sp;
Skin papilloma 21 <1 - - - - 30 - -
Cutaneous SCC† ‡ 24 22 - <1 <1 - 24 24 -
Seborrheic keratosis 10 <1 - 1 - - 14 - -
Investigations
Gamma-glutamyltransferase increased 5 3 <1 1 - - 15 6 4
Metabolism and nutrition disorders
Decreased appetite 18 - - 8 <1 - 21 - -
Respiratory, thoracic and mediastinal disorders
Cough 8 - - 7 - - 12 - -
Injury, poisoning and procedural complications
Sunburn 10 - - - - - 14 - -
*Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.
†Includes both squamous cell carcinoma of the skin and keratoacanthoma.
‡All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.
Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include:
Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome
Musculoskeletal and connective tissue disorders: arthritis
Nervous system disorders: dizziness, neuropathy peripheral, VIIth nerve paralysis
Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma
Infections and infestations: folliculitis
Investigations: weight decreased
Eye disorders: retinal vein occlusion, uveitis
Vascular disorders: vasculitis
Cardiac disorders: atrial fibrillation
Table 3 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 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4
Parameter 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 -
*For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm.
7 DRUG INTERACTIONS
7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes
Results from an in vivo drug-drug interaction study in patients with cancer demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)].
Coadministration of vemurafenib increased the AUC of caffeine (CYP1A2 substrate) 2.6-fold and increased the AUC of dextromethorphan (CYP2D6 substrate) by 47%, while it decreased the AUC of midazolam (CYP3A4 substrate) by 39% [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is not recommended as ZELBORAF may alter their concentrations. If coadministration cannot be avoided, exercise caution and consider a dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug.
Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology |
