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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
ZELBORAF
n=336
Dacarbazine
n=287
ZELBORAF
n=132
All Grades (%) Grade 3a (%) All Grades (%) Grade 3 (%) All Grades (%) Grade 3a (%)
Skin and subcutaneous tissue disorders
Rash 37 8 2 0 52 7
Photosensitivity reaction 33 3 4 0 49 3
Alopecia 45 < 1 2 0 36 0
Pruritus 23 1 1 0 30 2
Hyperkeratosis 24 1 < 1 0 28 0
Rash maculo-papular 9 2 < 1 0 21 6
Actinic keratosis 8 0 3 0 17 0
Dry skin 19 0 1 0 16 0
Rash papular 5 < 1 0 0 13 0
Erythema 14 0 2 0 8 0
Musculoskeletal and connective tissue disorders
Arthralgia 53 4 3 < 1 67 8
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
Fatigue 38 2 33 2 54 4
Edema peripheral 17 < 1 5 0 23 0
Pyrexia 19 < 1 9 < 1 17 2
Asthenia 11 < 1 9 < 1 2 0
Gastrointestinal disorders
Nausea 35 2 43 2 37 2
Diarrhea 28 < 1 13 < 1 29 < 1
Vomiting 18 1 26 1 26 2
Constipation 12 < 1 24 0 16 0
Nervous system disorders
Headache 23 < 1 10 0 27 0
Dysgeusia 14 0 3 0 11 0
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
Investigations
Gamma-glutamyltransferase increased 5 3 1 0 15 6
Metabolism and nutrition disorders
Decreased appetite 18 0 8 < 1 21 0
Respiratory, thoracic and mediastinal disorders
Cough 8 0 7 0 12 0
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 (%)
GGT 11.5 8.6
AST 0.9 0.4
ALT 2.8 1.9
Alkaline phosphatase 2.9 0.4
Bilirubin 1.9 0
* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.

Postmarketing Experience

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