ZELBORAF SIDE EFFECTS

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the label:

• New Primary Malignancies
• Hypersensitivity Reactions
• Dermatologic Reactions
• QT Prolongation
• Hepatotoxicity
• Photosensitivity
• Ophthalmologic Reactions
• Radiation Sensitization and Radiation Recall
• Renal Failure
• Dupuytren’s Contracture and Plantar Fascial Fibromatosis

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.

Unresectable or Metastatic Melanoma with BRAF V600E Mutation This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 . 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 unresectable or metastatic melanoma 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 Unresectable or Metastatic Melanoma Patients Treated with ZELBORAF*

Clinically relevant adverse reactions reported in < 10% of unresectable or metastatic melanoma 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, Dupuytren’s contracture 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 in Trial 1*

Erdheim-Chester Disease (ECD)

This section describes adverse reactions identified from analyses of Trial 4 [see Clinical Studies]. In Trial 4, 22 patients with BRAF V600 mutation-positive ECD received ZELBORAF 960 mg twice daily. The median treatment duration for ECD patients in this study was 14.2 months. Table 3 presents adverse reactions reported in at least 20% of BRAF V600 mutation-positive ECD patients treated with ZELBORAF.

In Trial 4, the most commonly reported adverse reactions (> 50%) in patients with BRAF V600 mutation-positive ECD treated with ZELBORAF were arthralgia, rash maculo-papular, alopecia, fatigue, electrocardiogram QT interval prolonged, and skin papilloma. The most common (≥ 10%) Grade ≥ 3 adverse reactions were squamous cell carcinoma of the skin, hypertension, rash maculo-papular, and arthralgia.

The incidence of adverse reactions resulting in permanent discontinuation of study medication was 32%.

Table 3 : Adverse Reactions Reported in ≥ 20% of ECD Patients Treated with ZELBORAF*

Clinically relevant adverse reactions reported in < 20% of ECD patients treated with ZELBORAF in Trial 4 include:

Neoplasms benign, malignant and unspecified (includes cysts and polyps): keratoacanthoma

Musculoskeletal and connective tissue disorders: Dupuytren’s contracture

Table 4 shows the incidence of worsening liver laboratory abnormalities in Trial 4 summarized as the proportion of ECD patients who experienced a shift from baseline to Grade 3 or 4.

Table 4 : Change from Baseline to Grade 3 Liver Laboratory Abnormalities in Trial 4

Postmarketing Experience

The following adverse reactions have been identified during post approval 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.

Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see WARNINGS AND PRECAUTIONS].

Blood and lymphatic systems disorder: Neutropenia

Injury, poisoning and procedural complications: Radiation sensitization and recall.

Gastrointestinal disorders: Pancreatitis

Renal and urinary disorders: Acute interstitial nephritis, acute tubular necrosis.

Musculoskeletal and connective tissue disorders: Dupuytren’s contracture and plantar fascial fibromatosis.

SRC: NLM .