Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Takeda Manufacturing Austria AG, Industriestrasse 67, A-1221 Vienna, Austria
Pharmacotherapeutic group: group antithrombotic;
ATC Code: B01AD12
Protein C is a vitamin K-dependent anticoagulant glycoprotein which is synthesised in the liver. It is converted by thrombin/thrombomodulin-complex on the endothelial 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 intravenous administration of CEPROTIN provides for an immediate but temporary increase in plasma levels of protein C. Replacement of protein C in protein C deficient patients is expected to control or – if given prophylactically – prevent thrombotic complications.
Twelve courses of short-term prophylaxis prior to surgery or invasive therapy and 7 courses of long-term prophylaxis were included in the efficacy analyses.
No formal clinical study in either paediatric or neonatal population with severe congenital protein C deficiency was ever conducted. However, several small retrospective and prospective studies investigating other clinical application areas have been published in this population. Indication was prevention and treatment of purpura fulminans and thrombotic disease, enrolling overall 14 subjects of 2 days old throughout adolescence.
Other experience with CEPROTIN covers case reports and a clinical study in overall 69 paediatric patients with acquired protein C deficiency. The study is a randomized, double-blind, placebo-controlled dose-finding study, in the indication of acquired protein C deficiency due to meningococcal sepsis (IMAG 112). The reports suggest that CEPROTIN is well tolerated in children and small infants.
Dosages of the above studies, covering 83 patients, indicate that dosing guidelines for adult subjects are also valid for neonatal and paediatric patient population.
In rare and exceptional cases, subcutaneous infusion of 250-350 IU/kg was able to produce therapeutic protein C plasma levels in patients with no intravenous access.
21 asymptomatic subjects with homozygous or double heterozygous protein C deficiency were evaluated for pharmacokinetic data. The protein C plasma activity was measured by chromogenic assay. The individual half-lives varied from 4.4 to 15.8 hours using a compartmental model and from 4.9 to 14.7 using the non-compartmental method. The individual incremental recovery ranged from 0.50 to 1.76 [(IU/dL)/(IU/kg)]. The patients differed significantly in age, body weight and plasma volume.
In patients with acute thrombotic disease, both the incremental increase in protein C plasma levels as well as half-life may be considerably reduced.
Protein C contained in CEPROTIN is a normal constituent of human plasma and acts like endogenous protein C. Therefore experimental studies on tumorigenic or mutagenic effects – particularly in heterologous species – are not considered necessary.
Single dose toxicity testing showed that even doses of several times the recommended human dosage per kilogram body weight (10-fold) did not result in toxic effects on rodents.
CEPROTIN proved to have no mutagenic potential in the Ames test performed.
Repeated toxicity studies were not conducted because prior experience with coagulation preparations had shown them to be of limited value. Difference between the recipient species and human Protein C will inevitably result in an immune response with antibody formation.
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