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Zelboraf

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Zelboraf

Side Effects
Interactions

SIDE EFFECTS

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

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

Read the Zelboraf (vemurafenib) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Effect Of Strong CYP3A4 Inhibitors Or Inducers On Vemurafenib

Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see CLINICAL PHARMACOLOGY]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.

Effect Of Vemurafenib On CYP1A2 Substrates

Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates [see CLINICAL PHARMACOLOGY]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.

Ipilimumab

Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see WARNINGS AND PRECAUTIONS].

Read the Zelboraf Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 12/15/2014
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
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