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Kogenate Fs

2013-11-22 13:07:06 来源: 作者: 【大中小】浏览:513次评论:0条

These highlights do not include all the information needed to use Kogenate FS safely and effectively. See full prescribing information for Kogenate FS. Kogenate FS (Antihemophilic Factor [Recombinant] Formulated with Sucrose) For Intravenous Use, Ly

Kogenate FS is an antihemophilic factor that is indicated for the control and prevention of bleeding episodes in adults and children (0-16 years) with hemophilia A.

Kogenate FS is indicated for surgical prophylaxis in adults and children with hemophilia A.

Kogenate FS is indicated for routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children with no pre-existing joint damage.

Kogenate FS is not indicated for the treatment of von Willebrand’s disease.

For Intravenous Use After Reconstitution

The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % normal) can be estimated using the following formulas:

Dosage (units) = body weight (kg) x desired factor VIII rise (IU/dL or % or normal) x 0.5 (IU/kg per IU/dL)

IU/dL (or % normal)=Total Dose (IU)/body weight (kg) x 2 [IU/dL]/[IU/kg]

Examples (assuming patient’s baseline factor VIII level is <1% of normal):

Doses administered should be titrated to the patient’s clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to Kogenate FS. Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests including serial factor VIII activity assays be performed. [See Warnings and Precautions (5.4) and Clinical Pharmacology (12.3).]

The careful control of treatment dose is especially important in cases of life-threatening bleeding episodes or major surgery.

The following table can be used to guide dosing in bleeding episodes.

Table 1 Control and Prevention of Bleeding Episodes for Children and Adults
Type of Bleeding Episode	Factor VIII Level Required (IU/dL or % of normal)	Dosage and Frequency Necessary to Maintain the Therapeutic Plasma Level
Minor Early hemarthrosis, minor muscle or oral bleeds.	20–40	10–20 IU per kgRepeat dose if there is evidence of further bleeding.
Moderate Bleeding into muscles, bleeding into the oral cavity, definite hemarthroses, and known trauma.	30–60	15–30 IU per kgRepeat dose every 12–24 hours until bleeding is resolved.
Major Gastrointestinal bleeding. Intracranial, intra-abdominal or intrathoracic bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath. Fractures.Head trauma.	80–100	Initial dose 40–50 IU per kgRepeat dose 20–25 IU per kg every 8–12 hours until bleeding is resolved.

The careful control of treatment dose is especially important in cases of major surgery or life-threatening bleeding episodes.

The following table can be used to guide dosing in surgery:

Table 2 Peri-operative Management for Adults and Children
Type of Surgery	Factor VIII Level Required (IU/dL or % of normal)	Dosage and Frequency Necessary to Maintain the Therapeutic Plasma Level
Minor Including tooth extraction	30–60	15–30 IU per kgRepeat dose every 12–24 hours until bleeding is resolved.
Major Examples include tonsillectomy, inguinal herniotomy, synovectomy, total knee replacement, craniotomy, osteosynthesis, trauma.	100	Pre-operative dose 50 IU per kgVerify 100% activity prior to surgery. Repeat as necessary after 6 to 12 hours initially, and for 10 to 14 days until healing is complete.

The recommended dose for routine prophylaxis is 25 IU/kg of body weight every other day.

Kogenate FS is administered by intravenous (IV) injection after reconstitution. Patients should follow the specific reconstitution and administration procedures provided by their physicians.

For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling. [See FDA-Approved Patient Labeling (17).]

Reconstitution, product administration, and handling of the administration set and needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Kogenate FS product, in an appropriate container.

The procedures below are provided as general guidelines for the reconstitution and administration of Kogenate FS with BIO-SET, a needleless self-contained reconstitution system. Always work on a clean surface and wash hands before performing the following procedures.

Vacuum Transfer and Reconstitution

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For Intravenous Use Only After Reconstitution

Kogenate FS is available as a lyophilized powder in single use glass vials containing 250, 500, 1000, 2000, and 3000 International Units (IU).

