CEPROTIN: Package Insert and Label Information

CEPROTIN- protein c concentrate human
Baxalta US Inc.

1 INDICATIONS AND USAGE

CEPROTIN, Protein C Concentrate (Human), is an anticoagulant indicated for neonates, pediatric and adult patients with severe congenital Protein C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.

2 DOSAGE AND ADMINISTRATION

For intravenous administration only.

2.1 Dose

  • Initiate treatment with CEPROTIN under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of protein C activity is feasible.
  • 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.
  • Adjust the dose regimen according to the pharmacokinetic profile for each individual patient. [See DOSAGE AND ADMINISTRATION: Protein C Activity Monitoring].

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 Prophylaxis *
Initial Dose Subsequent 3 Doses Maintenance Dose
NA = Not applicable; Q = every.
*
Dosing is based upon a clinical trial of 15 patients.
Adjust the dose according to the pharmacokinetic profile for each individual patient.
Continue CEPROTIN until desired anticoagulation is achieved.
Acute Episode / Short-term Prophylaxis 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
  • Determine protein C recovery and half-life with an initial dose of 100-120 IU/kg in patients receiving treatment for acute episodes and short-term prophylaxis.
  • Adjust the dose to maintain a target peak protein C activity of 100 %.
  • Continue the patient on the same dose after resolution of the acute episode to maintain trough protein C activity level above 25% for the duration of treatment.
  • Patients receiving prophylactic administration of CEPROTIN may warrant higher peak protein C activity levels in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention). Therefore it is recommended to maintain trough protein C activity levels above 25%.
  • 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)].

Protein C Activity Monitoring

  • Determine the patient’s protein C plasma level before and during treatment with CEPROTIN by measuring protein C activity using a chromogenic assay.Certain clinical conditions, such as acute thrombosis, purpura fulminans, and skin necrosis, may shorten the half-life of CEPROTIN. See CLINICAL PHARMACOLOGY: Pharmacokinetics (12.3). In case of an acute thrombotic event, immediately measure protein C activity before the next injection until the patient is stable and monitor 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. In addition to protein C activity measurement, check the coagulation parameters also;however, data were insufficient to establish correlation between protein C activity levels and coagulation parameters in clinical trials.

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 because protein C, 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 protein C activity is more rapidly suppressed than that of the procoagulant factors. For this reason, if the patient switched to oral anticoagulants, they must continue protein C replacement 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.

2.2 Preparation

Reconstitution: Use Aseptic Technique

  1. Bring the CEPROTIN (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
  2. Remove caps from the CEPROTIN and diluent vials.
  3. Cleanse stoppers with germicidal solution, and allow them to dry before use.
  4. Remove protective covering from one end of the double-ended transfer needle and insert the exposed needle through the center of the diluent vial stopper.
  5. 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 Baxalta Customer Service at 1-888-229-8379.
  6. 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.

2.3 Administration

Administration: Use Aseptic Technique

Visually inspect CEPROTIN for particulate matter and discoloration before administration.

After reconstitution, the solution should be colorless to slightly yellowish and clear to slightly opalescent, and free of visible particles. Do not use the solution if it does not meet these criteria. Administer CEPROTIN at room temperature not more than 3 hours after reconstitution.

  1. Attach the filter needle to a sterile, disposable syringe and draw back the plunger to admit air into the syringe.
  2. Insert the filter needle into the vial of reconstituted CEPROTIN.
  3. Inject air into the vial and then withdraw the reconstituted CEPROTIN into the syringe.
  4. Remove and discard the filter needle in a hard-walled Sharps container for proper disposal. Use filter needles to filter the contents of a single vial of CEPROTIN only.
  5. Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under Administration by infusion.

Record the name and batch number of the product every time CEPROTIN is administered to a patient.

Administration by Infusion

Administer CEPROTIN at a maximum injection rate of 2 mL per minute except for children with a bodyweight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/minute.

3 DOSAGE FORMS AND STRENGTHS

CEPROTIN is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human protein C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection respectively, to provide a single dose of human Protein C at a concentration of 100 IU/mL.

CEPROTIN, when reconstituted with the appropriate volume of diluent, contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate, and 8.8 mg/mL sodium chloride.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

CEPROTIN may contain traces of mouse protein and/or heparin as a result of the manufacturing process. Allergic reactions to mouse protein and/or heparin cannot be ruled out. If symptoms of hypersensitivity/allergic reaction occur, discontinue the injection/infusion. In case of anaphylactic shock, the current medical standards for treatment are to be observed.

