1.1 Unresectable or Metastatic Melanoma

ZELBORAF® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

1.2 Erdheim-Chester Disease

ZELBORAF® is indicated for the treatment of patients with Erdheim-Chester Disease (ECD) with BRAF V600 mutation.

2.1 Patient Selection for Treatment of Melanoma

Confirm the presence of BRAF V600E mutation in melanoma tumor specimens prior to initiation of treatment with ZELBORAF [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dose

The recommended dose of ZELBORAF is 960 mg (four 240 mg tablets) orally every 12 hours with or without a meal. A missed dose can be taken up to 4 hours prior to the next dose.

Treat patients with ZELBORAF until disease progression or unacceptable toxicity occurs.

Do not take an additional dose if vomiting occurs after ZELBORAF administration, but continue with the next scheduled dose.

Do not crush or chew the tablets.

2.3 Dose Modifications

2.4 Dose Modification for Strong CYP3A4 Inducers

Avoid concomitant use of strong CYP3A4 inducers during treatment with ZELBORAF [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. If concomitant use of a strong CYP3A4 inducer is unavoidable, increase the dose of ZELBORAF by 240 mg (one tablet) as tolerated. After discontinuation of a strong CYP3A4 inducer for two weeks, resume the ZELBORAF dose that was taken prior to initiating the strong CYP3A4 inducer.

5.1 New Primary Malignancies

5.2 Tumor Promotion in BRAF Wild-Type Melanoma

In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1)].

5.3 Hypersensitivity Reactions

Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)].

5.4 Dermatologic Reactions

Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)].

5.5 QT Prolongation

Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.2)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.

Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.

Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3)].

5.6 Hepatotoxicity

Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3)].

5.7 Photosensitivity

Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.

Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2)].

5.8 Ophthalmologic Reactions

Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.

5.9 Embryo-Fetal Toxicity

Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZELBORAF and for 2 weeks after the final dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

5.10 Radiation Sensitization and Radiation Recall

Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs have been reported in patients treated with radiation prior to, during, or subsequent to vemurafenib treatment. Fatal cases have been reported in patients with visceral organ involvement. [see Adverse Reactions (6.2)].

Monitor patients closely when vemurafenib is administered concomitantly or sequentially with radiation treatment.

5.11 Renal Failure

Renal failure, including acute interstitial nephritis and acute tubular necrosis, can occur with ZELBORAF. In Trial 1, in patients with metastatic melanoma, 26% of ZELBORAF-treated patients and 5% of dacarbazine-treated patients experienced Grade 1-2 creatinine elevations [greater than 1 and up to 3 times upper limit of normal (ULN)]; 1.2% of ZELBORAF-treated patients and 1.1% of dacarbazine-treated patients experienced Grade 3-4 creatinine elevations (greater than 3 times ULN).

In Trial 4, in patients with ECD, 86% (19/22) of patients experienced Grade 1/2 creatinine elevations and 9.1% (2/22) of patients experienced Grade 3 creatinine elevations.

Measure serum creatinine before initiation of ZELBORAF and periodically during treatment.

5.12 Dupuytren's Contracture and Plantar Fascial Fibromatosis

Dupuytren's contracture and plantar fascial fibromatosis have been reported with ZELBORAF. The majority of cases were mild to moderate, but severe, disabling cases of Dupuytren's contracture have also been reported [see Dosage and Administration (2.3), Adverse Reactions (6.1, 6.2)].

6.1 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 [see Clinical Studies (14)]. 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.

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.

6.2 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 [see Warnings and Precautions (5.1)].

Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)].

Blood and lymphatic systems disorder: Neutropenia

Injury, poisoning and procedural complications: Radiation sensitization and recall [see Warnings and Precautions (5.10)].

Gastrointestinal disorders: Pancreatitis

Renal and urinary disorders: Acute interstitial nephritis, acute tubular necrosis [see Warnings and Precautions (5.11)].

Musculoskeletal and connective tissue disorders: Dupuytren's contracture and plantar fascial fibromatosis [see Warnings and Precautions (5.12)].

7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib

7.2 Effect of Vemurafenib on CYP1A2 Substrates

Coadministration of ZELBORAF with tizanidine, a sensitive CYP1A2 substrate, increased tizanidine systemic exposure by 4.7-fold. Avoid concomitant use of ZELBORAF with drugs having a narrow therapeutic window that are predominantly metabolized by CYP1A2 [see Clinical Pharmacology (12.3)]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.

7.3 Concurrent Ipilimumab

Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6].

7.4 Effect of Vemurafenib on P-gp Substrates

Coadministration of ZELBORAF with digoxin, a sensitive P-glycoprotein (P-gp) substrate, increased digoxin systemic exposure by 1.8-fold. Avoid concurrent use of P-gp substrates known to have narrow therapeutic indices. If use of these medications is unavoidable, consider dose reduction of P-gp substrates with narrow therapeutic indices.

