Drug: Ceprotin

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/PRECAUTIONS: Transmission of Infectious Agents . The manufacturing process for CEPROTIN (protein c concentrate) includes processing steps designed to reduce the risk of viral transmission. Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of CEPROTIN (protein c concentrate) is collected only at FDA-approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), and for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, plasma pools for manufacturing are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found negative. To further improve the margin of safety, two dedicated, independent and effective virus inactivation steps (Polysorbate 80 [P80] treatment and vapor heating) have been integrated into the manufacturing process in addition to other purification steps such as immunoaffinity chromatography. Comprehensive virus clearance studies have been performed for the following steps: P80 treatment alone or coupled with an ion exchange chromatography step (IEX I), immunoaffinity chromatography (IAX) and vapor heating. In each study, the validity of the downscaled process has been confirmed by measuring process and biochemical parameters and comparing these with data from the large-scale manufacturing process. Where applicable (i.e. for P80 treatment and for vapor heating), the robustness of virus clearance has also been investigated by adjusting critical process parameters to levels least favorable for virus inactivation (e.g. temperature and incubation time for vapor heating). Virus clearance studies for CEPROTIN (protein c concentrate) 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 P80 Treatment >5.1 >4.7 n.d. 2.5* >3.8* 1.4* IAX 5.7 n.d. 4.8 5.4 3.1 3.6 Vapor Heating 4.6 >5.9 n.d. 5.9 >4.2 1.2 *Coupled with IEX. I
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); 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. CEPROTIN (protein c concentrate) is supplied as a sterile, white or cream colored, lyophilized powder for IV injection. It has a pH between 6.7 and 7.3 and an osmolality not lower than 240 mosmol/kg. One International Unit (IU) of protein C corresponds to the amidolytically measured activity of protein C in 1 mL of normal plasma. The potency (IU) is determined using a chromogenic substrate method referenced against the World Health Organization (WHO) International Standard (86/622).Last reviewed on RxList: 5/18/2007
This monograph has been modified to include the generic and brand name in many instances.

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Clinical Studies Experience The most serious and common adverse reactions related to CEPROTIN (protein c concentrate) 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 cannot 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 (protein c concentrate) 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 (protein c concentrate) . No inhibiting antibodies to CEPROTIN (protein c concentrate) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out. Post-marketing Experience The following adverse reactions have been identified during postapproval use of CEPROTIN (protein c concentrate) : 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. Read the Ceprotin (protein c concentrate) Side Effects Center for a complete guide to possible side effectsLearn More »

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General Treatment with CEPROTIN (protein c concentrate) 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 (protein c concentrate) 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. The dose, administration frequency and duration of treatment with CEPROTIN (protein c concentrate) 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. Table 1 provides the CEPROTIN (protein c concentrate) dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis. Table l
CEPROTIN Dosing Schedule for Acute Episodes, Short-term Prophylaxis and Long-term Prophylaxis*   Initial Dose* Subsequent 3 Doses** Maintenance-Dose** 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 * Dosing is based on a pivotal clinical trial of 15 patients.
** The dose regimen should be adjusted accdording to the pharmacokinetic profile of each individual
*** CEPROTIN (protein c concentrate) should be continued until desired anticoagulation is achieved.
NA - Not applicable; Q - every'. 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 (protein c concentrate) , 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 and CLINICAL PHARMACOLOGY: Pharmacokinetics . 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 (protein c concentrate) . The half-life of CEPROTIN (protein c concentrate) may be shortened in certain clinical conditions such as acute thrombosis, purpura fulminans and skin necrosis. See CLINICAL PHARMACOLOGY: Pharmacokinetics . 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. 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. Preparation of CEPROTIN [Protein C Concentrate (Human)] Reconstitution: Use Aseptic Technique
  1. Bring the CEPROTIN (protein c concentrate) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
  2. Remove caps from the CEPROTIN (protein c concentrate) and diluent vials.
  3. Cleanse stoppers with germicidal solution, and allow them to dry prior to use.
  4. Remove protective covering from one end of the double-ended transfer needle and insert 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 (protein c concentrate) vial; then rapidly insert the free end of the needle through the CEPROTIN (protein c concentrate) 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 (protein c concentrate) (237-7684).
  6. Disconnect the two vials by removing the needle from the diluent vial stopper. Then, remove the transfer needle from the CEPROTIN (protein c concentrate) vial. Gently swirl the vial until all powder is dissolved. Be sure that CEPROTIN (protein c concentrate) is completely dissolved; otherwise, active materials will be removed by the filter needle.
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 (protein c concentrate) should be administered 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 (protein c concentrate) .
  3. Inject air into the vial and then withdraw the reconstituted CEPROTIN (protein c concentrate) into the syringe.
  4. 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 (protein c concentrate) only.
  5. Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under
Administration by infusion CEPROTIN (protein c concentrate) 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. Dosage Forms And Strengths CEPROTIN (protein c concentrate) 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 (protein c concentrate) , 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.

