Ceprotin^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Takeda Manufacturing Austria AG (Austria)

Manufactured By

Baxter, AG (Austria)

Contact Information

Baxter (USA)

ATC Code

B01AD12 (Protein C)

Active Substance

Protein C (Ph.Eur. European Pharmacopoeia)

Dosage Forms

	Ceprotin®	Lyophilisate for preparation of solution for intravenous administration 500 IU: vial 1 pc. in a set with solvent
		Lyophilisate for preparation of solution for intravenous administration 1000 IU: vial 1 pc. in a set with solvent

Dosage Form, Packaging, and Composition

Excipients: sodium chloride – 44 mg, sodium citrate dihydrate – 22 mg.

Solvent water for injections – 5 ml.

* – 1 IU of protein C corresponds to the measured amylolytic activity of protein C in 1 ml of normal plasma. The activity (in IU) is determined using the chromogenic substrate method relative to the WHO international standard.

Vials (1) in a set with solvent (vial), transfer needle and filter needle – cardboard packs.

Excipients: sodium chloride – 88 mg, sodium citrate dihydrate – 44 mg.

Solvent water for injections – 10 ml.

* – 1 IU of protein C corresponds to the measured amylolytic activity of protein C in 1 ml of normal plasma. The activity (in IU) is determined using the chromogenic substrate method relative to the WHO international standard.

Vials (1) in a set with solvent (vial), transfer needle and filter needle – cardboard packs.

Clinical-Pharmacological Group

Anticoagulant – inhibitor of factors Va and VIIIa

Pharmacotherapeutic Group

Antithrombotic agent

Pharmacological Action

Anticoagulant. Protein C is a vitamin K-dependent anticoagulant glycoprotein that is synthesized in the liver. It is activated on the surface of the vascular endothelium by means of the thrombin/thrombomodulin complex, turning into activated protein C (APC). APC is a serine protease with a powerful anticoagulant effect, especially in the presence of protein S. The action of APC is associated with the inactivation of activated coagulation factors V and VIII, which leads to a decrease in thrombin formation. APC also has a profibrinolytic effect. Intravenous administration of Ceprotin^® causes a rapid but temporary increase in the level of protein C in the plasma. Replacement therapy in patients with protein C deficiency is designed to control thrombotic complications or prevent them when used for prophylaxis.

Pharmacokinetics

The pharmacokinetics of protein C were assessed by the HPLC method. T_1/2 varied from 4.4 to 15.9 hours when using an isolated elimination model and from 5.6 to 27.7 hours when using a complex model. The degree of recovery of protein C activity in vivo ranged from 20.4 to 83.2%. Patients differed significantly in age, body weight and plasma volume. In patients with acute thrombosis, the increase in protein C activity in response to therapy, as well as T_1/2, may have lower values.

Indications

Ceprotin^® is indicated for purpura fulminans and coumarin-induced skin necrosis in patients with severe congenital protein C deficiency.

In addition, short-term administration of Ceprotin^® for prophylaxis is indicated in patients with severe congenital protein C deficiency in the following cases

• If surgical or invasive intervention is unavoidable;
• At the beginning of a course of coumarin treatment;
• If the effect of treatment with coumarin alone is insufficient;
• If it is impossible to carry out a course of treatment with coumarin.

Ceprotin^® should be used only for severe congenital protein C deficiency, since there is no data on the efficacy and safety of the drug for other diseases.

ICD codes

Dosage Regimen

Treatment with Ceprotin^® should be initiated under the supervision of a physician experienced in replacement therapy with coagulation factors and fibrinolytic drugs, in conditions that allow monitoring of protein C activity.

The dose should be selected individually based on laboratory tests for each specific patient.

The patient’s serum protein C activity should be brought to 100% at the beginning of the course of treatment and should be maintained above 25% throughout the course. The recommended initial dose is 60-80 IU/kg, which allows determining the intensity of the therapeutic response and T_1/2. To measure serum protein C activity before and during treatment with Ceprotin^®, it is recommended to use the chromogenic substrate method.

