CEPROTIN Protein C Concentrate Human Kit — NDC 0944-4177-05 (Billing 00944-4177-05)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Protein C is the precursor of a vitamin K-dependent anticoagulant glycoprotein (serine protease) that is synthesized in the liver. See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) . It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to activated Protein C (APC).

APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor protein S. APC exerts its effect by the inactivation of the activated forms of factors V and VIII, which leads to a decrease in thrombin formation. APC has also been shown to have profibrinolytic effects.

The Protein C pathway provides a natural mechanism for control of the coagulation system and prevention of excessive procoagulant responses to activating stimuli. A complete absence of protein C is not compatible with life. A severe deficiency of this anticoagulant protein causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.

12.2Pharmacodynamics In clinical studies, the intravenous administration of CEPROTIN demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of protein C. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.

12.3Pharmacokinetics Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with protein C deficiency. Table 3: Pharmacokinetics of CEPROTIN in Subjects with Severe Congenital Protein C Deficiency C max = Maximum concentration after infusion; T max = Time at maximum concentration; AUC 0-Infinity = Area under the curve from 0 to infinity; MRT = Mean residence time; and Incremental recovery = Maximum increase in Protein C concentration following infusion divided by dose PK parameter N Median 95% CI for median Min Max C max [IU/dL] 21 110 106 to 127 40 141 T max [h] 21 0.50 0.50 to 1.05 0.17

1.33Incremental recovery [(IU/dL)/(IU/kg)] 21 1.42 1.32 to 1.59 0.50

1.76Initial half-life [h] 21 7.8 5.4 to 9.3 3.0

36.1Terminal half-life [h] 21 9.9 7.0 to 12.4 4.4

15.8Half-life by the non-compartmental approach [h] 21 9.8 7.1 to 11.6 4.9

14.7AUC 0-Infinity [IU*h/dL] 21 1500 1289 to 1897 344 2437 MRT [h] 21 14.1 10.3 to 16.7 7.1

21.3Clearance [dL/kg/h] 21 0.0533 0.0428 to 0.0792 0.0328 0.2324 Volume of distribution at steady state [dL/kg] 21 0.74 0.70 to 0.89 0.44

1.65The protein C plasma activity was measured by chromogenic and/or clotting assay. The maximum plasma concentrations (C max ) and area under the plasma concentration-time curve (AUC) appeared to increase dose-linearly between 40 and 80 IU/kg. The median incremental recovery was 1.42 [(IU/dL)/(IU/kg)] after intravenous administration of CEPROTIN.

The median half-lives, based on non-compartmental method, ranged from 4.9 to 14.7 hours, with a median of 9.8 hours. In patients with acute thrombosis, both the increase in protein C plasma levels as well as half-life may be considerably reduced. No formal study or analysis has been performed to evaluate the effect of covariates such as race and gender on the pharmacokinetics of CEPROTIN.

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of CEPROTIN may be different between very young children and adults. The systemic exposure (C max and AUC) may be considerably reduced due to a faster clearance, a larger volume of distribution, and/or a shorter half-life of protein C in very young children than in older subjects.

This fact must be considered when a dosing regimen for children is determined. Doses should be individualized based upon protein C activity levels. See DOSAGE AND ADMINISTRATION: Protein C Activity Monitoring (2.2) .

12.1Mechanism of Action Protein C is the precursor of a vitamin K-dependent anticoagulant glycoprotein (serine protease) that is synthesized in the liver. See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) . It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to activated Protein C (APC).

APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor protein S. APC exerts its effect by the inactivation of the activated forms of factors V and VIII, which leads to a decrease in thrombin formation. APC has also been shown to have profibrinolytic effects.

The Protein C pathway provides a natural mechanism for control of the coagulation system and prevention of excessive procoagulant responses to activating stimuli. A complete absence of protein C is not compatible with life. A severe deficiency of this anticoagulant protein causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.

