CEPROTIN Clinical Information

CEPROTIN® [Protein C Concentrate (Human)] is the only nonactivated Protein C concentrate approved by the US Food and Drug Administration (FDA) for severe congenital Protein C deficiency1

CEPROTIN Clinical Pharmacology
Rapid and effective increase of plasma Protein C levels2 CEPROTIN is a highly purified, stable concentrate of human Protein C zymogen produced from human plasma.3
  • Patients treated during the acute phase of their disease may display much lower increases in Protein C activity1
  • Coagulation parameters should be checked1
  • Data were insufficient in clinical trials to establish correlation between Protein C activity levels and coagulation parameters1
Impact of CEPROTIN on peak Protein C activity levels (N=11)2
Propotion of
CEPROTIN
infusions
(%)
  • 66-130%
  • 131-300%
  • >300%
  • 90
  • 80
  • 70
  • 60
  • 50
  • 40
  • 30
  • 20
  • 10
Peak Protein C activity level (% of normal)

Results from a prospective, open-label, multicenter, phase 2/3 study of patients with severe congenital Protein C deficiency. Median preinfusion Protein C activity was 2.00 IU/dL. After receiving the first infusion of 120 IU/kg, median Protein C activity increased to 165.00 IU/dL. Activity levels increased in most patients following subsequent infusions.2

CEPROTIN Primary Efficacy
Study Design

A prospective, multicenter, open-label, nonrandomized, phase 2/3 pivotal study evaluated the efficacy and safety of CEPROTIN in 18 subjects with severe congenital Protein C deficiency for the on-demand treatment of acute thrombotic episodes. The primary study endpoint assessed whether episodes of purpura fulminans and/or other acute thrombotic events, such as warfarin-induced skin necrosis, were treated effectively, effectively with complications, or not treated effectively. However, data were ultimately inadequate for warfarin-induced skin necrosis.1

CEPROTIN is administered intravenously.

Primary Efficacy Rating for the Treatment of Purpura Fulminans vs. Conventional Therapy1
  • Effective
  • Effective with
    complications
  • Not effective
  • 100%
  • 80%
  • 60%
  • 40%
  • 20%
  • Historical Controls (N=21)
  • CEPROTIN (N=18)

CEPROTIN was administered for the acute management of 18 purpura fulminans events (6 severe, 11 moderate, 1 mild). Historical control group comprised of 21 purpura fulminans events that were treated with modalities such as fresh frozen plasma or conventional anticoagulants.1

Patients were more effectively treated with CEPROTIN than with modalities such as fresh frozen plasma or conventional anticoagulants.1
CEPROTIN Secondary Efficacy
CEPROTIN rated an “excellent” treatment in nearly 3 out of 4 cases.1

The secondary efficacy rating for CEPROTIN was judged by study investigators. Efficacy of treatment in terms of distribution of responses for episodes of purpura fulminans and thromboembolic events was rated via a pre-defined four-point scale (excellent, good, fair, and not effective or not rated). A total of 11 patients with severe congenital Protein C deficiency received Protein C concentrate treatment for 24 acute thrombotic episodes, of which 19 were purpura fulminans (n=18)/coumarin-induced skin necrosis (n=1) and 5 were venous thrombosis.2

Secondary Efficacy Ratings for the Treatment of Skin Lesions and Other Thrombotic Episodes1
  • Purpura fulminans
    skin necrosis (N=18)
  • Venous thrombosis
    (N=5)
  • Total
    (N=23)
  • 100%
  • 80%
  • 60%
  • 40%
  • 20%
  • Fair
  • Good
  • Excellent
Mean number of days to COMPLETE healing of skin lesions in clinical trial1
4.6 days(Range
1 to 12 days)
Non-necrotic

(16 episodes/9 subjects)

21.1 days(Range
5 to 52 days)
Necrotic

(7 episodes/5 subjects)

CEPROTIN Adverse Events
Demonstrated tolerability1 The most common adverse reactions observed related to CEPROTIN treatment include:1
  • Light-headedness
  • Itching
  • Rash

Safety profile 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.1

CEPROTIN Prophylaxis
Prophylaxis is often necessary in certain severe congenital Protein C deficiency patients and situations of increased risk.4-6

Pivotal phase 2/3 trial data show CEPROTIN effective as a prophylaxis, as well as an on-demand treatment for acute thrombotic episodes in patients with severe congenital Protein C deficiency.1