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No formal drug interaction studies have been conducted. See WARNINGS AND PRECAUTIONS: Bleeding Episodes for information regarding simultaneous administration of CEPROTIN (protein c concentrate) and tissue plasminogen activator (tPA). See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists for information regarding use of CEPROTIN (protein c concentrate) and vitamin K antagonists.Read the Ceprotin Drug Interactions Center for a complete guide to possible interactions Learn More »

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Severe Congenital Protein C Deficiency CEPROTIN (protein c concentrate) is indicated for patients with severe congenital Protein C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. CEPROTIN (protein c concentrate) is indicated as a replacement therapy for pediatric and adult patients.

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None.Last reviewed on RxList: 5/18/2007
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

No symptoms of overdose with CEPROTIN (protein c concentrate) have been reported. The maximum infusion rate administered in clinical studies were doses of up to 600 IU/kg body weight (BW)/day (150 IU/kg BW every 6 hours) of CEPROTIN (protein c concentrate) . There have been no overdosages of CEPROTIN (protein c concentrate) reported during clinical studies. In long-term prophylactic treatment of doses up to 291.7 IU/kg BW/day, no adverse events were reported.

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Storage and Handling CEPROTIN (protein c concentrate) is available in single-dose vials that contain the following nominal product strengths: BLUE BAR: 500 IU per vial:
(NDC: 0944-4175-05) GREEN BAR: 1000 IU per vial:
(NDC: 0944-4175-10) Actual potency is printed on the vial label. One package of CEPROTIN (protein c concentrate) contains one glass vial of CEPROTIN (protein c concentrate) powder, one glass vial of Sterile Water for Injection, USP, one transfer needle, one filter needle, one full prescribing physician insert and one patient package insert. CEPROTIN (protein c concentrate) , packaged for sale, is stable for 3 years when stored refrigerated at 2°C-8°C (36°F-46°F). Do not freeze in order to prevent damage to the diluent vial. Store the vial in the original carton to protect it from light. The reconstituted solution should be used within 3 hours of reconstitution. Do not use beyond the expiration date on the CEPROTIN (protein c concentrate) vial.Last reviewed on RxList: 5/18/2007
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Hypersensitivity/Allergic Reactions CEPROTIN (protein c concentrate) 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. Transmission of Infectious Agents CEPROTIN (protein c concentrate) is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing a broad range of viruses during manufacture. See DESCRIPTION . Despite these measures, such products can still potentially transmit disease. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxter Healthcare Corporation, at 1-866-888-2472. The physician should discuss the risks and benefits of this product with the patient. Some viruses, such as Human Parvovirus B19 (B19V) or Hepatitis A, are particularly difficult to remove or inactivate. B19V most seriously affects pregnant women (fetal infection), or immune-compromised individuals. Symptoms of B19V infection include fever, drowsiness, chills and runny nose followed about two weeks later by a rash and joint pain. Evidence of Hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting and abdominal pain. Dark urine and a yellowed complexion are also common symptoms. Patients should be encouraged to consult their physician if such symptoms appear. Appropriate vaccination (hepatitis A and B) should be considered for patients in regular and/or repeated receipt of human plasma-derived Protein C. 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 (protein c concentrate) further contributed to these bleeding events. Simultaneous administration of CEPROTIN (protein c concentrate) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA. Heparin-induced Thrombocytopenia (HIT) CEPROTIN (protein c concentrate) contains trace amounts of heparin which may lead to Heparin-induced Thrombocytopenia. The platelet count should be determined immediately and discontinuation of CEPROTIN (protein c concentrate) should be considered. Low Sodium Diet/Renal Impairment Patients on a low sodium diet should be informed that the quantity of sodium in the maximum daily dose of CEPROTIN (protein c concentrate) exceeds 200 mg. Patients with renal impairment should be monitored more closely for sodium overload. Use In Specific Populations Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with CEPROTIN (protein c concentrate) . It is also not known whether CEPROTIN (protein c concentrate) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CEPROTIN (protein c concentrate) has not been studied for use in pregnancy. Labor and Delivery There has been one report of CEPROTIN (protein c concentrate) exposure during labor and delivery with no adverse outcome. CEPROTIN (protein c concentrate) has not been studied for use during labor and delivery. Nursing Mothers It is not known whether CEPROTIN (protein c concentrate) is excreted in human milk. CEPROTIN (protein c concentrate) has not been studied for use in nursing mothers. Pediatric Use Neonatal and pediatric subjects were included in several retrospective and prospective studies, evaluating the safety and effectiveness of CEPROTIN (protein c concentrate) . Subjects were enrolled from as early as 2 days old throughout adolescence. Geriatric Use Clinical studies of CEPROTIN (protein c concentrate) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Renal/Hepatic Impairment No experience in the treatment of patients with renal and/or hepatic impairment is available. Nonclinical Toxicology Carcinogenesis, Mutagenesis and Impairment of Fertility Protein C contained in CEPROTIN (protein c concentrate) is a normal constituent of human plasma and acts like endogenous protein C. Studies in heterologous species to evaluate carcinogenicity, reproductive toxicology and developmental toxicology have not been performed. CEPROTIN (protein c concentrate) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test). Last reviewed on RxList: 5/18/2007
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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