8.1 Pregnancy

8.2 Lactation

There is no information available regarding the presence of vemurafenib in human milk, effects on the breastfed infant, or effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, including malignancy, severe dermatologic reactions, QT prolongation, hepatotoxicity, photosensitivity, and ophthalmologic toxicity, [see Warnings and Precautions (5)], advise women not to breastfeed during treatment with ZELBORAF and for 2 weeks after the final dose.

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of ZELBORAF in pediatric patients have not been established. Vemurafenib was studied in 6 adolescent patients 15 to 17 years of age with unresectable or metastatic melanoma with BRAF V600 mutation. A maximum tolerated dose was not reached with doses up to vemurafenib 960 mg twice daily. No new safety signals were observed. Vemurafenib steady-state exposure in these 6 adolescent patients was generally similar to that in adults.

8.5 Geriatric Use

Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

8.7 Renal Impairment

No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment.

12.1 Mechanism of Action

Vemurafenib is a low molecular weight, orally available inhibitor of some mutated forms of BRAF serine- threonine kinase, including BRAF V600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAF V600E.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of vemurafenib were determined in patients with BRAF mutation-positive metastatic melanoma following 15 days of 960 mg twice daily with dosing approximately 12 hours apart. The population pharmacokinetic analysis pooled data from 458 patients. At steady-state, vemurafenib exhibits linear pharmacokinetics within the 240 mg to 960 mg dose range.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There have been no formal studies conducted assessing the carcinogenic potential of vemurafenib. ZELBORAF increased the development of cutaneous squamous cell carcinomas in patients in clinical trials.

Vemurafenib did not cause genetic damage when tested in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) or in the in vivo rat bone marrow micronucleus test.

No specific studies with vemurafenib have been conducted in animals to evaluate the effect on fertility; nevertheless, no histopathological findings were noted in reproductive organs in males and females in repeat-dose toxicology studies in rats at doses up to 450 mg/kg/day (approximately 0.6 and 1.6 times the human exposure based on AUC in males and females, respectively) and dogs at doses up to 450 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC in both males and females, respectively).

13.2 Animal Toxicology and/or Pharmacology

Consistent with the increased incidence of cutaneous squamous cell carcinomas in patients treated with vemurafenib, the treatment of mice implanted with human cuSCC cells with vemurafenib caused a dose- dependent acceleration of the growth of the implanted tumors.

Treatment-Naïve Patients with BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma

Trial 1, an international, open-label, randomized controlled trial, equally allocated 675 patients with treatment-naive, BRAF V600E mutation-positive unresectable or metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, to receive ZELBORAF 960 mg by mouth twice daily (n=337) or dacarbazine 1000 mg/m2 intravenously on Day 1 every 3 weeks (n=338). Randomization stratification factors were disease stage, lactate dehydrogenase (LDH), ECOG performance status, and geographic region. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. The major efficacy outcome measures of the trial were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate.

Baseline characteristics were balanced between treatment groups. Most patients were male (56%) and Caucasian (99%), the median age was 54 years (24% were ≥ 65 years), all patients had ECOG performance status of 0 or 1, and the majority of patients had metastatic disease (95%).

Trial 1 demonstrated statistically significant increases in overall survival and progression-free survival in the ZELBORAF arm compared to the dacarbazine control arm. Table 5 and Figure 1 summarize the efficacy results.

Figure 1 Kaplan-Meier Curves of Overall Survival – Treatment-Naïve Patients

The confirmed, investigator-assessed best overall response rate was 48.4% (95% CI: 41.6%, 55.2%) in the ZELBORAF arm compared to 5.5% (95% CI: 2.8%, 9.3%) in the dacarbazine arm. There were 2 complete responses (0.9%) and 104 partial responses (47.4%) in the ZELBORAF arm and all 12 responses were partial responses (5.5%) in the dacarbazine arm.

Patients with BRAF V600E Mutation-Positive Metastatic Melanoma Who Received Prior Systemic Therapy

In a single-arm, multicenter, multinational trial (Trial 2), 132 patients with BRAF V600E mutation-positive metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, who had received at least one prior systemic therapy, received ZELBORAF 960 mg by mouth twice daily. The median age was 52 years with 19% of patients being older than 65 years. The majority of patients were male (61%) and Caucasian (99%). Forty-nine percent of patients received ≥ 2 prior therapies. The median duration of follow-up was 6.87 months (range, 0.6 to 11.3).

The confirmed best overall response rate as assessed by an independent review committee (IRC) was 52% (95% CI: 43%, 61%). There were 3 complete responses (2.3%) and 66 partial responses (50.0%). The median time to response was 1.4 months with 75% of responses occurring by month 1.6 of treatment. The median duration of response by IRC was 6.5 months (95% CI: 5.6, not reached).

