Safety Information
Please consult the Ceprotin® Summary of Product Characteristics (SmPC) approved in your country before prescribing.
GUIDANCE FOR USE:
Treatment with CEPROTIN® should be initiated under the supervision of a physician experienced in substitution therapy with coagulation factors/inhibitors where monitoring of protein C activity is feasible.
The dose should be adjusted on the basis of laboratory assessment for each individual case.
A protein C activity of 100 % should be achieved initially and the activity should be maintained 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.
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. 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).
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 of 2 ml per minute except for children with a body weight of < 10 kg, where the injection rate should not exceed a ra te of 0.2 ml/kg/min.
CONTRAINDICATIONS:
Hypersensitivity to the active substance or to any of the excipients or to mouse protein or heparin, except for control of life-threatening thrombotic complications.
SPECIAL WARNINGS & PRECAUTIONS:
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.
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.
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 infec tion, 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 (fetal 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.
It is strongly recommended that every time that CEPROTIN® is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.
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.
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.
The quantity of sodium in the maximum daily dose may exceed 200 mg. This should be taken into consideration by patients on a controlled sodium diet.
INTERACTIONS:
No interactions with other medicinal products are currently known.
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 a nticoagulation 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.
ADVERSE REACTIONS:
As with a ny 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, 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.
During clinical studies with CEPROTIN®, a total of 6 non-serious adverse drug reactions (ADRs) were reported in 3 of 225 patients enrolled. In total 21,988 administrations of CEPROTIN® have been given. The reported ADRs were: dizziness, urticaria, pruritus, rash, pyrexia, increased C-reactive protein. With a calculated adverse experience rate (per number of administrations) of 0.005% the frequency of these ADRs can be classified as very rare.
The following ADRs have been reported in the post-marketing experience and the frequency remains unknown restlessness, haemothorax, hyperhydrosis, injection site reaction, increased body temperature, increased need of catecholamines to support blood pressure in the course of treatment.
If the preparation is used in patients with severe congenital protein C deficiency, antibodies inhibiting protein C may develop.
Adverse events should be reported at drugsafety@shire.com
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