mL; however, despite low trough concentrations, there was no recurrent thrombosis or relapse of purpura reported.
For the prevention and treatment of purpura fulminans:
-in patients with congenital protein C deficiency:
Intravenous dosage:
Adults: Dosage regimen dependent on phase of treatment, patient's age and condition, and severity of the protein C deficiency. Initial dose for acute episode/short-term prophylaxis: Loading dose of 100 to 120 International Units/kg/dose IV, followed by 3 doses of 60 to 80 International Units/kg/dose IV every 6 hours. This is followed by a maintenance dose of 45 to 60 International Units/kg/dose IV every 6 or 12 hours. Adjust doses as necessary to maintain target protein C activity (peak at 100% for acute episodes and trough more than 25% after resolution of the acute episode). Long-term prophylaxis: 45 to 60 International Units/kg/dose IV every 12 hours; adjust dose to maintain protein C activity more than 25%. Higher peak protein C concentrations for the prophylaxis of thrombosis may be warranted in situations of increased thrombotic risk (e.g., infection, trauma, surgical intervention).
Neonates, Infants, Children, and Adolescents: Dosage regimen dependent on phase of treatment, patient's age and condition, and severity of the protein C deficiency. Initial dose for acute episode/short-term prophylaxis: Loading dose of 100 to 120 International Units/kg/dose IV, followed by 3 doses of 60 to 80 International Units/kg/dose IV every 6 hours. This is followed by a maintenance dose of 45 to 60 International Units/kg/dose IV every 6 or 12 hours. Adjust doses as necessary to maintain target protein C activity (peak at 100% for acute episodes and trough more than 25% after resolution of the acute episode). Long-term prophylaxis: 45 to 60 International Units/kg/dose IV every 12 hours; adjust dose to maintain protein C activity more than 25%. Higher peak protein C concentrations for the prophylaxis of thrombosis may be warranted in situations of increased thrombotic risk (e.g., infection, trauma, surgical intervention).
Subcutaneous dosage*:
Infants and Children: Although not FDA-approved, the subcutaneous route of administration has been used successfully for long-term management of severe protein C deficiency in pediatric patients unable to use the IV route. Limited data have shown that doses of 250 to 350 International Units/kg/dose subcutaneously every 48 hours have resulted in goal trough protein C levels more than 0.25 International Units/mL and successful avoidance of thrombotic recurrence in reported cases (n = 4). A case report using approximately 200 International Units/kg/dose subcutaneously once daily reported trough levels of less than 0.25 International Units/mL; however, despite low trough levels, there was no recurrent thrombosis or relapse of purpura reported.
-in patients with acquired protein C deficiency (i.e., sepsis-induced coagulopathy)*:
Intravenous dosage:
Infants, Children, and Adolescents: 50 International Units/kg/dose IV every 4 hours or 100 to 150 International Units/kg/dose every 6 hours has been used; however, data are limited to small studies and case reports. Some studies have used loading doses of 80 to 120 International Units/kg/dose IV prior to the maintenance dose. In a randomized, placebo-controlled, dose-finding study in 40 children (1 month of age and older), patients received 50, 100, or 150 International Units/kg/dose IV every 6 hours for 72 hours, followed by every 12 hours thereafter for a maximum treatment duration of 7 days. A daily dose of 400 to 600 International Units/kg was demonstrated to be safe and effective. It was noted that a cumulative dose of 600 International Units/kg/day appeared to be required for sustained protein C activation. In a retrospective study in 94 children (neonates to adolescents) treated with protein C concentrate for purpura fulminans, a median dose of 100 International Units/kg/day (range 28 to 375 International Units/kg/day) divided every 4 to 6 hours, given for a median of 2 days (range 1 to 25 days), was reported; some patients received an initial IV bolus followed by continuous IV infusion.
Neonates: Loading doses of 100 to 200 International Units/kg/dose IV, followed by maintenance doses of 50 International Units/kg/dose IV every 6 hours for 72 hours have been used in premature (gestational age 25 to 35 weeks) and term neonates; however, data are limited to small studies and case reports. In a retrospective study in 94 children (8 neonates) treated with protein C concentrate for purpura fulminans, a median dose of 100 International Units/kg/day (range 28 to 375 International Units/kg/day) divided every 4 to 6 hours, given for a median of 2 days (range 1 to 25 days), was reported; some patients received an initial IV bolus followed by continuous IV infusion.
Therapeutic Drug Monitoring:
Protein C concentrations using a chromogenic assay should be measured before and during treatment with protein C concentrate.
-During an acute event or for short-term prophylaxis: To determine the dosage and frequency of administration during an acute thrombotic event, protein C activity should be measured immediately before the next dose until the patient is stabilized. The target peak protein C activity should be maintained at 100% during the acute episode. Once stabilized, protein C activity concentrations should still be monitored to maintain the trough protein C activity concentration > 25%. Lower increases in protein C activity may be seen during an acute thrombotic event. Coagulation parameters should also be monitored; however, in clinical trials, there was insufficient data to establish a correlation between coagulation markers and protein C activity.
