6 ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the labeling:
- New Primary Malignancies [see Warnings and Precautions (5.1)]
- Hemorrhage [see Warnings and Precautions (5.3)]
- Uveitis [see Warnings and Precautions (5.4)]
- QT Prolongation [see Warnings and Precautions (5.5)]
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.
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma
The safety of BRAFTOVI in combination with binimetinib is described in 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received BRAFTOVI (450 mg once daily) in combination with binimetinib (45 mg twice daily) in a randomized open-label, active-controlled trial (COLUMBUS).
The COLUMBUS trial [see Clinical Studies (14.1)] excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with BRAFTOVI in combination with binimetinib and 6.2 months for patients treated with vemurafenib.
The most common (≥25%) adverse reactions in patients receiving BRAFTOVI in combination with binimetinib were fatigue, nausea, vomiting, abdominal pain, and arthralgia.
Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 30% of patients receiving BRAFTOVI in combination with binimetinib; the most common were nausea (7%), vomiting (7%), and pyrexia (4%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 14% of patients receiving BRAFTOVI in combination with binimetinib; the most common were arthralgia (2%), fatigue (2%), and nausea (2%). Five percent (5%) of patients receiving BRAFTOVI in combination with binimetinib experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common were hemorrhage in 2% and headache in 1% of patients.
Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for BRAFTOVI in combination with binimetinib, as compared to vemurafenib, for any specific adverse reaction listed in Table 5.
Adverse Reaction | BRAFTOVI with binimetinib N=192 | Vemurafenib N=186 | ||
---|---|---|---|---|
All Grades (%) | Grades 3 and 4† (%) | All Grades (%) | Grades 3 and 4 (%) | |
General Disorders and Administration Site Conditions | ||||
Fatigue‡ | 43 | 3 | 46 | 6 |
Pyrexia‡ | 18 | 4 | 30 | 0 |
Gastrointestinal Disorders | ||||
Nausea | 41 | 2 | 34 | 2 |
Vomiting‡ | 30 | 2 | 16 | 1 |
Abdominal pain‡ | 28 | 4 | 16 | 1 |
Constipation | 22 | 0 | 6 | 1 |
Musculoskeletal and Connective Tissue Disorders | ||||
Arthralgia‡ | 26 | 1 | 46 | 6 |
Myopathy‡ | 23 | 0 | 22 | 1 |
Pain in extremity | 11 | 1 | 13 | 1 |
Skin and Subcutaneous Tissue Disorders | ||||
Hyperkeratosis‡ | 23 | 1 | 49 | 1 |
Rash‡ | 22 | 1 | 53 | 13 |
Dry skin‡ | 16 | 0 | 26 | 0 |
Alopecia‡ | 14 | 0 | 38 | 0 |
Pruritus‡ | 13 | 1 | 21 | 1 |
Nervous System Disorders | ||||
Headache‡ | 22 | 2 | 20 | 1 |
Dizziness‡ | 15 | 3 | 4 | 0 |
Peripheral neuropathy‡ | 12 | 1 | 13 | 2 |
Vascular Disorders | ||||
Hemorrhage‡ | 19 | 3 | 9 | 2 |
BRAFTOVI when used as a single agent increases the risk of certain adverse reactions compared to BRAFTOVI in combination with binimetinib. In patients receiving BRAFTOVI 300 mg orally once daily as a single agent, the following adverse reactions were observed at a higher rate (≥5%) compared to patients receiving BRAFTOVI in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%), back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%).
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with binimetinib were:
Nervous system disorders: Facial paresis
Gastrointestinal disorders: Pancreatitis
Skin and subcutaneous tissue disorders: Panniculitis
Immune system disorders: Drug hypersensitivity
Laboratory Abnormality | BRAFTOVI with binimetinib* N=192 | Vemurafenib* N=186 | ||
---|---|---|---|---|
All Grades (%) | Grades 3 and 4 (%) | All Grades (%) | Grades 3 and 4 (%) | |
| ||||
Hematology | ||||
Anemia | 36 | 3.6 | 34 | 2.2 |
Leukopenia | 13 | 0 | 10 | 0.5 |
Lymphopenia | 13 | 2.1 | 30 | 7 |
Neutropenia | 13 | 3.1 | 4.8 | 0.5 |
Chemistry | ||||
Increased Creatinine | 93 | 3.6 | 92 | 1.1 |
Increased Gamma Glutamyl Transferase | 45 | 11 | 34 | 4.8 |
Increased ALT | 29 | 6 | 27 | 2.2 |
Increased AST | 27 | 2.6 | 24 | 1.6 |
Hyperglycemia | 28 | 5 | 20 | 2.7 |
Increased Alkaline Phosphatase | 21 | 0.5 | 35 | 2.2 |
Hyponatremia | 18 | 3.6 | 15 | 0.5 |
Hypermagnesemia | 10 | 1.0 | 26 | 0.5 |
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (400 mg/m2 initial dose, followed by 250 mg/m2 weekly) was evaluated in 216 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BEACON CRC). The BEACON CRC trial [see Clinical Studies (14.2)] excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 4.4 months for patients treated with BRAFTOVI in combination with cetuximab and 1.6 months for patients treated with either irinotecan or infusional 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI) in combination with cetuximab.