The drug dose should be established based on laboratory measurement of protein C activity. In case of acute thrombosis, protein C activity should be measured every 6 hours until the patient’s condition stabilizes, then twice a day and before each subsequent injection. It should be taken into account that the T_1/2 of protein C can be significantly reduced in some clinical conditions, including acute thrombosis with purpura fulminans and skin necrosis.

If treatment with Ceprotin^® is started in the acute phase of the disease, the increase in protein C levels in response to therapy may be slow. Since the response to therapy with Ceprotin^® varies significantly, patients should undergo regular assessment of coagulation parameters.

There is no experience in treating patients with renal and/or hepatic impairment with Ceprotin^®, and therefore such patients require more careful monitoring.

If a patient is switched to continuous oral anticoagulants, protein C replacement therapy should be discontinued only after a stable anticoagulant effect is achieved. In this case, when treating with oral anticoagulants, it is preferable to start with a low dose and gradually increase it to the required level, rather than with standard dosages.

In patients prescribed Protein C for prophylactic purposes, when the risk of thrombosis increases (for example, with infection, trauma or surgery), it is advisable to increase the baseline level of protein C.

Data on the efficacy and safety of Ceprotin^® in patients with combined severe congenital protein C deficiency and APC resistance (APC – activated protein C) are limited.

Method of administration

Ceprotin^® is administered intravenously, after reconstitution of the lyophilisate with sterile water for injections at a rate not exceeding 2 ml/min; in children weighing less than 10 kg – at a rate not exceeding 0.2 ml/kg/min.

When administering Ceprotin^® intravenously, as with the use of other protein-containing drugs, allergic reactions may develop. If allergic symptoms increase rapidly or become life-threatening, the drug should be administered at a dose sufficient to maintain the patient’s life.

Rules for drug preparation

Reconstitute the lyophilized Ceprotin^® with sterile water for injections by connecting the vials using a transfer needle. Gently mix the contents of the vial until completely dissolved.

The solution is drawn into a sterile disposable syringe through a filter needle. A separate filter needle should be used for each vial of the prepared Ceprotin^® solution. The solution should not be used if particulate matter is visible. Immediately after preparation, the solution should be administered intravenously.

Adverse Reactions

There is limited information on adverse effects. No targeted studies related to the safety of the drug have been conducted.

In rare cases, symptoms of hypersensitivity to the drug and allergic reactions (such as angioedema, burning sensation at the injection site, chills, hyperemia, rash, urticaria, decreased blood pressure, lethargy, apathy, nausea, anxiety, tachycardia, feeling of tightness in the chest, vomiting, tingling, bronchospasm) have been noted.

There are isolated reports of fever, arrhythmia, bleeding and thrombosis during therapy with Ceprotin^®.

When using the drug in individuals with severe congenital protein C deficiency, the production of protein C inhibiting antibodies is possible.

Contraindications

• Hypersensitivity to the drug or to any of its components, to mouse proteins or to heparin, except in cases where it is necessary to control life-threatening thrombotic complications.

Use in Pregnancy and Lactation

Although Ceprotin^® has been successfully used in pregnant women with protein C deficiency, the safety of the drug during pregnancy has not been confirmed by controlled clinical studies. Therefore, Ceprotin^® can be prescribed during pregnancy and lactation only if there are clear indications, with a clear preponderance of expected benefit over risk.

Use in Hepatic Impairment

There is no experience in treating patients with hepatic impairment with Ceprotin^®, and therefore such patients require more careful monitoring.

Use in Renal Impairment

There is no experience in treating patients with renal impairment with Ceprotin^®, and therefore such patients require more careful monitoring.

Pediatric Use

Ceprotin^® is administered intravenously, after reconstitution of the lyophilisate with sterile water for injections at a rate not exceeding 2 ml/min; in children weighing less than 10 kg – at a rate not exceeding 0.2 ml/kg/min.

Special Precautions

Since there is a risk of developing allergic reactions, patients should be informed about the early symptoms of allergy, such as urticaria (including generalized), feeling of tightness in the chest, bronchospasm, drop in blood pressure and anaphylaxis. If these symptoms appear, patients should immediately discontinue treatment and consult their doctor.

