Зелбораф

Unresectable Or Metastatic Melanoma

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

Limitation Of Use

Зелбораф is not indicated for treatment of patients with wild-type BRAF melanoma.

Erdheim-Chester Disease

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

Patient Selection For Treatment Of Melanoma

Confirm the presence of BRAF V600E mutation in melanoma tumor specimens prior to initiation of treatment with Зелбораф. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at http://www.fda.gov/CompanionDiagnostics.

Recommended Dose

The recommended dose of Зелбораф 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 Зелбораф until disease progression or unacceptable toxicity occurs.

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

Do not crush or chew the tablets.

Dose Modifications

For New Primary Cutaneous Malignancies

No dose modifications are recommended.

For Other Adverse Reactions

Permanently discontinue Зелбораф for any of the following:

• Grade 4 adverse reaction, first appearance (if clinically appropriate) or second appearance
• QTc prolongation > 500 ms and increased by > 60 ms from pre-treatment values

Withhold Зелбораф for NCI-CTCAE (v4.0) intolerable Grade 2 or greater adverse reactions.

Upon recovery to Grade 0–1, restart Зелбораф at a reduced dose as follows:

• 720 mg twice daily for first appearance of intolerable Grade 2 or Grade 3 adverse reactions
• 480 mg twice daily for second appearance of Grade 2 (if intolerable) or Grade 3 adverse reactions or for first appearance of Grade 4 adverse reaction (if clinically appropriate)

Do not dose reduce to below 480 mg twice daily.

Dose Modification For Strong CYP3A4 Inducers

Avoid concomitant use of strong CYP3A4 inducers during treatment with Зелбораф. If concomitant use of a strong CYP3A4 inducer is unavoidable, increase the dose of Зелбораф by 240 mg (one tablet) as tolerated. After discontinuation of a strong CYP3A4 inducer for two weeks, resume the Зелбораф dose that was taken prior to initiating the strong CYP3A4 inducer.

None.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

New Primary Malignancies

Cutaneous Malignancies

Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving Зелбораф compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the Зелбораф arm was 24% compared to < 1% in the dacarbazine arm. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving Зелбораф experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using Зелбораф included age (≥ 65 years), prior skin cancer, and chronic sun exposure.

In Trial 4, in patients with ECD, the incidence of cuSCC and/or keratoacanthomas was 40.9% (9/22). The median time to first appearance of cuSCC amongst patients with at least one occurrence was 12.1 weeks.

In Trial 1, in patients with unresectable or metastatic melanoma, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving Зелбораф compared to none of the patients receiving dacarbazine.

Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of Зелбораф.

Non-Cutaneous Squamous Cell Carcinoma

Non-cutaneous squamous cell carcinomas (non-cuSCC) of the head and neck can occur in patients receiving Зелбораф. Monitor patients receiving Зелбораф closely for signs or symptoms of new non-cuSCC.

Other Malignancies

Based on mechanism of action, Зелбораф may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving Зелбораф closely for signs or symptoms of other malignancies.

Cases of myeloid neoplasms amongst patients with ECD have been observed, including in patients who have received Зелбораф. Monitoring complete blood count in ECD patients with co-existing myeloid malignancies is recommended.

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 Зелбораф.

Hypersensitivity Reactions

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

Dermatologic Reactions

Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving Зелбораф. Permanently discontinue Зелбораф in patients who experience a severe dermatologic reaction.

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. 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 Зелбораф 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 Зелбораф in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue Зелбораф 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).

Hepatotoxicity

Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with Зелбораф. 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.

Concurrent Administration With Ipilimumab

The safety and effectiveness of Зелбораф in combination with ipilimumab have not been established. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).

Photosensitivity

Mild to severe photosensitivity can occur in patients treated with Зелбораф. 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.

Ophthalmologic Reactions

Uveitis, blurry vision, and photophobia can occur in patients treated with Зелбораф. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving Зелбораф 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.

Embryo-Fetal Toxicity

Based on its mechanism of action, Зелбораф 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 Зелбораф and for 2 weeks after the final dose.

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..

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

Renal Failure

Renal failure, including acute interstitial nephritis and acute tubular necrosis, can occur with Зелбораф. In Trial 1, in patients with metastatic melanoma, 26% of Зелбораф-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 Зелбораф-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 Зелбораф and periodically during treatment.

Dupuytren’s Contracture And Plantar Fascial Fibromatosis

Dupuytren’s contracture and plantar fascial fibromatosis have been reported with Зелбораф. The majority of cases were mild to moderate, but severe, disabling cases of Dupuytren’s contracture have also been reported.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Healthcare providers should advise patients of the potential benefits and risks of Зелбораф and instruct their patients to read the Medication Guide before starting Зелбораф therapy. Inform patients of the following:

• Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients with melanoma for whom treatment with Зелбораф is indicated.
• Зелбораф increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their healthcare provider immediately for any changes in their skin.
• Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon reinitiation of treatment with Зелбораф. Advise patients to stop taking Зелбораф and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity.
• Severe dermatologic reactions can occur in patients receiving Зелбораф. Advise patients to stop taking Зелбораф and to contact their health-care provider for severe dermatologic reactions.
• Зелбораф can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during Зелбораф treatment.
• Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with Зелбораф. Advise patients of the importance of laboratory monitoring of their liver during Зелбораф treatment and to contact their health-care provider for relevant symptoms.
• Зелбораф can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn.
• Ophthalmologic reactions can occur in patients treated with Зелбораф. Advise patients to contact their health-care provider immediately for ophthalmologic symptoms.