The most common (≥25%) adverse reactions in patients receiving BRAFTOVI in combination with cetuximab were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.
Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 33% of patients receiving BRAFTOVI in combination with cetuximab; the most common were vomiting (4%), fatigue (4%), nausea (4%), pyrexia (3%), and diarrhea (3%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 9% of patients receiving BRAFTOVI in combination with cetuximab; the most common were fatigue (2%), arthralgia (2%), and peripheral neuropathy (2%). Ten percent (10%) of patients receiving BRAFTOVI in combination with cetuximab experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI. None of the adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in more than one patient (>0.5%).
Table 7 and Table 8 present adverse drug reactions and laboratory abnormalities, respectively, identified in BEACON CRC.
Adverse Reaction | BRAFTOVI with cetuximab N=216 | Irinotecan with cetuximab or FOLFIRI with cetuximab N=193 | ||
---|---|---|---|---|
All Grades (%) | ≥ Grade 3† (%) | All Grades (%) | ≥ Grade 3 (%) | |
General Disorders and Administration Site Conditions | ||||
Fatigue‡ | 51 | 7 | 50 | 8 |
Pyrexia‡ | 17 | 1 | 15 | 1 |
Gastrointestinal Disorders | ||||
Nausea | 34 | 1 | 41 | 1 |
Diarrhea‡ | 33 | 2 | 48 | 10 |
Abdominal pain‡ | 30 | 4 | 32 | 5 |
Vomiting | 21 | 1 | 29 | 3 |
Constipation | 15 | 0 | 18 | 1 |
Metabolism and Nutrition Disorders | ||||
Decreased appetite | 27 | 1 | 27 | 3 |
Musculoskeletal and Connective Tissue Disorders | ||||
Arthralgia‡ | 27 | 1 | 3 | 0 |
Myopathy‡ | 15 | 1 | 4 | 0 |
Pain in extremity | 10 | 0 | 1 | 0 |
Skin and Subcutaneous Tissue Disorders | ||||
Dermatitis acneiform‡ | 32 | 1 | 43 | 3 |
Rash‡ | 26 | 0 | 26 | 2 |
Pruritus‡ | 14 | 0 | 6 | 0 |
Melanocytic nevus | 14 | 0 | 0 | 0 |
Dry skin‡ | 13 | 0 | 12 | 1 |
Nervous System Disorders | ||||
Headache‡ | 20 | 0 | 3 | 0 |
Peripheral neuropathy‡ | 12 | 1 | 6 | 0 |
Vascular Disorders | ||||
Hemorrhage‡ | 19 | 2 | 9 | 0 |
Psychiatric Disorders | ||||
Insomnia‡ | 13 | 0 | 6 | 0 |
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with cetuximab were:
Gastrointestinal disorders: Pancreatitis
Laboratory Abnormality† | BRAFTOVI with cetuximab | Irinotecan with cetuximab or FOLFIRI with cetuximab | ||
---|---|---|---|---|
All Grades (%) | Grades 3 and 4 (%) | All Grades (%) | Grades 3 and 4 (%) | |
Hematology | ||||
Anemia | 34 | 4 | 48 | 5 |
Lymphopenia | 24 | 7 | 35 | 5 |
Increased Activated Partial Thromboplastin Time | 13 | 1 | 7 | 1 |
Chemistry | ||||
Hypomagnesemia | 19 | 0 | 22 | 1 |
Increased Alkaline Phosphatase | 18 | 4 | 30 | 7 |
Increased ALT | 17 | 0 | 29 | 3 |
Increased AST | 15 | 1 | 22 | 2 |
Hypokalemia | 12 | 3 | 32 | 5 |
Hyponatremia | 11 | 2 | 13 | 2 |