12.3Pharmacokinetics Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with protein C deficiency. Table 3: Pharmacokinetics of CEPROTIN in Subjects with Severe Congenital Protein C Deficiency C max = Maximum concentration after infusion; T max = Time at maximum concentration; AUC 0-Infinity = Area under the curve from 0 to infinity; MRT = Mean residence time; and Incremental recovery = Maximum increase in Protein C concentration following infusion divided by dose PK parameter N Median 95% CI for median Min Max C max [IU/dL] 21 110 106 to 127 40 141 T max [h] 21 0.50 0.50 to 1.05 0.17

1.33Incremental recovery [(IU/dL)/(IU/kg)] 21 1.42 1.32 to 1.59 0.50

1.76Initial half-life [h] 21 7.8 5.4 to 9.3 3.0

36.1Terminal half-life [h] 21 9.9 7.0 to 12.4 4.4

15.8Half-life by the non-compartmental approach [h] 21 9.8 7.1 to 11.6 4.9

14.7AUC 0-Infinity [IU*h/dL] 21 1500 1289 to 1897 344 2437 MRT [h] 21 14.1 10.3 to 16.7 7.1

21.3Clearance [dL/kg/h] 21 0.0533 0.0428 to 0.0792 0.0328 0.2324 Volume of distribution at steady state [dL/kg] 21 0.74 0.70 to 0.89 0.44

1.65The protein C plasma activity was measured by chromogenic and/or clotting assay. The maximum plasma concentrations (C max ) and area under the plasma concentration-time curve (AUC) appeared to increase dose-linearly between 40 and 80 IU/kg. The median incremental recovery was 1.42 [(IU/dL)/(IU/kg)] after intravenous administration of CEPROTIN.

The median half-lives, based on non-compartmental method, ranged from 4.9 to 14.7 hours, with a median of 9.8 hours. In patients with acute thrombosis, both the increase in protein C plasma levels as well as half-life may be considerably reduced. No formal study or analysis has been performed to evaluate the effect of covariates such as race and gender on the pharmacokinetics of CEPROTIN.

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of CEPROTIN may be different between very young children and adults. The systemic exposure (C max and AUC) may be considerably reduced due to a faster clearance, a larger volume of distribution, and/or a shorter half-life of protein C in very young children than in older subjects.

This fact must be considered when a dosing regimen for children is determined. Doses should be individualized based upon protein C activity levels. See DOSAGE AND ADMINISTRATION: Protein C Activity Monitoring (2.2) .

12.2Pharmacodynamics In clinical studies, the intravenous administration of CEPROTIN demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of protein C. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.

14 CLINICAL STUDIES

14.1Pivotal Study This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of CEPROTIN in subjects with severe congenital protein C deficiency for the (on-demand) treatment of acute thrombotic episodes, such as purpura fulminans (PF), warfarin-induced skin necrosis (WISN) and other thromboembolic events, and for short-term or long-term prophylaxis. Eighteen subjects (9 male and 9 female), ages ranging from 0 (newborn) to 25.7 years participated in this study.

The clinical endpoint of the study was to assess whether episodes of PF and/or other thromboembolic events were treated effectively, effectively with complications, or not treated effectively. Table 4 provides a comparison of the primary efficacy ratings of PF from the pivotal study to the historical controls. Inadequate data is available for treatment of WISN.

Table 4: Comparison of Primary Efficacy Ratings of Episodes of Purpura Fulminans in the Protein C Concentrate (Human) Pivotal Study to Historical Controls N = Number of episodes Protein C Concentrate (Human) Historical Controls Episode Type Primary Efficacy Rating N % N % Purpura Fulminans Effective 17 94.4 11

52.4Effective with Complication 1 5.6 7

33.3Not Effective 0 0.0 3

14.3Total 18 100.0 21 100.0 Of 18 episodes of PF (6 severe, 11 moderate, 1 mild) treated with CEPROTIN for the primary efficacy rating, 17 (94.4%) were rated as effective, and 1 (5.6%) was rated as effective with complications; none (0%) were rated not effective. When compared with the efficacy ratings for 21 episodes of PF (historical control group), subjects with severe congenital protein C deficiency were more effectively treated with CEPROTIN than those treated with modalities such as fresh frozen plasma or conventional anticoagulants.