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
• Advise females of reproductive potential to use effective contraception during treatment with Зелбораф and for 2 weeks after the final dose.
• Advise female patients to contact their health-care provider immediately with a known or suspected pregnancy.

Lactation

• Advise a woman not to breastfeed during treatment with Зелбораф and for 2 weeks after the final dose.
• Radiation sensitization and recall can occur in patients treated with radiation prior to, during, or subsequent to Зелбораф treatment. Advise patients to inform their health care provider if they have had or are planning to receive radiation therapy.
• Renal failure can occur in patients treated with Зелбораф. Advise patients of the importance of monitoring serum creatinine prior to and during Зелбораф treatment.
• Advise patients to contact their health care provider for symptoms of Dupuytren’s contracture or plantar fascial fibromatosis.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

There have been no formal studies conducted assessing the carcinogenic potential of vemurafenib. Зелбораф 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).

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action, Зелбораф can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Зелбораф in pregnant women to determine the drug-associated risk; however, placental transfer of vemurafenib to a fetus has been reported. Exposure to vemurafenib could not be achieved in animals at levels sufficient to fully address its potential toxicity in pregnant women. Advise pregnant women of the potential harm to a fetus.

The estimated background risks of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Vemurafenib showed no evidence of developmental toxicity in rat fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the clinical exposure at 960 mg twice daily based on AUC) or rabbit fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the clinical exposure at 960 mg twice daily based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus.

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, , advise women not to breastfeed during treatment with Зелбораф and for 2 weeks after the final dose.

Females And Males Of Reproductive Potential

Contraception

Based on its mechanism of action, Зелбораф can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Зелбораф and for 2 weeks after the final dose.

Pediatric Use

The safety and effectiveness of Зелбораф 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.

Geriatric Use

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

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.

The appropriate dose of Зелбораф has not been established in patients with severe hepatic impairment.

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. The appropriate dose of Зелбораф has not been established in patients with severe renal impairment.

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 Зелбораф 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 Зелбораф 960 mg orally twice daily.

Table 1 presents adverse reactions reported in at least 10% of unresectable or metastatic melanoma patients treated with Зелбораф. The most common adverse reactions of any grade (≥30% in either study) in Зелбораф-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 Зелбораф 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 Зелбораф-treated patients. The median duration of study treatment was 4.2 months for Зелбораф and 0.8 months for dacarbazine in Trial 1, and 5.7 months for Зелбораф in Trial 2.

Table 1: Adverse Reactions Reported in ≥10% of Unresectable or Metastatic Melanoma Patients Treated with Зелбораф*

Clinically relevant adverse reactions reported in < 10% of unresectable or metastatic melanoma patients treated with Зелбораф 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, VII^th 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. In Trial 4, 22 patients with BRAF V600 mutation-positive ECD received Зелбораф 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 Зелбораф.

In Trial 4, the most commonly reported adverse reactions (> 50%) in patients with BRAF V600 mutationpositive ECD treated with Зелбораф 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 Зелбораф*

Clinically relevant adverse reactions reported in < 20% of ECD patients treated with Зелбораф 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 Зелбораф. 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).

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 .

There is no information on overdosage of Зелбораф.

Cardiac Electrophysiology

In a multi-center, open-label, single-arm study in 132 patients with BRAF V600E mutation-positive metastatic melanoma, patients administered vemurafenib 960 mg orally twice daily did not experience large changes in mean QTc interval (i.e., > 20 ms) from baseline. Vemurafenib is associated with concentrationdependent QTc interval prolongation. The largest mean change from baseline in the first month of treatment occurred at 2 hours post-dose on Day 15–an increase of 12.8 ms (upper boundary of the two-sided 90% confidence interval of 14.9 ms). In the first 6 months of treatment, the largest observed mean change from baseline occurred at a pre-dose time point–an increase of 15.1 ms (upper boundary of the two-sided 90% confidence interval of 17.7 ms).

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.

Absorption

The bioavailability of vemurafenib has not been determined. The median Tmax was approximately 3 hours following multiple doses.

The mean (± SD) Cmax and AUC0-12 were 62 ± 17 μg/mL and 601 ± 170 μg*h/mL, respectively. The median accumulation ratio estimate from the population pharmacokinetic analysis for the twice daily regimen is 7.4, with steady-state achieved at approximately 15 to 22 days.

In clinical trials, vemurafenib was administered without regard to food. A food effect study has demonstrated that a single dose of vemurafenib administered with a high-fat meal increased AUC by approximately 5-fold, increased Cmax by 2.5-fold, and delayed Tmax by approximately 4 hours as compared to the fasted state.

QTc prolongation may occur with increased exposures as vemurafenib is associated with concentration-dependent QTc interval prolongation.

Distribution

Vemurafenib is highly bound (> 99%) to human albumin and alpha-1 acid glycoprotein plasma proteins. The population apparent volume of distribution is estimated to be 106 L (with 66% inter-patient variability).

Metabolism

Following oral administration of 960 mg of ¹⁴C-vemurafenib, mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma over 48 hours, respectively.

Elimination

Following oral administration of 960 mg of ¹⁴C-vemurafenib, approximately 94% of the radioactive dose was recovered in feces and approximately 1% was recovered in the urine. The population apparent clearance is estimated to be 31 L/day (with 32% inter-patient variability). The median elimination half-life estimate for vemurafenib is 57 hours (the 5th and 95th percentile range is 30 to 120 hours).