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Kogenate FS

"The U.S. Food and Drug Administration today approved Alprolix, Coagulation Factor IX (Recombinant), Fc Fusion Protein, for use in adults and children who have Hemophilia B. Alprolix is the first Hemophilia B treatment designed to require less fre"...

Kogenate FS

CLINICAL PHARMACOLOGY

Mechanism Of Action

Kogenate FS temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.

Pharmacodynamics

The aPTT is prolonged in patients with hemophilia. Determination of activated partial thromboplastin time (aPTT) is a conventional in vitro assay for biological activity of factor VIII. Treatment with Kogenate FS normalizes the aPTT over the effective dosing period.

Pharmacokinetics

The pharmacokinetic properties of Kogenate FS were investigated in two separate studies in previously treated patients, adults and children.

Pharmacokinetic studies with Kogenate FS were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A in North America. The pharmacokinetic parameters for Kogenate FS were measured in a randomized, crossover clinical trial with the predecessor KOGENATE product with a single dose administration of 50 IU/kg. After 24 weeks, the same dose of Kogenate FS was administered to the same patients. The recovery and half-life data for Kogenate FS were unchanged after 24 weeks of continued treatment with sustained efficacy and no evidence of factor VIII inhibition. [See Table 9.]

Table 9 : Pharmacokinetic Parameters for Kogenate FS Compared to KOGENATE

Parameter Kogenate FS KOGENATE
Initial PK Mean (±SD) PK at week 24 Mean (±SD) Reference Mean (±SD)
AUC (IU • h/dL) 1588.05 ± 344.32 1487.08 ± 381.73 1879.02 ± 412.32
Cmax (IU/dL) 114.95 ± 20.19 109.42 ± 20.09 127.40 ± 33.21
Half-life (hr) 13.74 ± 1.82 14.60 ± 4.38 14.07 ± 2.62
In Vivo Recovery (IU/dL / IU/kg) 2.20 ± 0.34 2.11 ± 0.37 2.43 ± 0.60

The pharmacokinetics of Kogenate FS were investigated in pediatric PTPs (4.4-18.1 years of age, average age 12).7 The pharmacokinetic parameters in children compared to adults show differences in higher clearance, lower incremental in vivo factor VIII recovery and a shorter factor VIII half-life. This might be explained by differences in body composition such as body surface area and plasma volume. The pharmacokinetic parameters are depicted in Table 10.

Table 10 : Pharmacokinetic Parameters for Kogenate FS in Children

Parameter Mean (range)
AUC (IU • h/dL) 1320.0
Clearance (mL/h•kg) 4.1
Half-life (hr) 10.7 (7.8-15.3)
In Vivo Recovery (IU/dL / IU/kg) 1.9 (1.25-2.76)

Clinical Studies

Previously Treated Patients

A total of 73 patients with severe ( ≤ 2% FVIII) hemophilia A, ages 12–59, who had been previously treated with other recombinant or with plasma-derived AHF products, were treated up to 54-months in open label studies with Kogenate FS in Europe and North America. A total of 5,684 bleeding episodes were treated during the studies. Patients could be treated on demand or on prophylaxis. Regularly scheduled prophylaxis treatment represented 76% of all infusions (treatment regimens of 2-3 infusions per week). [See Table 11.]

Table 11 : Previously Treated Patients (PTPs) Clinical Trial Results

Clinical Parameters Results
No. of Infusions of Kogenate FS Administered 24,924
No. of IU Administered 45 million IU
No. of Bleeds Treated with Kogenate FS 5,684
Percentage of Bleeds Treated with One or Two Infusions of Kogenate FS one infusion: 79.7%, two infusions: 13.0% total: 92.7%
Mean Kogenate FS Dose per Treatment Infusion (in Europe and North America, Respectively) Approximately 32.5 and 29.6 IU/kg per treatment infusion

A total of 30 patients received Kogenate FS for 41 surgical procedures during the PTP studies. There were both minor and major surgery types, 16 and 25 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; “excellent”, “good,” “moderate,” or “none.” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases. [See Table 13.]

Previously Untreated And Minimally Treated Patients

Kogenate FS has been used in the treatment of bleeding episodes in pediatric previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe ( < 2% FVIII) hemophilia A. There were 37 PUPs and 24 MTPs (defined as having equal to or less than 4 exposure days) treated with a total of 9,419 infusions of Kogenate FS for a follow up duration up to 3.1 years. A total of 1047 bleeding episodes were treated.

Table 12 : Previously Untreated and Minimally Treated Patients (PUPs and MTPs) Clinical Trial Results

Clinical Parameters Results
No. of Infusions of Kogenate FS Administered 9,419
No. of Exposure Days to Kogenate FS (median) 115 exposure days
No. of IU Administered 7.5 million IU
No. of Bleeds Treated with Kogenate FS 1,047
Percentage of Bleeds Treated with One or Two Infusions of Kogenate FS one infusion 73.1% two infusions 15.0% total: 88.1%

A total of 27 surgical procedures were performed in 22 patients during the PUPs and MTPs study. There were both minor and major surgery types, 21 and 6 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; “excellent,” “good,” “moderate,” or “none.” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases. [See Table 13.]