Patients with BRAF V600E Mutation-Positive Melanoma with Brain Metastases

The activity of ZELBORAF for the treatment of BRAF V600E mutation-positive melanoma, metastatic to the brain was evaluated in an open-label, multicenter, single-arm, two cohort trial (Trial 3). All patients received ZELBORAF 960 mg orally twice daily until disease progression or unacceptable toxicity. Patients were required to have at least one measurable brain lesion of 0.5 cm or greater on contrast-enhanced MRI, a stable or decreasing corticosteroid dose and no prior treatment with a BRAF or MEK inhibitor. Patients in Cohort A had received no prior local therapy for brain metastases. Patients in Cohort B had received at least one prior local therapy for brain metastases (surgical resection, whole brain radiotherapy, or stereotactic radiotherapy) with CNS progression following this therapy. Patients were followed until death, disease progression, withdrawal, or up to 24 months. The primary efficacy outcome measure was the confirmed best overall response rate in the brain in Cohort A, as assessed by an independent radiology review committee using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Secondary efficacy outcome measures included duration of response in Cohort A, and confirmed best overall response rate and duration of response in Cohort B.

A total of 146 patients (Cohort A: n=90; Cohort B: n=56) were enrolled and received at least one dose of ZELBORAF. In Cohort A, the median age of patients was 56 years, 62% were male, 47% had a pre- treatment ECOG performance status (PS) of 0, 57% had an elevated LDH value at baseline, and 20% received one or more systemic regimens for the treatment of metastatic disease. In Cohort B, the median age of patients was 53 years, 61% were male, 38% had a pre-treatment ECOG PS of 0, 55% had an elevated LDH value at baseline, and 39% received one or more systemic regimens for the treatment of metastatic disease. All patients enrolled on Trial 3 whose race was identified were White. The efficacy results are summarized in Table 6.

Patients with Wild-Type BRAF Melanoma

ZELBORAF has not been studied in patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].

Patients with Erdheim-Chester Disease (ECD)

An open-label, multicenter, single-arm, multiple cohort study of ZELBORAF (Trial 4) was conducted in patients ≥ 16 years of age with non-melanoma BRAF V600 mutation–positive diseases.

The trial included 22 patients with ECD. Fifteen patients (68.2%) had received prior systemic therapies. The median age was 58.5 years (range, 34 to 77 years). Fifty-five percent of patients were men.

All 22 patients received a starting dose of 960 mg orally twice daily with or without food. For 8 patients, the dose was reduced to 720 mg twice daily. For the remaining 14 patients, the dose was ultimately reduced to 480 mg. The median duration of treatment following a dose reduction to 720 mg was 77 days (range, 4 to 1325) and to 480 mg was 236 days (range, 21 to 924). The efficacy was maintained in these patients based on the overall response rate.

The efficacy of ZELBORAF in ECD was based on best overall response rate maintained on two occasions at least four weeks apart, as assessed by the investigator using RECIST v 1.1, and is presented in Table 7 below. The median duration of follow up was 26.6 months in ECD patients (range, 3.0 to 44.3 months). The median time to response was 11 months (95% CI: 3.7, 14.6). The median DOR was not estimable.

Storage and Stability: Store at room temperature 20°C–25°C (68°F–77°F); excursions permitted between 15°C and 30°C (59°F and 86°F), See USP Controlled Room Temperature. Store in the original container with the lid tightly closed.

Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems," if available in your location.

Embryo-fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].
• Advise females of reproductive potential to use effective contraception during treatment with ZELBORAF and for 2 weeks after the final dose [see Warnings and Precautions (5.9) and Use in Special Populations (8.1, 8.3)].
• Advise female patients to contact their health-care provider immediately with a known or suspected pregnancy [see Warnings and Precautions (5.9) and Use in Special Populations (8.1, 8.3)].

Lactation

• Advise a woman not to breastfeed during treatment with ZELBORAF and for 2 weeks after the final dose [see Use in Specific Populations (8.2)].
• Radiation sensitization and recall can occur in patients treated with radiation prior to, during, or subsequent to ZELBORAF treatment. Advise patients to inform their health care provider if they have had or are planning to receive radiation therapy [see Warnings and Precautions (5.10), Adverse Reactions (6.2)].
• Renal failure can occur in patients treated with ZELBORAF. Advise patients of the importance of monitoring serum creatinine prior to and during ZELBORAF treatment [see Warnings and Precautions (5.11), Adverse Reactions (6.2)].
• Advise patients to contact their health care provider for symptoms of Dupuytren's contracture or plantar fascial fibromatosis [see Warnings and Precautions (5.12)].