If shock develops, action should be taken in accordance with current shock treatment guidelines.

When administering drugs made from human blood or plasma, the possibility of transmitting infectious agents cannot be completely excluded. This also applies to pathogens of unknown nature.

In order to reduce the risk of transmission of infectious agents, a number of safety measures are included in the drug manufacturing process

• Donor selection is carried out based on medical examination data and screening of each donor’s blood for markers of hepatitis B, C, and HIV viruses;
• Plasma pools are tested for the presence of hepatitis C virus genomic material;
• Inactivation/removal procedures recognized as effective against hepatitis A, B and C viruses, HIV are used.

However, the effectiveness of the applied inactivation/removal procedures may be insufficient against parvovirus B19. Parvovirus B19 can cause particularly serious consequences in immunocompromised individuals, individuals with increased erythrocyte production (e.g., hemolytic anemia), and in pregnant women (fetal infection), so the risk of parvovirus B19 transmission should be particularly considered when using the drug in these categories of patients.

Patients prescribed drugs made from human blood or plasma are recommended to be vaccinated against hepatitis A and B.

The amount of sodium in the maximum daily dose may exceed 200 mg. This should be taken into account if the patient is prescribed a low-sodium diet.

Ceprotin^® may contain trace amounts of heparin. Therefore, patients may experience heparin-induced allergic reactions accompanied by thrombocytopenia (heparin-induced thrombocytopenia). In heparin-induced thrombocytopenia (HIT), complications such as arterial or venous thrombosis, DIC syndrome, purpura, petechiae and gastrointestinal bleeding are possible. If HIT is suspected, the platelet level should be determined as soon as possible and, if necessary, treatment with Ceprotin^® should be discontinued. The identification of HIT is complicated by the fact that in the acute phase of severe hereditary protein C deficiency, similar symptoms may be present even before the start of treatment. Patients with HIT should subsequently avoid taking drugs containing heparin.

Several cases of bleeding have been noted with the use of Ceprotin^®. This could be associated with concomitant use of anticoagulants (e.g., heparin). However, it cannot be ruled out that the administration of Ceprotin^® could also contribute to hemorrhagic episodes.

Preclinical trial data

Protein C contained in Ceprotin^®, which is isolated from human plasma, is identical in its action to natural human protein C. Therefore, experimental studies of the mutagenic and carcinogenic effects of this drug using laboratory animals are not appropriate. Assessment of single-dose toxicity in laboratory animals showed that even a 10-fold excess of the recommended human dose per unit of body weight does not cause toxic manifestations. The Ames test showed the absence of mutagenic potential for Ceprotin^®.

Effect on ability to drive vehicles and mechanisms

No effect on the ability to drive a car and moving mechanisms was noted.

Overdose

There are no reports of symptoms of Ceprotin^® overdose.

Drug Interactions

No interactions of Ceprotin^® with other drugs have been noted.

Until the anticoagulant effect of Ceprotin^® occurs in patients who have started treatment with oral anticoagulants from the vitamin K antagonist group (e.g., warfarin), a transient state of hypercoagulation is possible. This can be explained by the fact that Protein C itself is a vitamin K-dependent plasma protein and has a shorter T_1/2 than other vitamin K-dependent plasma proteins (such as factors II, IX and X). Therefore, in the initial phase of treatment, Protein C is inactivated faster than procoagulant factors. It is for this reason that when transferring a patient to oral anticoagulants, protein C replacement therapy should be continued until a stable anticoagulant effect is achieved.

In the initial stage of therapy with oral anticoagulants, any patient may develop warfarin-induced skin necrosis. Individuals with congenital protein C deficiency belong to a group with an increased risk.

Incompatibility

No studies on the incompatibility of Ceprotin^® have been conducted, so it should not be mixed with other drugs.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature from 2°C (35.6°F) to 8°C (46.4°F); do not freeze.

Shelf Life

The shelf life is 3 years. Do not use after the expiration date indicated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.