Table 13 : Surgical Procedures Performed During PTPs and PUPs/MTPs Clinical Trials

Type of Surgery PTPs
(N=30)
PUPs/MTPs
(N=22)
No. of Surgical Events Outcome “Good” or “Excellent” No. of Surgical Events Outcome “Good” or “Excellent”
Minor Surgery (i.e., tooth extractions, catheter implantations, liver biopsies) 16 100% 21 100%
Major Surgery (i.e., joint replacements, craniotomies, gastrointestinal resection) 25 100% 6 100%
Total 41 27

Pediatric Prophylaxis And Joint Damage Risk Reduction

A total of 65 boys less than 30 months of age with severe hemophilia A (FVIII level ≤ 2 IU/dL) and with ≤ 2 bleeds into each index joint and normal baseline joint imaging, were observed for up to 5.5 years in a multicenter, open-label, prospective, randomized, controlled clinical study.5 Patients received either 25 IU/kg every other day (primary prophylaxis; n=32) or at least 3 doses totaling a minimum of 80 IU/kg at the time of a bleeding episode (enhanced episodic; n=33). Joint damage was evaluated by magnetic resonance imaging (MRI) or radiography, as well as the frequency of bleeding episodes. Joint damage detected by MRI or radiography in the ankles, knees, and elbows (i.e., index joints) was statistically significantly lower (p=0.002) for subjects receiving prophylactic therapy (7%) than for subjects receiving episodic therapy (42%). This corresponds to a 6.29-fold relative risk of joint damage for subjects treated with enhanced episodic therapy compared to prophylaxis. The mean rate of index joint hemorrhages for subjects on episodic therapy was 4.89 bleeds per year, versus 0.63 bleeds per year observed in the prophylaxis arm. Three of 33 (9.1%) subjects in the episodic arm experienced recurrent life threatening bleeds (intracranial, gastrointestinal) compared to no subjects in the prophylaxis arm. On a per joint basis, joints in the regular prophylaxis arm were 8-fold more likely to remain damage-free than those in the episodic arm. Joint damage was most frequently observed in ankle joints and was detected at higher rates by MRI than by radiography. Ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study (left ankle, mean 2.7 hemorrhages; right ankle, mean 2.6 hemorrhages).

As shown in Table 14 below, the incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group when assessed by MRI, or either MRI or radiography, using predefined criteria (described below) for establishing joint damage. However, there was no statistically significant difference between the two groups when joint damage was assessed by radiography alone.

To evaluate joint damage, MRIs were scored using a scale developed by Nuss et al.,22 and X-rays were scored using the method of Pettersson et al.23 Both scales have been validated in various clinical trials and are routinely used for joint damage evaluation in hemophiliacs. Joint damage was defined as bone and/or cartilage damage including subchondral cysts, erosions and cartilage loss with narrowing of joint space. This corresponded to a total MRI score of ≥ 7 or an X-ray score of ≥ 1 in any of the following categories: subchondral cysts, erosions of joint surfaces or narrowing of joint spaces. Images were read separately by two independent radiologists centrally. Any discrepant reading was read by an independent third radiologist who was not aware of the initial reading results. The concordant reading of two out of three readers was used for analysis purposes.

Table 14 : Subjects with Joint Damage (Subjects with Available Baseline and Endpoint Data)

Endpoint Assessment Prophylaxis Episodic Therapy p-value
Incidence (%) Relative Risk (95% CI) Incidence (%) Relative Risk (95% CI)
MRI 2/27 (7%) 0.17 (0.04, 0.67) 13/29 (45%) 6.05 (1.50, 24.38) 0.002
Radiography 1/28 (4%) 0.19 (0.02, 1.55) 5/27 (19%) 5.19 (0.65, 41.54) 0.101
MRI or Radiography 2/30 (7%) 0.16 (0.04, 0.65) 13/31 (42%) 6.29 (1.55, 25.55) 0.002

Relative Risk is the risk of damage to one or more index joints on the given therapy as compared to the other therapy.

P-value is from the 2-sided Fisher Exact Test comparing the incidence of joint damage between treatment groups.

As shown in Table 15 below, the assessment of endpoints in all randomized subjects assuming that those without complete baseline and endpoint data are treatment failures (intention-to-treat analysis). The incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group, with similar pvalues, when assessed by MRI, or either MRI or radiography.

Table 15 : Subjects with Joint Damage (All Randomized Subjects Assuming Subjects without Complete Baseline and Endpoint Data as Treatment Failures)

Endpoint Assessment Prophylaxis (n=32) Episodic Therapy (n=33) p-value
Incidence (%) Relative Risk (95% CI) Incidence (%) Relative Risk (95% CI)
MRI 7 (22%) 0.42 (0.20, 0.88) 17 (52%) 2.35 (1.13, 4.90) 0.020
Radiography 5 (16%) 0.47 (0.18, 1.20) 11 (33%) 2.13 (0.83, 5.45) 0.150
MRI or Radiography 8 (25%) 0.43 (0.22, 0.85) 19 (58%) 2.30 (1.18, 4.49) 0.012

Relative Risk is the risk of damage to one or more index joints on the given therapy as compared to the other therapy.

P-value is from the 2-sided Fisher Exact Test comparing the incidence of joint damage between treatment groups.

REFERENCES

22. Nuss R, Kilcoyne RF, Geraghty S, et al: MRI findings in haemophilic joints treated with radiosynoviorthesis with development of an MRI scale of joint damage. Haemophilia 6:162-169, 2000.

23. Pettersson H, Ahlberg A, Nilsson IM: A radiologic classification of hemophilia arthropathy. Clin Orthop Relat Res 149:153-159, 1980.

Last reviewed on RxList: 4/4/2014
This monograph has been modified to include the generic and brand name in many instances.

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