Table 5 provides a summary of the secondary treatment ratings for treatment of skin lesions and other thrombotic episodes from part one of the study. Table 5: Summary of Secondary Treatment Ratings for Treatment of Skin Lesions and Other Thrombotic Episodes - Protein C Concentrate (Human) Pivotal Study Part 1 N = Number of episodes Purpura Fulminans Skin Necrosis Other Thrombotic Events Total Mild Moderate Severe Total Total Rating Category N % N % N % N % N % N % Excellent 1 5.6 7 38.9 5 27.8 13 72.2 4 80.0 17

73.9Good 0 0.0 4 22.2 0 0.0 4 22.2 1 20.0 5

21.7Fair 0 0.0 0 0.0 1 5.6 1 5.6 0 0 1

4.3Total 1 5.6 11 61.1 6 33.3 18 100.0 5 100.0 23 100.0 In a secondary efficacy rating, 13 (72.2%) of the 18 episodes of PF treated with CEPROTIN were rated as excellent, 4 (22.2%) were rated as good, and 1 (5.6%) episode of severe PF was rated as fair; all were rated as effective. Four (80%) of the 5 episodes of venous thrombosis had treatment ratings of excellent, while 1 (20%) was rated as good. CEPROTIN was also demonstrated to be effective in reducing the size and number of skin lesions.

Non-necrotic skin lesions healed over a maximum 12-day (median 4-day) period and necrotic skin lesions healed over a maximum 52-day (median 11-day) period of CEPROTIN treatment, as shown in Table 6 . Table 6: Number of Days to Complete Healing of Skin Lesions in the Protein C Concentrate (Human) Pivotal Study Lesion Type Number of Episodes (Number of Subjects) Mean Median Minimum Maximum Non-necrotic 16 (9 subjects) 4.6 4.0 1 12 Necrotic 7 (5 subjects) 21.1 11.0 5 52 Changes in the extent of venous thrombus were also measured for the 5 thromboembolic episodes.

CEPROTIN prevented an increase in the extent of thrombus during 4 (80%) of the thromboembolic episodes by Day 3 of treatment, and 1 (20%) episode by Day 5 of treatment. All seven of the short-term prophylaxis treatments with CEPROTIN were free of complications of PF or thromboembolic events, as shown in Table 7 . Table 7: Summary of Complications During Short Term Prophylaxis in the Protein C Concentrate (Human) Pivotal Study Reason for Treatment Number of Treatments Presentation of Purpu… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Protein C contained in CEPROTIN 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 has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).

13.2Animal Toxicology and/or Pharmacology Safety Pharmacology: Cardio-respiratory studies performed in dogs evaluating mean arterial pressure, cardiac output, systemic vascular resistance, heart rate, QT interval changes, pulmonary artery pressure, respiratory rate and respiratory minute volume demonstrated no adverse effects at a maximum dose of 500 IU/kg. Anaphylactoid reactions as determined by measurement of bronchospastic activity in guinea pigs demonstrated no adverse effects at the maximum dose of 300 IU/kg.

Thrombogenic potential was evaluated in rabbits using the Wessler stasis model and demonstrated no adverse effects at 200 IU/kg. Overall, safety pharmacology studies evaluating cardio-respiratory function, acute dose anaphylactoid potential and thrombogenicity demonstrated no adverse effects in a range of doses from 1.6 to 4.2 times the maximum single human dosage per kilogram body weight. Acute Dose Toxicity: Toxicity testing in rats and mice following single dosing of 2000 IU/kg or 1500 IU/kg, respectively, demonstrated no adverse clinical effects or gross pathology at 14 days post dosing.

Repeated Dose Toxicity : Studies were not conducted to evaluate repeated-dose toxicity in animals. Prior experience with CEPROTIN has suggested immunogenic response in heterologous species following repeated dosing of this human derived protein. Thus, the long-term toxicity potential of CEPROTIN following repeated dosing in animals is unknown.

Local Tolerance Testing: Investigation of route of injection tolerance demonstrated that CEPROTIN did not result in any local reactions after intravenous, intra-arterial injections of 500 IU/kg (5 mL) and paravenous injections of 100 IU/kg (1 mL) in rabbits. Citrate Toxicity : CEPROTIN contains 4.4 mg of Trisodium Citrate Dihydrate (TCD) per mL of reconstituted product. Studies in mice evaluating 1000 IU vials reconstituted with 10 mL vehicle followed by dosing at 30 mL/kg (132 mg/kg TCD) and 60 mL/kg (264 mg/kg TCD) resulted in signs of citrate toxicity (dyspnea, slowed movement, hemoperitoneum, lung and thymus hemorrhage and renal pelvis dilation).