The following adverse reactions are discussed in greater detail in other sections of the label:
- New Primary Malignancies [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- Dermatologic Reactions [see WARNINGS AND PRECAUTIONS]
- QT Prolongation [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Photosensitivity [see WARNINGS AND PRECAUTIONS]
- Ophthalmologic Reactions [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.
This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m² intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily.
Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade ( ≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common ( ≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.
The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.
Table 1 : Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*
|ADRs||Trial 1: Treatment Naïve Patients||Trial 2: Patients with Failure of at Least One Prior Systemic Therapy|
|All Grades (%)||Grade 3a (%)||All Grades (%)||Grade 3 (%)||All Grades (%)||Grade 3a (%)|
|Skin and subcutaneous tissue disorders|
|Rash maculo-papular||9||2||< 1||0||21||6|
|Rash papular||5||< 1||0||0||13||0|
|Musculoskeletal and connective tissue disorders|
|Myalgia||13||< 1||1||0||24||< 1|
|Pain in extremity||18||< 1||6||2||9||0|
|Musculoskeletal pain||8||0||4||< 1||11||0|
|Back pain||8||< 1||5||< 1||11||< 1|
|General disorders and administration site conditions|
|Edema peripheral||17||< 1||5||0||23||0|
|Pyrexia||19||< 1||9||< 1||17||2|
|Asthenia||11||< 1||9||< 1||2||0|
|Diarrhea||28||< 1||13||< 1||29||< 1|
|Nervous system disorders|
|Neoplasms benign, malignant and unspecified (includes cysts and polyps)|
|Skin papilloma||21||< 1||0||0||30||0|
|Cutaneous SCC†#||24||22||< 1||< 1||24||24|
|Seborrheic keratosis||10||< 1||1||0||14||0|
|Metabolism and nutrition disorders|
|Decreased appetite||18||0||8||< 1||21||0|
|Respiratory, thoracic and mediastinal disorders|
|Injury, poisoning and procedural complications Sunburn||10||0||0||0||14||0|
|*Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.
aGrade 4 adverse reactions limited to gamma-glutamyltransferase increased ( < 1% in Trial 1 and 4% in Trial 2).
† Includes both squamous cell carcinoma of the skin and keratoacanthoma.
#Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.
Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include:
Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, panniculitis, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders: arthritis
Nervous system disorders: neuropathy peripheral, VIIth nerve paralysis
Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma
Infections and infestations: folliculitis
Eye disorders: retinal vein occlusion
Vascular disorders: vasculitis
Cardiac disorders: atrial fibrillation Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.
Table 2 : Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities*
|Parameter||Change From Baseline to Grade 3/4|
|ZELBORAF (%)||Dacarbazine (%)|
|* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.|
The following adverse reactions have been identified during postapproval use of ZELBORAF. 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.
Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of pre-existing chronic myelomonocytic leukemia with NRAS mutation [see WARNINGS AND PRECAUTIONS].
Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see WARNINGS AND PRECAUTIONS].
Blood and lymphatic systems disorder: Neutropenia