5.2 Transmissible Infectious Agents

Because CEPROTIN is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease agent.

All infections suspected by a physician to have been possibly transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-888-229-8379. Discuss the risks and benefits of this product with your patient.

5.3 Bleeding Episodes

Several bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication 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.

Simultaneous administration of CEPROTIN and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia (HIT)

CEPROTIN contains trace amounts of heparin which may lead to Heparin-induced Thrombocytopenia, which can be associated with a rapid decrease of the number of thrombocytes. Identifying HIT is complicated because these symptoms may already be present in acute phase patients with severe congenital protein C deficiency. Determine the platelet count immediately and consider discontinuation of CEPROTIN.

5.5 Low Sodium Diet/Renal Impairment

Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of CEPROTIN exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to CEPROTIN treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared to rates in the clinical trials of 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 cannot be ruled out.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of CEPROTIN. 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.

Psychiatric Disorders: Restlessness

Skin and Subcutaneous Tissue Disorders: Hyperhydrosis

General Disorders and Administration Site Conditions: Injection Site Reaction

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: Dose (2.1) Initiation of Vitamin K Antagonists].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no data with CEPROTIN use in pregnant women to inform a drug-associated risk. 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 during labor and delivery.

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively, regardless of drug exposure.

8.2 Lactation

Risk Summary

There is no information regarding the presence of CEPROTIN in human milk, the effect on the breastfed infant, or the effects on milk production. CEPROTIN has not been studied for use in nursing mothers.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CEPROTIN and any potential adverse effects on the breastfed child from CEPROTIN or from the underlying maternal condition.

8.4 Pediatric Use

Neonatal and pediatric subjects were enrolled during the prospective and retrospective studies described in CLINICAL STUDIES (14). Of the 18 subjects enrolled during the prospective study, 1 was newborn, 3 were between 28 days and 23 months, 9 were between 2 and 11 years, 1 was between 12 and 16 years, and 4 were older than 16 years. Of the 11 subjects enrolled and treated during the retrospective study, 9 were between 2 and 11 years, and 2 were older than 16 years [see CLINICAL STUDIES (14)].

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.

11 DESCRIPTION

CEPROTIN [Protein C Concentrate (Human)] is manufactured from human plasma purified by a combination of filtration and chromatographic procedures, including a column of immobilized mouse monoclonal antibodies on gel beads [See WARNINGS AND PRECAUTIONS: Transmissible Infectious Agents (5.2)].

The manufacturing process for CEPROTIN includes processing steps designed to reduce the risk of viral transmission. The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: Human Immunodeficiency Virus Type 1 (HIV-1), Bovine Viral Diarrhea Virus (BVDV ), Tick-Borne Encephalitis Virus (TBEV), Pseudorabies Virus (PRV), Hepatitis A Virus (HAV) and Mice Minute Virus (MMV). Virus reduction steps consist of detergent treatment (Polysorbate 80, P80), heat inactivation (Vapor Heating) and immunoaffinity chromatography (IAX).

Virus clearance studies for CEPROTIN have demonstrated that the process provides for a robust overall virus clearance capacity. A summary of log10 virus reduction factors per virus and manufacturing step is presented in Table 2.

Table 2: Summary of Mean Log10 Virus Reduction Factors for the CEPROTIN Manufacturing Process
Manufacturing Step HIV-1 HCV Model Viruses PRV HAV MMV
BVDV TBEV
Abbreviations: IEX, Ion Exchange Chromatography; IAX, Immunoaffinity Chromatography; HIV-1, Human Immunodeficiency Virus Type I; TBEV, Tick-Borne Encephalitis Virus (model for hepatitis C virus [HCV]); BVDV, Bovine Viral Diarrhea Virus (model virus for HCV and other small, enveloped RNA viruses); PRV, Pseudorabies Virus (model virus for enveloped DNA viruses, e.g. HBV, Hepatitis B Virus); HAV, Hepatitis A Virus; MMV, Mice Minute Virus (model for Human Parvovirus B19 and for non enveloped viruses); n.d., not done.
*
Coupled with IEX. I
P80 Treatment >5.1 >4.7 n.d. 2.5* >3.8* 1.4*
IAX 3.9 2.9 3.8 4.0 0.9 3.5
Vapor Heating 4.6 >5.9 n.d. 5.9 >4.2 1.2
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