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.
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 clinical studies conducted in 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 (PTPs) with Frequency of ≥ 4%
|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|
|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 (PUPs) and Minimally Treated Patients (MTPs) with Frequency of ≥ 4% (Age Range 2-27 months)
|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)1||N/A|
|General Disorders and Administration Site Conditions||Infusion site reactions||4 (6.6)||0.04|
|SOC = System Organ Class
1 Denominator for de novo inhibitors is N=60, since one patient had a pre-existing 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. 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)
|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)||181(55)|
|Infections and Infestations||Central line infection||6 (19)||6 (18)|
|General Disorders and Administration Site Conditions||Pyrexia||1 (3)||4 (12)|
|SOC = System Organ Class
1 Three patients from the enhanced episodic arm had catheter removal.
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 titer1 ( > 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,5 de novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer1 ( > 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
|MedDRA Primary SOC||Preferred Term|
|Immune System Disorders||Anaphylactic reaction, other hypersensitivity reactions|
|Nervous System Disorders||Dysgeusia|
|SOC = System Organ Class|