Each vial of Kogenate FS is labeled with the recombinant antihemophilic factor activity expressed in IU per vial. This potency assignment employs a factor VIII concentrate standard that is referenced to a WHO International Standard for factor VIII concentrates, and is eva luated by appropriate methodology to ensure accuracy of the results.

Kogenate FS is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including mouse or hamster proteins.

The clinical response to Kogenate FS may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined and a sufficient dose of Kogenate FS should be administered to achieve a satisfactory clinical response. If the patient’s plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and appropriate testing performed. [See Warnings and Precautions ( 5.4 ).]

Allergic-type hypersensitivity reactions including anaphylaxis have been reported with Kogenate FS and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Discontinue Kogenate FS if symptoms occur and seek immediate emergency treatment.

Kogenate FS contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster (BHK) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Patients treated with antihemophilic factor (AHF) products should be carefully monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of Kogenate FS predominantly in previously untreated patients. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor VIII inhibitor concentration should be performed.[See Warnings and Precautions ( 5.4 ).]

Adequate hemostasis may not be achieved if Inhibitor titers are above 10 BU per mL. The inhibitor titer may rise following Kogenate FS infusion as a result of an anamnestic response to factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.

The most serious adverse reactions are systemic hypersensitivity reactions including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to AHF.

The most common adverse reactions observed in clinical trials (frequency ≥ 4% of patients) are inhibitor formation in previously untreated patients (PUPs) and minimally treated patients (MTPs), skin-related hypersensitivity reactions (e.g., rash, pruritus), infusion site reactions (e.g., inflammation, pain), and central venous access device (CVAD) line-associated infections in patients requiring a CVAD for intravenous administration.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

During the clinical studies conducted in PTPs, 451 adverse events (irrespective of the relationship to the study drug) were reported in the course of 24,936 infusions (1.8%). Twenty-four of the 451 adverse events were assessed as related to Kogenate FS (0.1%).

Adverse reactions reported by ≥ 4% of the patients are listed in Table 3 below.

Table 3 Adverse Reactions (AR) in Previously Treated Patients (PTPs) with Frequency of ≥ 4%
SOC = System Organ Class
MedDRA Primary SOC	Preferred Term	Total No. of Patients: 73 No. of Patients with AR (%)	Total No. of Infusions: 24,936 AR per Infusion (%)
Skin and Subcutaneous Tissue Disorders	Rash, pruritus	6 (8.2%)	0.02
General Disorders and Administration Site Conditions	Infusion site reactions	3 (4.1%)	0.01

In clinical studies with pediatric PUPs and MTPs, 726 adverse events were reported in the course of 9,389 infusions (7.7%). Twenty-nine of the 726 adverse events were assessed as related to Kogenate FS (0.3%).

Adverse reactions reported by ≥ 4% of the patients are listed in Table 4 below.

Table 4 Adverse Reactions (AR) in Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) with Frequency of ≥ 4% (Age Range 2-27 months)
SOC = System Organ Class
MedDRA Primary SOC	Preferred Term	Total No. of patients: 61 No. of Patients with AR (%)	Total No. of Infusions: 9,389 AR per Infusion (%)
Skin and Subcutaneous Tissue Disorders	Rash, pruritus, urticaria	10 (16.4)	0.01
Blood and Lymphatic System Disorders	Factor VIII inhibition	9 (15)*Denominator for de-novo inhibitors is N=60, since one patient had a pre-existing inhibitor.	N/A
General Disorders and Administration Site Conditions	Infusion site reactions	4 (6.6)	0.04

In the Joint Outcome Study with pediatric MTPs treated with routine prophylaxis or episodic enhanced treatment for 5.5 years, 46 of the 65 randomized patients experienced adverse events over the study duration. Adverse events were not assessed for their relationship with Kogenate FS.

