Written in Blood
because of disease progression ( n = 42 ), adverse events ( AEs ; n = 5 ), withdrawal of consent ( n = 2 ), or loss to followup ( n = 1 ). ( The remaining reasons for discontinuation were not specified .) Eight patients died because of disease progression ( n = 6 ), lung disorder ( n = 1 ), or brain hemorrhage following trauma ( n = 1 ). At the time of reporting , 11 patients were still on study ( including 8 with t [ 11 ; 14 ]).
All patients experienced at least one AE , the most common of which “ were mild to moderate gastrointestinal toxicities [ including nausea , diarrhea , and vomiting ] and grade 3 / 4 hematologic toxicities , which were manageable and did not result in study drug discontinuation ,” the authors wrote . The most common grade 3 / 4 AEs were thrombocytopenia ( 26 %), neutropenia ( 21 %), anemia ( 14 %), and leukopenia ( 14 %). Serious AEs ( occurring in ≥2 percent of patients ) included pneumonia ( 8 %), sepsis ( 5 %), cough ( 3 %), hypotension ( 3 %), pain ( 3 %), and pyrexia ( 3 %).
Among all patients , the overall response rate ( ORR ) was 21 percent ( n = 14 ), including a very good partial response or better ( ≥VGPR ) in 10 patients ( 15 %). Nearly all of these responses ( n = 12 ) occurred in the 30 patients with t ( 11 ; 14 ), the researchers reported , for an ORR of 40 percent in this cohort ( including 1 stringent response , 3 complete responses , and 4 VGPRs ).
The median duration of response ( DOR ) was similar in the overall patient population and for those with t ( 11 ; 14 ): 9.7 months ( 95 % CI 7.0 – not reached ) and 9.7 months ( 95 % CI 6.3 – not reached ; p value not provided ), respectively . However , the time to progression ( TTP ) was longer among those with t ( 11 ; 14 ): 6.6 months ( 95 % CI 3.9-10.2 ) versus 2.6 months ( 95 % CI 1.9-4.7 ; p value not
KOGENATE FS ( Antihemophilic Factor [ Recombinant ], Formulated with Sucrose ) For Intravenous Use , Lyophilized Powder for Reconstitution with Vial Adapter Initial U . S . Approval : 1993
BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Kogenate ® FS is a recombinant antihemophilic factor indicated for :
• On-demand treatment and control of bleeding episodes in adults and children with hemophilia A .
• Perioperative management of bleeding in adults and children with hemophilia A .
• Routine prophylaxis to reduce the frequency of bleeding episodes in children with hemophilia A and to reduce the risk of joint damage in children without pre-existing joint damage .
• Routine prophylaxis to reduce the frequency of bleeding episodes in adults with hemophilia A .
Kogenate FS is not indicated for the treatment of von Willebrand disease .
4 CONTRAINDICATIONS Kogenate FS is contraindicated in patients who have life-threatening hypersensitivity reactions , including anaphylaxis to mouse or hamster protein or other constituents of the product ( sucrose , glycine , histidine , sodium , calcium chloride , polysorbate 80 , imidazole , tri-n-butyl phosphate , and copper ).
5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Hypersensitivity reactions , including anaphylaxis have been reported with Kogenate FS . Reported symptoms included facial swelling , flushing , hives , decrease in blood pressure , nausea , rash , restlessness , shortness of breath , tachycardia , tightness of the chest , tingling , urticaria , and vomiting .
Kogenate FS contains trace amounts of mouse immunoglobulin G ( MuIgG ) and hamster ( BHK ) proteins [ see Description ( 11 )]. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins .
Discontinue Kogenate FS if symptoms occur and seek immediate emergency treatment .
5.2 Neutralizing Antibodies
Neutralizing antibodies ( inhibitors ) have been reported following administration of Kogenate FS , predominantly in previously untreated patients ( PUPs ) [ see Adverse Reactions ( 6 )]. Carefully monitor patients for the development of factor VIII inhibitors , using appropriate clinical observations and laboratory tests . 6 If expected plasma factor VIII activity levels are not attained , or if bleeding is not controlled with an expected dose , perform an assay that measures factor VIII inhibitor concentration [ see Warnings and Precautions ( 5.4 )].