Summary of Complications During Short-Term Prophylaxis in the Protein C Concentrate (Human) Pivotal Study1
Reason for Treatment Number of Treatments Presentation of Purpura Fulminans (PF) During Treatment Episodes Thromboembolic Complications During Treatment Episode Number of Treatments Free of Complications
 %
 %
N%
Anticoagulation
Therapy
3
  0.0
  0.0
3100.0
Surgical
Procedure
4
  0.0
  0.0
4100.0
TOTAL 7
  0.0
  0.0
7100.0
All 7 short-term prophylaxis treatments were free of complications of purpura fulminans or thromboembolic events.1
Number and Rate of Episodes of Skin Lesions or Thrombosis for 4 Subjects Who Received Long-Term Prophylactic Treatment and Were Treated On-Demand in the Protein C Concentrate (Human) Pivotal Study1
LONG-TERM PROPHYLACTIC TREATMENT WHILE ON-DEMAND*
Summary Statistic
Mean
Median
Minimum
Maximum
Number of Episodes Per Subject Number of Days Receiving Prophylactic Treatment Monthly Rate of Episodes
0 229 0.0
0 268 0.0
0 42 0.0
0 338 0.0
Number of Episodes Per Subject Number of Days Receiving Prophylactic Treatment Monthly Rate of Episodes
3.3 165 1.91
3.0 159 0.49
1.0 19 0.25
6.0 323 6.40
Time to First Episode After Exiting Long-term Prophylaxis
23.3
24.5
12.0
32.0
*Total number of episodes while subjects were On-Demand was 13. No episodes of purpura fulminans occurred in 4 subjects on long-term prophylaxis treatment with CEPROTIN (range 42 to 338 days).1
CEPROTIN Manufacturing
CEPROTIN is subject to robust viral clearance processes to help reduce the risk of viral transmission1

Products made from human plasma, such as CEPROTIN, may contain infectious agents such as viruses that can cause disease. To help ensure that viruses are removed and/or inactivated, CEPROTIN has several processing steps.1

CEPROTIN Production Process7

Human Plasma

Centrifugation

Cryoprecipitate

Isolation
of proteins

Purification, concentration,
adjustment of protein and
salt, and lyophilization

Protein C concentrate
Virus inactivation with
polysorbate 80
Purification
Intermediate product rich in prothrombin, factors VII, IX and X, and proteins C and S
Protein C
concentrate powder
Virus inactivation with
vapor heating
Reconstitution with sterile water,
purification, adding of human albumin
for stabilization, sterile filtration,
and lyophilization
Final product:
CEPROTIN
Simplified depiction of the production process. Purification involves various chromatography steps, including immunoaffinity chromatography. For more details, please see Knoebl, 2008.7
    REFERENCES:
  1. Baxalta. CEPROTIN [Protein C Concentrate (Human)]: Prescribing information.
  2. Manco-Johnson MJ, Bomgaars L, Palascak J, et al. Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency. Thromb Haemost. 2016;116(1):58-68.
  3. Knoebl PN. Blood Coagulation and Inflammation in Critical Illness: the Importance of the Protein C Pathway. UNI-MED Verlag; 2008.
  4. Kroiss S, Albisetti M. Use of human protein C concentrates in the treatment of patients with severe congenital protein C deficiency. Biologics. 2010;4:51-60.
  5. Tcheng WY, Dovat S, Gurel Z, Donkin J, Wong W-Y. Severe congenital protein C deficiency: description of a new mutation and prophylactic protein C therapy and in vivo pharmacokinetics. J Pediatr Hematol Oncol. 2008;30(2):166-171.
  6. Chalmers E, Cooper P, Forman K, et al. Purpura fulminans: recognition, diagnosis and management. Arch Dis Child. 2011;96(11):1066-1071.
  7. Knoebl PN. Human protein C concentrates for replacement therapy in congenital and acquired protein C deficiency. Drugs Today (Barc). 2008;44(6):429-441.

Indication and Important Safety Information

WARNINGS and PRECAUTIONS
  • Hypersensitivity/Allergic reactionsCEPROTIN® [Protein C Concentrate (Human)] may contain trace amounts 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. In case of hypersensitivity/allergic reaction, discontinue CEPROTIN administration immediately and institute appropriate treatment.
  • Transmission of infectious agentsCEPROTIN is made from human plasma. It may carry a risk of transmitting infectious agents, e.g. viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
  • Bleeding episodesSeveral bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. CEPROTIN administration may have further contributed to these bleeding events. Simultaneous administration of CEPROTIN and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.
  • Heparin-induced thrombocytopenia (HIT)CEPROTIN contains trace amounts of heparin that may lead to HIT, which can be associated with a rapid decrease of thrombocytes. If HIT is suspected, determine the platelet count immediately and discontinue CEPROTIN administration.
  • Low sodium diet/Renal impairmentPatients on a low sodium diet or who have renal impairment should be informed that the quantity of sodium in the maximum daily dose of CEPROTIN exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.
ADVERSE REACTIONS

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

Indication

CEPROTIN® [Protein C Concentrate (Human)] is indicated for pediatric and adult patients with severe congenital Protein C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans

Please review the CEPROTIN Prescribing Information for full prescribing details.