Table 5 Adverse Events (AE) in MTPs in the Joint Outcome Study (Age Range 0-6 years)
SOC = System Organ Class
MedDRA Primary SOC	Preferred Term	Total No. of Prophylaxis Arm Patients: 32 No. of Patients with AE (%)	Total No. of Enhanced Episodic Arm Patients: 33 No. of Patients with AE (%)
Surgical and Medical Procedures	Central venous catheterization, Catheter removal	19 (59)	18Three patients from the enhanced episodic arm had catheter removal. (55)
Infections and Infestations	Central line infection	6 (19)	6 (18)
General Disorders and Administration Site Conditions	Pyrexia	1 (3)	4 (12)

In clinical studies with 73 PTPs (defined as having more than 100 exposure days), one patient had a pre-existing inhibitor. In the other 72 patients, followed over 4 years, no de-novo inhibitors were observed.

In clinical studies with pediatric PUPs and MTPs, inhibitor development was observed in 9 out of 60 patients (15%), 6 were high titer (>5BU) and 3 were low-titer inhibitors. Inhibitors were detected at a median number of 7 exposure days (range 2 to 16 exposure days).

In the Joint Outcome Study with Kogenate FS, de-novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer (>5 BU) and were withdrawn from the study. Six patients developed low-titer inhibitors. Inhibitors were detected at a median number of 44 exposure days (range 5 to 151 exposure days).

The following adverse reactions have been identified during post approval use of Kogenate FS. 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.

Among patients treated with Kogenate FS, cases of serious allergic/hypersensitivity reactions (which may include facial swelling, flushing, hives, blood pressure decrease, nausea, rash, restlessness, shortness of breath, tachycardia, tightness of the chest, tingling, urticaria, vomiting) have been reported, particularly in very young patients or patients who have previously reacted to other factor VIII concentrates.

The following table represents the post-marketing adverse reactions as MedDRA Preferred Terms.

Table 6 Post-Marketing Experience
SOC = System Organ Class
MedDRA Primary SOC	Preferred Term
Blood and Lymphatic System Disorders	FVIII inhibition
Skin and Subcutaneous Tissue Disorders	Pruritus, urticaria, rash
General Disorders and Administration Site Conditions	Infusion site reaction
General Disorders and Administration Site Conditions	Pyrexia
Immune System Disorders	Anaphylactic reaction, other hypersensitivity reactions

None known.

Animal reproduction studies have not been conducted with Kogenate FS. It is also not known whether Kogenate FS can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. Kogenate FS should be used during pregnancy only if clinically needed.

There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Kogenate FS should be used only if clinically needed.

It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Kogenate FS is administered to nursing mothers. Kogenate FS should be given to nursing mothers only if clinically needed.

Safety and efficacy studies have been performed in previously untreated and minimally treated pediatric patients. Children in comparison to adults present higher factor VIII clearance values and thus lower recovery of factor VIII. This may be explained by differences in body composition and should be taken into account when dosing or following factor VIII levels in such a population. [See Clinical Pharmacology ( 12.3 ).] Routine prophylactic treatment in children ages 0-2.5 years with no pre-existing joint damage has been shown to reduce spontaneous joint bleeding and the risk of joint damage. This data can be extrapolated to ages >2.5-16 years for children who have no existing joint damage. [See Clinical Studies ( 14 ).]

Clinical studies with Kogenate FS did not include patients aged 65 and over. Dose selection for an elderly patient should be individualized.

Kogenate FS Antihemophilic Factor (Recombinant) is a coagulation factor VIII produced by recombinant DNA technology. It is produced by Baby Hamster Kidney (BHK) cells into which the human factor VIII gene has been introduced. The cell culture medium contains Human Plasma Protein Solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources. Kogenate FS is a purified glycoprotein consisting of multiple peptides including an 80 kD and various extensions of the 90 kD subunit. It has the same biological activity as factor VIII derived from human plasma. No human or animal proteins, such as albumin, are added during the purification and formulation processes of Kogenate FS.

