The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ] The most common (≥15%) adverse reactions include fatigue, headache, COVID-19, musculoskeletal pain, diarrhea, nausea, and seizure. Grade 3 or 4 (≥2%) laboratory abnormalities were ALT increased, AST increased, GGT increased, and neutrophils decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Servier Pharmaceuticals at 1-800-807-6124 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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. Adverse reactions described in the WARNINGS AND PRECAUTIONS reflect exposure to VORANIGO 40 mg orally once daily until disease progression or unacceptable toxicity in the 244 patients with astrocytoma or oligodendroglioma with susceptible IDH1 or IDH2 mutation in trials AG881-C-002 (NCT02481154, n=11), AG120-881-001 (NCT03343197, n=14) and INDIGO (NCT04164901, n=167 randomized patients and n=52 crossover patients).
Among the 244 patients who received VORANIGO, 78% were exposed for 6 months or longer and 44% were exposed for greater than one year. In this pooled safety population, the most common (≥15%) adverse reactions were fatigue (33%), headache (28%), COVID-19 (28%), musculoskeletal pain (24%), diarrhea (21%), nausea (20%), and seizure (16%). In this pooled safety population, the most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased ALT (9%), increased AST (4.8%), increased GGT (2.2%), and decreased neutrophils (2.2%).
INDIGO The safety of VORANIGO was evaluated in 330 patients with Grade 2 astrocytoma or oligodendroglioma with an IDH1 or IDH2 mutation who received at least one dose of either VORANIGO 40 mg daily (N=167) or placebo (N=163) in the INDIGO trial [see Clinical Studies (14) ] . Patients received VORANIGO 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity. Among the 167 patients who were randomized and received VORANIGO, the median duration of exposure to VORANIGO was 12.7 months (range: 1 to 30 months) with 153 patients (92%) exposed to VORANIGO for at least 6 months and 89 (53%) exposed for at least 1 year.
The demographics of patients randomized to VORANIGO were: median age 41 years (range: 21 to 71 years); 60% male, 74% White, 20% race not reported, 3% Asian, and 1.2% Black or African American; and 5% were Hispanic or Latino. Serious adverse reactions occurred in 7% of patients who received VORANIGO. The most common serious adverse reactions occurring in ≥2% of patients who received VORANIGO includes seizure (3%). Permanent discontinuation of VORANIGO due to an adverse reaction occurred in 3.6% of patients.
Adverse reactions which resulted in permanent discontinuation of VORANIGO in ≥2% of patients included ALT increased (3%). Dosage interruptions of VORANIGO due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dose interruption in ≥5% of patients included ALT increased (14%), COVID-19 (9%), and AST increased (6%). Dose reductions of VORANIGO due to an adverse reaction occurred in 11% of patients.
Adverse reactions which required dose reduction in ≥5% of patients included ALT increased (8%). The most common (≥15%) adverse reactions were fatigue (37%), COVID-19 (33%), musculoskeletal pain (26%), diarrhea (25%), and seizure (16%). Grade 3 or 4 (≥2%) laboratory abnormalities were ALT increased (10%), AST increased (4.8%), GGT increased (3%) and neutrophil decreased (2.4%). Adverse reactions and select laboratory abnormalities reported in the INDIGO trial are shown in Tables 3 and 4.
Table 3: Adverse Reactions (≥5%) in Patients with Grade 2 IDH1/2 Mutant Glioma Who Received VORANIGO Compared with Placebo in the INDIGO Trial VORANIGO 40 mg daily (n=167) Placebo (n=163) Adverse Reaction Adverse reactions are based on NCI CTCAE v5.0. All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) General Disorders Fatigue Grouped term includes asthenia. 37 0.6 36
3.7Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain Grouped term includes arthralgia, back pain, non-cardiac chest pain, pain in extremity, myalgia, neck pain, musculoskeletal chest pain, arthritis, and musculoskeletal stiffness. 26 0 25
0.6Constipation 13 0 12 0
Abdominal pain Grouped term includes abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness, and epigastric discomfort. 13 0 12 0 Decreased appetite 9 0 3.7 0 Table 4: Select Laboratory Abnormalities (≥5%) That Worsened from Baseline in Patients with Grade 2 IDH1/2 Mutant Glioma Who Received VORANIGO in the INDIGO Trial VORANIGO 40 mg daily N=167 Placebo N=163 Parameter All Grades Based on NCI CTCAE v5.0.
(% The denominator used to calculate percentages is N, the number of subjects in the Safety Analysis Set within each treatment group. ) Grades 3 or 4 (% ) All Grades (% ) Grades 3 or 4 (% ) Abbreviations: AST = Aspartate Aminotransferase; ALT = Alanine Aminotransferase; GGT = Gamma-Glutamyl Transferase; ALP = Alkaline Phosphatase Chemistry Increased ALT 59 10 25 0 Increased AST 46 4.8 20 0 Increased Creatinine 11 0.6 7 0 Decreased Calcium 10 0 7 0 Increased Glucose Includes adverse reaction term hyperglycemia. 10 0 4.3 0 Increased GGT 38 3 10
