CEPROTIN 1000UI powder + solvent for injection medication leaflet

CEPROTIN 1,000 IU powder and solvent for solution for injection

Protein C from human plasma purified by mouse monoclonal antibodies. CEPROTIN 1,000 IU* isprepared as a powder containing nominally 1,000 IU human protein C per container. The productreconstituted with 10 ml of Sterilised Water for Injections contains approximately 100 IU/ml humanprotein C.

The potency (IU) is determined using a chromogenic substrate method against the World Health

Organisation (WHO) International standard.

*One International Unit (IU) of protein C corresponds to the amidolytically measured activity ofprotein C in 1 ml of normal plasma.

This medicinal product contains 44.9 mg sodium per vial.

For the full list of excipients see section 6.1.

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 pHof between 6.7 and 7.3 and an osmolality of not lower than 240 mosmol/kg.

- CEPROTIN is indicated for prophylaxis and treatment of purpura fulminans, coumarin-inducedskin necrosis and venous thrombotic events in patients with severe congenital protein Cdeficiency. .

Treatment with CEPROTIN should be initiated under the supervision of a physician experienced insubstitution therapy with coagulation factors/inhibitors where monitoring of protein C activity isfeasible.

The dose should be adjusted on the basis of laboratory assessment for each individual case.

Treatment of acute episodes and short-term prophylaxis (including invasive procedures)

A protein C activity of 100 % (1 IU/ml) should be achieved initially and the activity should bemaintained 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 thedetermination 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 isstabilised, thereafter twice a day and always immediately before the next injection. It should be keptin mind that the half-life of protein C may be severely shortened in certain clinical conditions such asacute thrombosis with purpura fulminans and skin necrosis.

If the response to CEPROTIN injection is satisfactory (measured by chromogenic assays), dosing maybe gradually reduced to 12 hourly dosing ensuring trough protein C activity >25% (>0.25 IU/ml).

Patients treated during the acute phase of their disease may display much lower increases in protein Cactivity. The wide variation in individual responses implies that the effects of CEPROTIN oncoagulation parameters should be checked regularly.

In patients receiving prophylactic administration of protein C, higher trough levels may be warrantedin situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention).

Long-term prophylaxis

For the long-term prophylactic treatment, a dose of 45 to 60 IU/kg every 12 ours is recommended.

Measurement of the protein C activity should be performed to ensure trough levels of 25% or more.

Dose or frequency of infusions should be adjusted accordingly.

In rare and exceptional cases, subcutaneous infusion of 250 - 350 IU/kg was able to producetherapeutic protein C plasma levels in patients with no intravenous access.

If the patient is switched to permanent prophylaxis with oral anticoagulants, protein C replacement isto be discontinued only when stable anticoagulation is obtained (see section 4.5). Furthermore, duringthe initiation of oral anticoagulant therapy it is advisable to start with a low dose and adjust thisincrementally, rather than use a standard loading dose.

At start of a combination treatment of anticoagulants (especially Vitamin K antagonists) with Protein

C, stable activity levels of Protein C above 0.25 IU/ml (chromogenic) should be maintained beforestarting the anticoagulation. Careful monitoring of the international normalized ratio (INR) isrecommended. In the combination of Protein C Concentrate and anticoagulants, a Protein C troughlevel of about 10% or more is recommended to be maintained.

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).

Activated Protein C (APC) resistance

In patients with combined severe congenital protein C deficiency and with APC resistance, there arelimited clinical data to support the safety and efficacy of CEPROTIN.

Safety and efficacy of CEPROTIN in patients with renal and/or hepatic impairment have not beenestablished. Patients with any of these conditions should be monitored more closely.

CEPROTIN is administered by intravenous injection after reconstitution of the powder for solution forinjection with Sterilised Water for Injections.

CEPROTIN should be administered at a maximum injection rate of 2 ml per minute except forchildren with a body weight of < 10 kg, where the injection rate should not exceed a rateof 0.2 ml/kg/min.

As with any intravenous protein product, allergic type hypersensitivity reactions are possible. For theevents that allergic symptoms arise which are of an acute and life-threatening nature, administrationshould be made within reach of life-supporting facilities.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouseprotein or heparin, except for control of life-threatening thrombotic complications.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

As the risk of an allergic type hypersensitivity reaction cannot be excluded, patients should beinformed of the early signs of hypersensitivity reactions including hives, generalized urticaria,tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur, theyshould 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.

If the preparation is used in patients with severe congenital protein C deficiency, antibodies inhibitingprotein C may develop.

Transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared fromhuman blood or plasma include selection of donors, screening of individual donations and plasmapools for specific markers of infection, and the inclusion of effective manufacturing steps for theinactivation/removal of viruses. Despite this, when medicinal products prepared from human bloodor 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 HCVand for the non-enveloped virus HAV. The measures taken may be of limited value againstnon-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnantwomen (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/repeatedreceipt of human plasma-derived Protein C products.

Heparin induced thrombocytopenia (HIT)

CEPROTIN may contain trace amounts of heparin. Heparin induced allergic reactions, which can beassociated with a rapid decrease of the number of thrombocytes, may be observed (HIT). In patientswith HIT, symptoms such as arterial and venous thrombosis, disseminated intravascular coagulation(DIC), purpura, petechiae and gastrointestinal bleeding (melena), may occur. If HIT is suspected, thenumber 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 mayalready 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. Concurrentanticoagulant 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 contributedto these bleeding events.

