Data from FDA (Food and Drug Administration, USA) - Curated by Toby Galbraith - Last updated 17 April 2017

Indication(s)

1 INDICATIONS AND USAGE CEPROTIN is indicated for patients with severe congenital Protein C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.

CEPROTIN is indicated as a replacement therapy for pediatric and adult patients.

(1.1) 1.1 Severe Congenital Protein C Deficiency CEPROTIN is indicated for patients with severe congenital Protein C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.

CEPROTIN is indicated as a replacement therapy for pediatric and adult patients.

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions

6 ADVERSE REACTIONS The most serious and common adverse reactions observed in clinical trials were rash, itching and lightheadedness.

(2.1, 5.1, 6.1) The most serious adverse reactions postmarketing were hemothorax and hypotension.

(6.2) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience The most serious and common adverse reactions related to CEPROTIN treatment observed were hypersensitivity or allergic reactions (itching and rash) and lightheadedness.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in one clinical study of a drug can not be directly compared with rates in the clinical studies of the same drug or another drug and may not reflect the rates observed in practice.

The safety profile of CEPROTIN was based on 121 patients from clinical studies and compassionate use in severe congenital Protein C deficiency.

Duration of exposure ranged from 1 day to 8 years.

One patient experienced hypersensitivity/allergic reactions (itching and rash) and lightheadedness which were determined by the investigator to be related to CEPROTIN. No inhibiting antibodies to CEPROTIN have been observed in clinical studies.

However, the potential for developing antibodies can not be ruled out.

6.2 Post-marketing Experience The following adverse reactions have been identified during postapproval use of CEPROTIN: hemothorax, hypotension, hyperhydrosis, fever and restlessness.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of Protein C activity is feasible.

(2.1) NA = Not applicable; Q = every.

CEPROTIN Dosing Schedule for Acute Episodes, Short-term Prophylaxis and Long-term ProphylaxisDosing is based upon a pivotal clinical trial of 15 patients.

Initial Dose The dose regimen should be adjusted according to the pharmacokinetic profile for each individual (2.1, 2.2) Subsequent 3 Doses Maintenance Dose Acute Episode/Short-term ProphylaxisCEPROTIN should be continued until desired anticoagulation is achieved.

100-120 IU/kg 60 - 80 IU/kg Q 6 hours 45 - 60 IU/kg Q 6 or 12 hours Long-term Prophylaxis NA NA 45 - 60 IU/kg Q 12 hours Store at 2°C - 8°C (36°F-46°F) and protect from light.

Avoid freezing.

Administer via intravenous injection within 3 hours of reconstitution.

(16) 2.1 General Treatment with CEPROTIN should be initiated under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of protein C activity is feasible.

CEPROTIN is administered by intravenous injection after reconstitution of the powder for solution for injection with Sterile Water for Injection.

Allergic type hypersensitivity reactions are possible.

See WARNINGS/PRECAUTIONS: Hypersensitivity/Allergic Reactions (5.1).

The dose, administration frequency and duration of treatment with CEPROTIN depends on the severity of the protein C deficiency, the patient 's age, the clinical condition of the patient and the patient 's plasma level of protein C. Therefore, the dose regimen should be adjusted according to the pharmacokinetic profile for each individual patient.

See DOSAGE AND ADMINISTRATION: Protein C Activity Monitoring (2.2).

Table 1 provides the CEPROTIN dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis.

Table 1: CEPROTIN Dosing Schedule for

Acute Episodes, Short-term

Prophylaxis and Long-term ProphylaxisDosing is based upon a pivotal clinical trial of 15 patients.

NA = Not applicable; Q = every.

Initial Dose The dose regimen should be adjusted according to the pharmacokinetic profile for each individual (2.1, 2.2) Subsequent 3 Doses Maintenance Dose Acute Episode/Short-term ProphylaxisCEPROTIN should be continued until desired anticoagulation is achieved.

100-120 IU/kg 60 - 80 IU/kg Q 6 hours 45 - 60 IU/kg Q 6 or 12 hours Long-term Prophylaxis NA NA 45 - 60 IU/kg Q 12 hours An initial dose of 100-120 IU/kg for determination of recovery and half-life is recommended for acute episodes and short-term prophylaxis.

Subsequently, the dose should be adjusted to maintain a target peak protein C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough protein C activity level above 25 % for the duration of treatment.

In patients receiving prophylactic administration of CEPROTIN, higher peak protein

C activity levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention).

Maintenance of trough protein C activity levels above 25 % is recommended.

These dosing guidelines are also recommended for neonatal and pediatric patients.

See USE IN SPECIFIC POPULATIONS: Pediatric Use (8.4) and CLINICAL PHARMACOLOGY: Pharmacokinetics (12.3).

2.2 Protein C Activity Monitoring The measurement of protein C activity using a chromogenic assay is recommended for the determination of the patient 's plasma level of protein C before and during treatment with CEPROTIN.

