Summary of medicine characteristics - Ceprotin
1. NAME OF THE MEDICINAL PRODUCT
CEPROTIN 500 IU powder and solvent for solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Protein C from human plasma purified by mouse monoclonal antibodies. CEPROTIN 500 IU is prepared as a powder containing nominally 500 IU human protein C per container. The product reconstituted with 5 ml of Sterilised Water for Injections contains approximately 100 IU/ml human protein C.
The potency (IU) is determined using a chromogenic substrate method against the World Health Organisation (WHO) International standard.
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*One International Unit (IU) of protein C corresponds to the amidolytically measured activity of protein C in 1 ml of normal plasma.
Excipients with known effect :
This medicinal product contains 22.5 mg sodium per vial.
For the full list of excipients see section 6.1.
3. PHARMACEUTICAL FORM
Human protein C, powder and solvent for solution for injection.
Lyophilised white or cream coloured powder or friable solid. After reconstitution the solution has a pH of between 6.7 and 7.3 and an osmolality of not lower than 240 mosmol/kg.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
CEPROTIN is indicated in purpura fulminans and coumarin-induced skin necrosis in patients with severe congenital protein C deficiency. Furthermore, CEPROTIN is indicated for short-term prophylaxis in patients with severe congenital protein C deficiency if one or more of the following conditions are met:
above 25 % for the duration of the treatment.
An initial dose of 60 to 80 IU/kg for determination of recovery and half-life is advised.
The measurement of protein C activity using chromogenic substrates is recommended for the determination of the patient’s plasma level for protein C before and during treatment with CEPROTIN.
The dosage should be determined on the basis of laboratory measurements of the protein C activity. In the case of an acute thrombotic event these should be performed every 6 hours until the patient is stabilised, thereafter twice a day and always immediately before the next injection. It should be kept in mind that the half-life of protein C may be severely shortened in certain clinical conditions such as acute thrombosis with purpura fulminans and skin necrosis.
Patients treated during the acute phase of their disease may display much lower increases in protein C activity. The wide variation in individual responses implies that the effects of CEPROTIN on coagulation parameters should be checked regularly.
Patients with renal and/or hepatic impairment should be monitored more closely. (see section 4.4)
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.
If the patient is switched to permanent prophylaxis with oral anticoagulants, protein C replacement is to be discontinued only when stable anticoagulation is obtained (see section 4.5). Furthermore, during the initiation of oral anticoagulant therapy it is advisable to start with a low dose and adjust this incrementally, rather than use a standard loading dose.
In patients receiving prophylactic administration of protein C, higher trough levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention).
In patients with combined severe congenital protein C deficiency and with APC resistance, there are limited clinical data to support the safety and efficacy of CEPROTIN.
Paediatric population
Based on the limited clinical experience in children from reports and studies covering 83 patients, dosing guidelines for adult subjects are considered valid for neonatal and paediatric patient population (see section 5.1).
Method of administration
CEPROTIN is administered by intravenous injection after reconstitution of the powder for solution for injection with Sterilised Water for Injections.
CEPROTIN should be administered at a maximum injection rate of2 ml per minute except for children with a body weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 ml/kg/min.
As with any intravenous protein product, allergic type hypersensitivity reactions are possible. For the events that allergic symptoms arise which are of an acute and life-threatening nature, administration should be made within reach of life-supporting facilities.
For instructions on reconstitution of the medicinal product before administration, see section.6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse protein or heparin, except for control of life-threatening thrombotic complications.
4.4 Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Hypersensitivity
As the risk of an allergic type hypersensitivity reaction cannot be excluded, patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur, they should inform the physician. Immediate discontinuation of product use is advised.
In case of shock, the current medical standards for shock treatment are to be observed.
Renal and/or hepatic impairment
No experience in the treatment of patients with renal and/or hepatic impairment is available and therefore it is recommended that such patients be monitored more closely.
Inhibitors
If the preparation is used in patients with severe congenital protein C deficiency, antibodies inhibiting protein C may develop.
Transmissible agents
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection, and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV and for the non-enveloped virus HAV.
The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).
Appropriate vaccination (hepatitis A and B) should be considered for patients in regular / repeated receipt of human plasma-derived Protein C products.
Heparin induced thrombocytopenia
CEPROTIN may contain trace amounts of heparin. Heparin induced allergic reactions, which can be associated with a rapid decrease of the number of thrombocytes, may be observed (heparin induced thrombocytopenia [HIT]). In patients with HIT, symptoms such as arterial and venous thrombosis, disseminated intravascular coagulation (DIC), purpura, petechiae and gastrointestinal bleeding (melena), may occur. If HIT is suspected, the number of thrombocytes should be determined immediately and if necessary, therapy with CEPROTIN should be stopped. Identifying HIT is complicated by the fact that these symptoms may already be present in acute phase patients with severe congenital protein C deficiency. Patients with HIT should avoid the use of heparin containing drugs in the future.