-For long-term prophylaxis: Maintenance of trough protein C activity levels > 25% is recommended. During periods where the risk of thrombosis is increased (e.g., infection, trauma, surgery), higher peak protein C activity levels may be warranted.
Maximum Dosage Limits:
Maximum dosage information is not available; dosages should be based on the degree of protein C deficiency, the patient's age, the clinical condition of the patient, and the patient's plasma concentration of protein C. The maximum dose infused during clinical trials was 600 International Units/kg/day IV (150 International Units/kg IV every 6 hours). For long-term prophylaxis, a dose of 291.7 International Units/kg/day IV was administered without adverse events.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Alteplase: (Major) The concomitant use of protein C concentrate and alteplase, tPA may further increase the risk of bleeding from tPA. In clinical trials, several episodes of bleeding were reported. Concurrent anticoagulant medication may have been responsible for these bleeding episodes.
Factor X: (Major) Use factor X cautiously with other plasma products that may contain factor X (e.g., fresh frozen plasma, prothrombin complex concentrate, human).
Prothrombin Complex Concentrate, Human: (Major) Use factor X cautiously with other plasma products that may contain factor X (e.g., fresh frozen plasma, prothrombin complex concentrate, human).
Warfarin: (Major) Concomitant administration of vitamin K antagonists (coumarin anticoagulants such as warfarin) and protein C concentrate should be done with close monitoring. Upon initiation of vitamin K antagonists, patients may experience a transient hypercoagulable state before the desired anticoagulant effect becomes apparent. This transient effect may occur because protein C also is a vitamin K-dependent plasma protein with a much shorter half-life than other vitamin K-dependent proteins such as Factor II, IX and X. Upon initiation of treatment, the activity of protein C is more rapidly suppressed than that of the procoagulant factors. Therefore, if a patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is established. In addition, patients with severe congenital protein C deficiency are at a higher risk of developing warfarin-induced skin necrosis. Monitor patients closely during treatment.
Protein C, a vitamin K dependent plasma protein that is part of the coagulation pathway, is a precursor to activated protein C (APC). APC and its cofactor, protein S, are potent anticoagulants that inactivate coagulation factors V and VIII leading to a reduction in the production of thrombin. In addition, APC has also been shown to have profibrinolytic effects. Replacement of protein C during acute thrombotic episodes in patients with a severe deficiency is expected to control or prevent thrombotic complications.
Protein C concentrate is administered intravenously. The half-life ranges from 4.9 to 14.7 hours (median 9.8 hours). The intravenous administration of protein C concentrate results in a temporary increase of protein C concentrations within approximately 30 minutes. In patients with acute thrombosis, purpura fulminans, and skin necrosis, half-life and protein C concentrations may be considerably reduced.
Affected cytochrome P450 isoenzymes: None
-Route-Specific Pharmacokinetics
Intravenous Route
The maximum plasma concentration (Cmax) and area under the plasma-concentration time curve (AUC) increase linearly with doses between 40 and 80 International Units/kg. The median incremental recovery is 1.42 [(International Units/dl)/(International Units/kg)] after IV administration of protein C concentrate.
Subcutaneous Route
Data are limited. Due to a slower mean absorption time (MAT), peak concentrations (Cmax) are reached later following subcutaneous administration compared with IV administration. A pharmacokinetic study in an infant (approximately 5 months old) receiving subcutaneous protein C concentrate (350 International Units/kg) revealed that a Cmax of 0.59 International Units/mL occurred approximately 12 hours after administration. In association with a longer mean residence time (MRT), the elimination half-life was approximately 16 hours, which is more than twice as long as that which occurred after IV administration (approximately six hours). At doses up to 350 International Units/kg into one single subcutaneous site, dose-dependent decreases in systemic bioavailability were noted (approximately 75%), but not of absorption rate. Erratic absorption was noted for large doses (475 to 700 International Units/kg) injected into the same subcutaneous site. After subcutaneous administration, detectable levels of plasma protein C were noted for at least 48 hours.
-Special Populations
Pediatrics
Neonates, Infants, and Children
The pharmacokinetic profile of protein C concentrate has not been formally studied in pediatric patients. Limited data suggest that the Cmax and AUC (markers of systemic exposure) may be significantly reduced in very young children as compared to older patients due to faster clearance, a larger volume of distribution, and/or shorter half-life of protein C in very young children. Pharmacokinetic data from one infant (approximately 5 months old) in a case study reported an elimination half-life of six hours after IV administration of 80 International Units/kg. Pharmacokinetic data from another case report in a child (age not specified) reported an elimination half-life of 12.8 hours.