The purification process includes a solvent/detergent virus inactivation step in addition to the use of the purification methods of ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, along with other chromatographic steps designed to purify recombinant factor VIII and remove contaminating substances.

Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents. Several of the individual production and raw material preparation steps in the Kogenate FS manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps include the Fraction II+III separation step for HPPS (6.0 log10) and an anion exchange chromatography step (3.6 log10).

Kogenate FS is formulated with the following as stabilizers [see Table 7] in the final container and is then lyophilized. The final product is a sterile, nonpyrogenic, preservative-free, powder preparation for intravenous (IV) injection. Intravenous administration of sucrose contained in Kogenate FS will not affect blood glucose levels.

The following inactive ingredients/excipients are also contained in the final product:

Each vial of Kogenate FS contains the labeled amount of recombinant factor VIII in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation factor VIII, human, is approximately equal to the level of factor VIII activity found in 1 mL of fresh pooled human plasma.

Table 7 Stabilizers Contained in Kogenate FS Final Container
Stabilizer	250 IU, 500 IU, 1000 IU	2000 IU , 3000 IU
Sucrose	0.9–1.3%	0.9–1.2%
Glycine	21–25 mg/mL	20–24 mg/mL
Histidine	18–23 mmol/L	17–22 mmol/L

Table 8 Inactive Ingredients/Excipients
Inactive Ingredient/Excipient	250 IU, 500 IU, 1000 IU	2000 IU , 3000 IU
Sodium	27–36 mEq/L	26–34 mEq/L
Calcium	2.0–3.0 mmol/L	1.9–2.9 mmol/L
Chloride	32–40 mEq/L	31–38 mEq/L
Polysorbate 80	64–96 µg/mL	64–96 µg/mL
Sucrose	28 mg/vial	52 mg/vial
Imidazole, tri-n-butyl phosphate, and copper	Trace amounts	Trace amounts

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

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.

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.]

The pharmacokinetics of Kogenate FS were investigated in pediatric PTPs (4.4-18.1 years of age, average age 12). 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 9 Pharmacokinetic Parameters for Kogenate FS Compared to KOGENATE
Parameter	Kogenate FS		KOGENATE
Parameter	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

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)

Preclinical studies eva luating Kogenate FS in hemophilia A with mice, rats, rabbits, and dogs demonstrated safe and effective restoration of hemostasis. Doses several fold higher than the recommended clinical dose (related to body weight) did not demonstrate any acute or subacute toxic effect for Kogenate FS in laboratory animals.

No studies have been conducted with Kogenate FS to assess its mutagenic or carcinogenic potential and impairment of fertility. Kogenate FS has been shown to be comparable to the predecessor product with respect to its biochemical and physiochemical properties, as well as its non-clinical in vivo pharmacology and toxicology. By inference, the predecessor product and Kogenate FS would be expected to have equivalent mutagenic and carcinogenic potential.

The predecessor product did not demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo eva luation with the predecessor product in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that the predecessor product did not possess a mutagenic potential. Long-term investigations of carcinogenic potential in animals have not been performed due to the immune response to heterologous proteins in all non-human mammalian species.

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.]

A total of 31 patients received Kogenate FS for 43 surgical procedures during the PTP studies. There were both minor and major surgery types, 27 and 16 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 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

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.

A total of 29 surgical procedures were performed in 23 patients during the PUPs and MTPs study. There were both minor and major surgery types, 23 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 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%

Table 13 Surgical Procedures Performed During PTPs and PUPs/MTPs Clinical Trials
Type of Surgery	PTPs (N=31)		PUPs/MTPs (N=23)
Type of Surgery	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)	24	100%	21	100%
Major Surgery (i.e., joint replacements, craniotomies, gastrointestinal resection)	16	100%	6	100%
Total	43		29