This medicinal product contains 44.9 mg sodium per vial, equivalent to 2.2% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

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 effectbecomes 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 morerapidly suppressed than that of the procoagulant factors. For this reason, if the patient is switched tooral 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 oralanticoagulant therapy, individuals with congenital protein C deficiency are particularly at risk.(See section 4.2).

Although CEPROTIN has been used safely in the treatment of pregnant protein C-deficient women, itssafety 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 andshould be used only if clearly needed.

For information on parvovirus B19 infection, see section 4.4.

CEPROTIN has no influence or negligible influence on the ability to drive and use machines.

As with any intravenous product allergic type hypersensitivity reactions are possible. Patients shouldbe informed of the early signs of hypersensitivity reactions, which may include angioedema, burningand stinging at the injection site, chills, flushing, rash, pruritus, generalised urticaria, headache, hives,hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting andwheezing. Patients should be advised to immediately contact their physician if these symptoms occur(see section 4.4).

During clinical studies with CEPROTIN, a total of 3 non-serious adverse drug reactions (ADRs) werereported in 1 of 67 patients enrolled (rash and pruritus (grouped as hypersensitivity), and dizziness). Intotal 6375 administrations of CEPROTIN have been given. The distribution of the related ADRs is asfollows:

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), veryrare (< 1/10,000); not known (cannot be estimated from the available data).

System Organ Class Adverse Reaction Preferred Term Frequency Categoryby infusions

Immune System Hypersensitivity Rash Rare

Disorders

Pruritus Rare

Nervous System Dizziness Dizziness Rare

Disorders

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: hyperhidrosis

General disorders and administration site conditions: injection site reaction

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. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No symptoms of overdose with CEPROTIN have been reported.

Pharmacotherapeutic group: group antithrombotic; ATC Code: B01AD12

Protein C is a vitamin K-dependent anticoagulant glycoprotein which is synthesised in the liver. It isconverted by thrombin/thrombomodulin-complex on the endothelial surface to APC. APC is a serineprotease with potent anticoagulant effects, especially in the presence of its cofactor protein S. APCexerts its effect by the inactivation of the activated forms of factors V and VIII which leads toa 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 inplasma levels of protein C. Replacement of protein C in protein C deficient patients is expected tocontrol or - if given prophylactically - prevent thrombotic complications.

One prospective, multicenter, open-label, non-randomized, 3-part, phase 2/3 clinical study in subjectswith severe congenital Protein C deficiency to evaluate the efficacy and safety of Protein C

Concentrate was completed (pivotal study 400101). This study enrolled 18 subjects with severecongenital Protein C deficiency defined as protein C activity level <20% and with median age 5.8years (range 0 to 26 years). In the long-term prophylaxis group the median age was 2.8 years (range 0to 22 years). A total of 24 episodes of purpura fulminans (PF), coumarin-induced skin necrosis (CISN)and other vascular thromboembolic events were treated with CEPROTIN in 11 subjects. Sevencourses of short-term prophylaxis prior to surgery or initiation of anticoagulation therapyand 8 courses of long-term prophylaxis were analysed. The results of this study demonstrate that

CEPROTIN is efficacious for the treatment of acute thrombotic episodes and support the use of

CEPROTIN for both short-term and long-term thrombotic prophylactic treatment.

Other experience with CEPROTIN covers case reports and a clinical study in overall 69 paediatricpatients 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 tomeningococcal sepsis (IMAG 112). The reports suggest that CEPROTIN is well tolerated in childrenand small infants.

Dosages of the above studies, covering 87 patients, indicate that dosing guidelines for adult subjectsare also valid for neonatal and paediatric patient population.

21asymptomatic subjects with homozygous or double heterozygous protein C deficiency wereevaluated for pharmacokinetic data. The protein C plasma activity was measured by chromogenicassay. The individual half-lives varied from 4.4 to 15.8 hours using a compartmental model andfrom 4.9 to 14.7 using the non-compartmental method. The individual incremental recovery rangedfrom 0.50 to 1.76 [(IU/dL)/(IU/kg)]. The patients differed significantly in age, body weight andplasma volume.

In patients with acute thrombotic disease, both the incremental increase in protein C plasma levels aswell as half-life may be considerably reduced.

Protein C contained in CEPROTIN is a normal constituent of human plasma and acts like endogenousprotein C. Therefore, experimental studies on tumorigenic or mutagenic effects - particularly inheterologous species - are not considered necessary.

Single dose toxicity testing showed that even doses of several times the recommended human dosageper 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 preparationshad shown them to be of limited value. Difference between the recipient species and human protein Cwill inevitably result in an immune response with antibody formation.

Human albumin

Trisodium citrate dihydrate

Sodium chloride

Sterilised Water for Injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

The reconstituted solution should be used immediately.

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.

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 hydrolytictype 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.

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 powderis dissolved. After reconstitution the solution is colourless to slightly yellowish and clear to slightlyopalescent and essentially free from visible particles.

The solution is drawn through the sterile filter needle into a sterile disposable syringe. A separateunused filter needle must be used to withdraw each vial of reconstituted CEPROTIN. The solutionshould 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 localrequirements.

Takeda Manufacturing Austria AG

Industriestrasse 671221 Vienna

Austria

EU/1/01/190/002

Date of first authorisation: 16 July 2001

Date of last renewal: 16 July 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.