KOSELUGO (Page 4 of 9)
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 the clinical trials of another drug and may not reflect the rates observed in practice.
The data in the WARNINGS AND PRECAUTIONS reflects exposure to KOSELUGO in 74 pediatric patients who received a dosage ranging from 20 mg/m2 to 30 mg/m2 orally twice daily in SPRINT. Among these patients, the duration of KOSELUGO exposure, including dose interruptions, was 12 months or longer (91%), more than 2 years (74%), or more than 4 years (23%). The WARNINGS AND PRECAUTIONS also includes additional data from adult and pediatric patients who received KOSELUGO administered at various doses across a range of tumors in other clinical trials.
Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN)
The safety of KOSELUGO was evaluated in SPRINT Phase II Stratum 1 [see Clinical Studies (14)]. Eligible patients were 2-18 years of age with NF1 who had inoperable PN that was causing significant morbidity. Patients were excluded for abnormal LVEF, uncontrolled hypertension (blood pressure > the 95th percentile for age, height, and sex), any current or past history of RVO or RPED, intraocular pressure > 21 mmHg (or upper limit of normal adjusted by age), uncontrolled glaucoma, and inability to swallow whole capsules. Patients received KOSELUGO 25 mg/m2 orally twice daily (n=50). Among these patients, 88% were exposed for 12 months or longer and 66% were exposed for greater than 2 years.
Serious adverse reactions occurred in 24% of patients who received KOSELUGO. Serious adverse reactions that occurred in 2 or more patients were anemia, hypoxia and diarrhea.
Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received KOSELUGO. Adverse reactions resulting in permanent discontinuation of KOSELUGO included increased blood creatinine, increased weight, diarrhea, paronychia, malignant peripheral nerve sheath tumor, acute kidney injury, and skin ulcer.
Dosage interruptions and dose reductions due to adverse reactions occurred in 80% and 24% of patients who received KOSELUGO, respectively. Adverse reactions requiring a dosage interruption or reduction in ≥ 5% of patients were vomiting, paronychia, diarrhea, nausea, abdominal pain, rash, skin infection, influenza-like illness, pyrexia and weight gain.
The most common adverse reactions (≥ 40%) were vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.
Table 6 presents the adverse reactions in SPRINT Phase II Stratum 1.
| ||
Adverse Reaction | KOSELUGO N=50 | |
All Grades (%) | Grade ≥ 3 (%) * | |
Gastrointestinal | ||
Vomiting | 82 | 6 |
Abdominal pain * | 76 | 0 |
Diarrhea | 70 | 16 |
Nausea | 66 | 2 |
Stomatitis † | 50 | 0 |
Constipation | 34 | 0 |
Skin and Subcutaneous Tissue | ||
Rash (all)‡ | 80 | 6 |
Dry skin | 60 | 0 |
Rash acneiform § | 50 | 4 |
Paronychia ¶ | 48 | 6 |
Pruritus | 46 | 0 |
Dermatitis # | 36 | 4 |
Hair changes Þ | 32 | 0 |
Musculoskeletal and Connective Tissue | ||
Musculoskeletal pain ß | 58 | 0 |
General | ||
Fatigue à | 56 | 0 |
Pyrexia | 56 | 8 |
Edema è | 20 | 0 |
Nervous System | ||
Headache | 48 | 2 |
Respiratory, Thoracic and Mediastinal | ||
Epistaxis | 28 | 0 |
Renal and Urinary System | ||
Hematuria | 22 | 2 |
Proteinuria | 22 | 0 |
Metabolism and Nutrition | ||
Decreased appetite | 22 | 0 |
Cardiac System | ||
Decreased ejection fraction | 22 | 0 |
Sinus tachycardia | 20 | 0 |
Infections | ||
Skin infection ð | 20 | 2 |
* All events were Grade 3. |
Clinically relevant adverse reactions that occurred < 20% of patients include:
- •
- Eye: visual impairment
- •
- Gastrointestinal Disorders: dry mouth
- •
- General Disorders: facial edema, including periorbital edema and face edema
- •
- Metabolism and Nutrition: increased weight
- •
- Renal and Urinary System: acute kidney injury
- •
- Respiratory, Thoracic & Mediastinal: dyspnea, including exertional dyspnea and dyspnea at rest
- •
- Vascular: hypertension
Table 7 presents the laboratory abnormalities in SPRINT Phase II Stratum 1.
Laboratory Abnormality | KOSELUGO | |
All Grades (%) * | Grade ≥ 3 (%) | |
Chemistry | ||
Increased creatine phosphokinase (CPK) | 79 | 7† |
Decreased albumin | 51 | 0 |
Increased aspartate aminotransferase (AST) | 41 | 2 |
Increased alanine aminotransferase (ALT) | 35 | 4 |
Increased lipase | 32 | 5 |
Increased potassium | 27 | 4 |
Decreased potassium | 18 | 2§ |
Increased alkaline phosphatase | 18 | 0 |
Increased amylase | 18 | 0 |
Increased sodium | 18 | 0 |
Decreased sodium | 16 | 0 |
Hematology | ||
Decreased hemoglobin | 41 | 4 |
Decreased neutrophils | 33 | 4 |
Decreased lymphocytes | 20 | 2 |
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