Concurrent anticoagulant medication
In the context of clinical experience several bleeding episodes have been observed. Concurrent anticoagulant medication (such as heparin) may have been responsible for these bleeding episodes. However, it cannot be completely ruled out that the administration of CEPROTIN further contributed to these bleeding events.
Sodium
This medicinal product contains 22.5 mg sodium per vial, equivalent to 1.1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
4.5 Interaction with other medicinal products and other forms of interaction
No interactions with other medicinal products are currently known.
Interaction with Vitamin K antagonists
In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists (e.g. warfarin), a transient hypercoagulable state may arise before the desired anticoagulant effect becomes apparent. This transient effect may be explained by the fact that protein C, itself a vitamin K dependent plasma protein, has a shorter half-life than most of the vitamin K dependent proteins (i.e. II, IX and X). Subsequently, in the initial phase of treatment, the activity of protein C is more rapidly suppressed than that of the procoagulant factors. For this reason, if the patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is obtained. Although Warfarin-induced skin necrosis can occur in any patient during the initiation of oral anticoagulant therapy, individuals with congenital protein C deficiency are particularly at risk. (See section 4.2).
4.6 Fertility, pregnancy and lactation
Although CEPROTIN has been used safely in the treatment of pregnant protein C-deficient women, its safety for use in human pregnancy has not been established in controlled clinical trials. Furthermore, no information on excretion of protein C in the milk is available. Therefore, the benefit of using CEPROTIN during pregnancy or lactation must be judged against the risk for the mother and baby and should be used only if clearly needed.
For information on parvovirus B19 infection, see section 4.4.
4.7 Effects on ability to drive and use machines
CEPROTIN has no influence or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
As with any intravenous product allergic type hypersensitivity reactions are possible. Patients should be informed of the early signs of hypersensitivity reactions, which may include angioedema, burning and stinging at the injection site, chills, flushing, rash, pruritus, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, and wheezing. Patients should be advised to immediately contact their physician if these symptoms occur (see section 4.4).
Tabulated list of adverse reactions
During clinical studies with CEPROTIN, a total of 3 non-serious adverse drug reactions (ADRs) were reported in 1 of67 patients enrolled (rash and pruritus (grouped as hypersensitivity), and dizziness). In total 6375 administrations of CEPROTIN have been given.
Frequencies have been evaluated according to the following convention: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000); not known (cannot be estimated from the available data).
The distribution of the related ADRs is as follows:
| System Organ Class | Adverse Reaction | Preferred Term | Frequency Category by infusions |
| Immune System Disorders | Hypersensitivity | Rash | Rare |
| Pruritus | Rare | ||
| Nervous System Disorders | Dizziness | Dizziness | Rare |
Post-marketing experience
The following ADRs have been reported in the post-marketing experience and the frequency of these ADRs is not known:
Psychiatric disorders: restlessness
Skin and subcutaneous tissue disorders: hyperhydrosis
General disorders and administration site conditions: injection site reaction
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9 Overdose
No symptoms of overdose with CEPROTIN have been reported.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: group antithrombotic; ATC Code: B01AD12
Mechanism of action
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
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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.
Clinical efficacy and safety
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 of2 days old throughout adolescence.
Paediatric population
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.
5.2 Pharmacokinetic properties
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.
5.3 Preclinical safety data
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.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Powder
Human albumin
Trisodium citrate dihydrateSodium chloride
Solvent
Sterilised Water for Injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
3 years
The reconstituted solution should be used immediately.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze. Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
500 IU and 1,000 IU: CEPROTIN powder comes in vials of neutral glass of either hydrolytic type I (500 IU) or hydrolytic type II (1,000 IU).
The solvent comes in vials of neutral glass of hydrolytic type I. The product and the solvent vials are closed with butyl rubber stoppers.
Each pack also contains:
- • one transfer needle
- • one filter needle
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Reconstitute lyophilised CEPROTIN powder for solution for injection, with the supplied solvent (Sterilised Water for Injections) using the sterile transfer needle. Gently rotate the vial until all powder is dissolved. After reconstitution the solution is colourless to slightly yellowish and clear to slightly opalescent and essentially free from visible particles.
The solution is drawn through the sterile filter needle into a sterile disposable syringe. A separate unused filter needle must be used to withdraw each vial of reconstituted CEPROTIN. The solution should be discarded if particulate matter is visible.
The reconstituted solution should be administered immediately by intravenous injection.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Takeda Manufacturing Austria AG
Industriestrasse 67
1221 Vienna
Austria
8. MARKETING AUTHORISATION NUMBER
EU/1/01/190/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 16 July 2001
Date of last renewal: 16 July 2006