Mechanism of Action
Protein 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
. It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to activated Protein C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor protein 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 Protein 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 protein C is not compatible with life. A severe deficiency of this anticoagulant protein causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.
In clinical studies, the intravenous administration of CEPROTIN demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of protein C. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.
Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with protein C deficiency.
Table 3: Pharmacokinetics of CEPROTIN in Subjects with Severe Congenital Protein C Deficiency
|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 Protein C concentration following infusion divided by dose
95% CI for median
||106 to 127
||0.50 to 1.05
||1.32 to 1.59
|Initial half-life [h]
||5.4 to 9.3
|Terminal half-life [h]
||7.0 to 12.4
|Half-life by the non-compartmental approach [h]
||7.1 to 11.6
||1289 to 1897
||10.3 to 16.7
||0.0428 to 0.0792
|Volume of distribution at steady state [dL/kg]
||0.70 to 0.89
The protein 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 CEPROTIN. 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 CEPROTIN.
The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of CEPROTIN 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 protein C in very young children than in older subjects. This fact must be considered when a dosing regimen for children is determined. Doses should be individualized based upon protein C activity levels. See
DOSAGE AND ADMINISTRATION: Protein C Activity Monitoring
Carcinogenesis, Mutagenesis, Impairment of Fertility
Protein C contained in CEPROTIN 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.
CEPROTIN has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).
Animal Toxicology and/or 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 CEPROTIN has suggested immunogenic response in heterologous species following repeated dosing of this human derived protein. Thus, the long-term toxicity potential of CEPROTIN following repeated dosing in animals is unknown.
Local Tolerance Testing:
Investigation of route of injection tolerance demonstrated that CEPROTIN 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.
CEPROTIN 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).