ave been achieved and maintained [see Dosage and Administration (2.1)].
•Monitor for development of Factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected Factor VIII plasma levels are not attained or if bleeding is not controlled with the expected dose of KOVALTRY. Use Bethesda Units (BU) to report inhibitor titers.
6 ADVERSE REACTIONS
The most frequently reported adverse reactions in clinical trials (≥3%) were headache, pyrexia, and pruritus (see TABLE 3).
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.
The safety profile of KOVALTRY was eva luated in 193 previously treated patients (PTPs) (inclusive of 51 pediatric patients <12 years of age) with at least three months of exposure to KOVALTRY. The safety analysis was done using a pooled database from three multi-center, prospective, open-label clinical studies. The median time on study for patients ≥12 years of age was 372 days with a median of 159 exposure days (EDs). The median time on study for patients <12 years of age was 182 days with a median of 73 EDs. Subjects who received KOVALTRY for perioperative management (n=5) with treatment period of 2 to 3 weeks and those who received single doses of KOVALTRY for PK studies (n=6) were excluded from safety analysis. TABLE 3 lists the adverse reactions reported during clinical studies. The frequency, type, and severity of adverse reactions in children are similar to those in adults.
Table 3: Adverse Reactions in PTPs (N=193)
MedDRA Primary System Organ Class
Preferred term Frequency
N (%)
* Includes injection site extravasation and hematoma, infusion site pain, pruritus, and swelling † Includes rash, rash erythematous, and rash pruritic
Blood and the Lymphatic System Disorders
Lymphadenopathy
2 (1.0%)
Cardiac Disorders
Palpitation
Sinus tachycardia
2 (1.0%)
2 (1.0%)
Gastrointestinal Disorders
Abdominal pain
Abdominal discomfort
Dyspepsia
4 (2.1%)
3 (1.6%)
4 (2.1%)
General Disorders and Administration Site Conditions
Pyrexia
Chest discomfort
Injection site reactions*
8 (4.1%)
2 (1.0%)
5 (2.6%)
Immune System Disorders
Hypersensitivity
1 (0.5%)
Nervous System Disorders
Dizziness
Dysgeusia
Headache
2 (1.0%)
1 (0.5%)
14 (7.3%)
Psychiatric Disorders
Insomnia
5 (2.6%)
Skin and Subcutaneous Tissue Disorders
Dermatitis allergic
Pruritus
Rash†
Urticaria
2 (1.0%)
6 (3.1%)
5 (2.6%)
1 (0.5%)
Vascular disorders
Flushing
1 (0.5%)
Immunogenicity
All clinical trial subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII by the modified Bethesda assay using blood samples obtained prior to the first infusion of KOVALTRY, at defined intervals during the studies and at the completion visit.
Clinical trials (Phases 1 through 3) with KOVALTRY eva luated a total of 204 pediatric and adult patients diagnosed with severe hemophilia A (Factor VIII <1%) with previous exposure to Factor VIII concentrates ≥50 EDs, and no history of inhibitors.
In