5.3 Cardiovascular Risk Factors Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with factor VIII .
5.4 Monitoring Laboratory Tests
• Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained , when clinically indicated [ see Dosage and Administration ( 2 )].
• Monitor for development of factor VIII inhibitors . Perform assay to determine if factor VIII inhibitor is present . If expected factor VIII activity plasma levels are not attained or if bleeding is not controlled with the expected dose of Kogenate FS , use Bethesda Units ( BU ) to titer inhibitors .
If the inhibitor is less than 10 BU per mL , the administration of additional Kogenate FS concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response . If inhibitor titers are above 10 BU per mL , adequate hemostasis may not be achieved . The inhibitor titer may rise following Kogenate FS infusion as a result of an anamnestic response to factor VIII . The on-demand treatment and control of bleeding in such patients requires the use of alternative therapeutic approaches and agents .
6 ADVERSE REACTIONS Serious adverse reactions seen with Kogenate FS are systemic hypersensitivity reactions , including bronchospastic reactions and / or hypotension and anaphylaxis , and the development of high-titer inhibitors necessitating alternative treatments to factor VIII .
The most common adverse reactions ( ≥ 4 %) observed in clinical trials were 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 ) associated infections .
6.1 Clinical Trials Experience 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 . |
Previously Treated Patients ( PTPs ) |
During the open-label clinical studies conducted in 73 PTPs , there were 24 |
adverse reactions reported in the course of 24,936 infusions . |
Adverse reactions reported by ≥ 4 % of the patients are listed in Table 3 below . |
Table 3 Adverse Reactions ( AR ) in Previously Treated Patients with |
Frequency of ≥ 4 % ( Age Range 12 – 59 years ) |
MedDRA Primary SOC |
Preferred Term |
N = 73 AR (%) |
Skin and Subcutaneous Tissue Disorders |
Rash , pruritus |
6 ( 8.2 %) |
General Disorders and |
Infusion site |
3 ( 4.1 %) |
Administration Site Conditions |
reactions |
|
SOC = System Organ Class |
|
|
Previously Untreated Patients ( PUPs ) and Minimally Treated Patients ( MTPs ) |
In clinical studies with pediatric PUPs and MTPs , there were 29 adverse reactions |
reported in the course of 9,389 infusions . |
Adverse reactions reported by ≥ 4 % of the patients are listed in Table 4 below . |
Table 4 Adverse Reactions ( AR ) in Previously Untreated Patients and |
Minimally Treated Patients with Frequency of ≥ 4 % ( Age Range 2 – 27 months ) |
MedDRA Primary SOC |
Preferred Term |
N = 61 AR (%) |
Skin and Subcutaneous Tissue Disorders |
Rash , pruritus , urticaria |
10 ( 16 %) |
Blood and Lymphatic System Disorders
Factor VIII inhibition ( neutralizing antibodies ) Infusion site reactions
9 ( 15 %) †
General Disorders and
4 ( 7 %)
Administration Site Conditions SOC = System Organ Class
† Denominator for de novo inhibitors is N = 60 , since one patient had a preexisting inhibitor .
Minimally Treated Patients ( MTPs ) in the Joint Outcome Study 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 .
Table 5 Adverse Reactions in Minimally Treated Patients in the Joint Outcome Study ( Age Range 0 – 6 years )
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MedDRA Primary SOC |
Preferred Term |
Prophylaxis Arm N = 32 AR (%) |
Surgical and Medical Procedures
Infections and Infestations
General Disorders and Administration Site Conditions
Enhanced Episodic Arm N = 33 AR (%)
Central venous catheterization , Catheter removal |
19 ( 59 %) |
18 ( 55 %) ‡ |
Central line |
6 ( 19 %) |
6 ( 18 %) |
infection |
|
|
Pyrexia |
1 ( 3 %) |
4 ( 12 %) |
SOC = System Organ Class ‡ Three patients from the enhanced episodic arm had catheter removal .
Immunogenicity 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 1 (> 5 BU ) 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 , 5 de novo inhibitor development was observed in 8 of 64 patients with negative baseline values ( 12.5 %), 2 patients developed high titer 1 (> 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 ).
Inhibitor data in PUPs have been collected in several postmarketing registries [ see Postmarketing Experience ( 6.2 )].
The detection of antibody formation is dependent on the sensitivity and specificity of the assay . Additionally , the observed incidence of antibody