The half-life of CEPROTIN may be shortened in certain clinical conditions such as acute thrombosis, purpura fulminans and skin necrosis.

See CLINICAL PHARMACOLOGY: Pharmacokinetics (12.3).

In the case of an acute thrombotic event, it is recommended that protein C activity measurements be performed immediately before the next injection until the patient is stabilized.

After the patient is stabilized, continue monitoring the protein C levels to maintain the trough protein C level above 25 %.

Patients treated during the acute phase of their disease may display much lower increases in protein C activity.

Coagulation parameters should also be checked; however, in clinical trials data were insufficient to establish correlation between protein C activity levels and coagulation parameters.

2.3 Initiation of Vitamin K Antagonists In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists, 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. Factor II, IX and X).

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 treatment with oral anticoagulant therapy, individuals with severe congenital protein C deficiency are particularly at risk.

During the initiation of oral anticoagulant therapy, it is advisable to start with a low dose of the anticoagulant and adjust this incrementally, rather than use a standard loading dose of the anticoagulant.

2.4 Preparation of CEPROTIN [Protein C Concentrate (Human)] Reconstitution: Use Aseptic Technique Bring the CEPROTIN (powder) and Sterile Water for Injection, USP (diluent) to room temperature.

Remove caps from the CEPROTIN and diluent vials.

Cleanse stoppers with germicidal solution, and allow them to dry prior to use.

Remove protective covering from one end of the double-ended transfer needle and insert exposed needle through the center of the diluent vial stopper.

Remove protective covering from the other end of the double-ended transfer needle.

Invert diluent vial over the upright CEPROTIN vial; then rapidly insert the free end of the needle through the CEPROTIN vial stopper at its center.

The vacuum in the vial will draw in the diluent.

If there is no vacuum in the vial, do not use the product, and contact Baxter Customer Service at 1-888-CEPROTIN (237-7684).

Disconnect the two vials by removing the needle from the diluent vial stopper.

Then, remove the transfer needle from the CEPROTIN vial.

Gently swirl the vial until all powder is dissolved.

Be sure that CEPROTIN is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of CEPROTIN [Protein C Concentrate (Human)] Administration: Use Aseptic Technique Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

After reconstitution, the solution is colorless to slightly yellowish and clear to slightly opalescent and essentially free from visible particles.

Do not use the product if the solution does not meet these criteria.

CEPROTIN should be administered at room temperature not more than 3 hours after reconstitution.

Attach the filter needle to a sterile, disposable syringe and draw back the plunger to admit air into the syringe.

Insert the filter needle into the vial of reconstituted CEPROTIN. Inject air into the vial and then withdraw the reconstituted CEPROTIN into the syringe.

Remove and discard the filter needle in a hard-walled Sharps container for proper disposal.

Filter needles are intended to filter the contents of a single vial of CEPROTIN only.

Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under Administration by infusion.

Administration by Infusion 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 rate of 0.2 mL/kg/minute.

Use in special populations

8 USE IN SPECIFIC POPULATIONS Pregnancy: Not studied.

(8.1) Labor and Delivery: Not studied.

(8.2) Nursing Mothers: Not studied.

(8.3) Pediatric Use: Recommended for neonate and pediatric use.

(2.1, 8.4, 12.3) Renal/Hepatic Impairment: Not studied.

(8.6) 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with CEPROTIN.

It is also not known whether CEPROTIN can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

CEPROTIN has not been studied for use in pregnancy.

8.2 Labor and Delivery There has been one report of CEPROTIN exposure during labor and delivery with no adverse outcome.

CEPROTIN has not been studied for use during labor and delivery.

8.3 Nursing Mothers It is not known whether CEPROTIN is excreted in human milk.

CEPROTIN has not been studied for use in nursing mothers.

8.4 Pediatric Use Neonatal and pediatric subjects were included in several retrospective and prospective studies, evaluating the safety and effectiveness of CEPROTIN. Subjects were enrolled from as early as 2 days old throughout adolescence.

8.5 Geriatric Use Clinical studies of CEPROTIN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal/Hepatic Impairment No experience in the treatment of patients with renal and/or hepatic impairment is available.

Pregnancy and lactation
8.3 Nursing Mothers It is not known whether CEPROTIN is excreted in human milk. CEPROTIN has not been studied for use in nursing mothers.

Interactions

7 DRUG INTERACTIONS No formal drug interaction studies have been conducted. See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of CEPROTIN and tissue plasminogen activator (tPA). See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of CEPROTIN and vitamin K antagonists. None known. (7)

More information

Category Value
Authorisation number BLA125234
Orphan designation No
Product NDC 0944-4175
Date Last Revised 12-08-2010
Type HUMAN PRESCRIPTION DRUG
RXCUI 723871
Marketing authorisation holder Baxter Healthcare Corporation