Zelboraf

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

  Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma

  [see Warnings and Precautions (5.2)]

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

Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma (

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with ZELBORAF. (
  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.
  )
• Recommended dose: 960 mg orally twice daily taken approximately 12 hours apart with or without a meal. (
  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.
  )

Tablet: 240 mg.

• Lactation: Do not breastfeed while taking ZELBORAF. (
  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.
  )

• New Primary Cutaneous Malignancies: Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and for up to 6 months following discontinuation of ZELBORAF. Manage with excision and continue treatment without dose adjustment. (
  5.1 New Primary Malignancies

  Cutaneous Malignancies

  Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm

  [see Adverse Reactions (6.1)]

  . The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF 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 ZELBORAF 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 ZELBORAF 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 ZELBORAF.

  Non-Cutaneous Squamous Cell Carcinoma

  Non-cutaneous squamous cell carcinomas (non-cuSCC) of the head and neck can occur in patients receiving ZELBORAF

  [see Adverse Reactions (6.1)]

  . Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cuSCC.

  Other Malignancies

  Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms

  [see Warnings and Precautions (5.2)]

  . Monitor patients receiving ZELBORAF 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 ZELBORAF. Monitoring complete blood count in ECD patients with co-existing myeloid malignancies is recommended.
  )
• New Non-Cutaneous Squamous Cell Carcinoma: Evaluate for symptoms or clinical signs of new non-cutaneous SCC before initiation of treatment and periodically during treatment. (
  5.1 New Primary Malignancies

  Cutaneous Malignancies

  Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm

  [see Adverse Reactions (6.1)]

  . The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF 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 ZELBORAF 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 ZELBORAF 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 ZELBORAF.

  Non-Cutaneous Squamous Cell Carcinoma

  Non-cutaneous squamous cell carcinomas (non-cuSCC) of the head and neck can occur in patients receiving ZELBORAF

  [see Adverse Reactions (6.1)]

  . Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cuSCC.

  Other Malignancies

  Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms

  [see Warnings and Precautions (5.2)]

  . Monitor patients receiving ZELBORAF 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 ZELBORAF. Monitoring complete blood count in ECD patients with co-existing myeloid malignancies is recommended.
  )
• Other Malignancies: Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies (
  5.1 New Primary Malignancies

  Cutaneous Malignancies

  Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm

  [see Adverse Reactions (6.1)]

  . The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF 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 ZELBORAF 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 ZELBORAF 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 ZELBORAF.

  Non-Cutaneous Squamous Cell Carcinoma

  Non-cutaneous squamous cell carcinomas (non-cuSCC) of the head and neck can occur in patients receiving ZELBORAF

  [see Adverse Reactions (6.1)]

  . Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cuSCC.

  Other Malignancies

  Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms

  [see Warnings and Precautions (5.2)]

  . Monitor patients receiving ZELBORAF 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 ZELBORAF. Monitoring complete blood count in ECD patients with co-existing myeloid malignancies is recommended.
  ).
• Tumor Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors (
  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)]

  .
  ).
• Serious Hypersensitivity Reactions including anaphylaxis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome): Discontinue ZELBORAF for severe hypersensitivity reactions. (
  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)]

  .
  )
• Severe Dermatologic Reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Discontinue ZELBORAF for severe dermatologic reactions. (
  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)].
  )
• QT Prolongation: Monitor ECG and electrolytes before and during treatment. Withhold ZELBORAF for QTc of 500 ms or greater. Correct electrolyte abnormalities and control for cardiac risk factors for QT prolongation. (
  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)]

  .
  )
• Hepatotoxicity: Measure liver enzymes and bilirubin before initiating ZELBORAF and monitor monthly during treatment. (
  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)]

  .

  Concurrent Administration with Ipilimumab

  The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established

  [see Indications and Usage (1)]

  . 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)

  [see Drug Interactions (7.3)].
  )
• Photosensitivity: Advise patients to avoid sun exposure. (
  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)]

  .
  )
• Serious Ophthalmologic Reactions: Monitor for signs and symptoms of uveitis. (
  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.
  )
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of the potential risk to the fetus and to use effective contraception. (
  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)]

  .
  ,
  8.1 Pregnancy

  Risk Summary

  Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology (12.1)]

  . There are no available data on the use of ZELBORAF 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.
  ,
  8.3 Females and Males of Reproductive Potential

  Contraception

  Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)]

  . Advise females of reproductive potential to use effective contraception during treatment with ZELBORAF and for 2 weeks after the final dose.
  )
• Radiation Sensitization and Radiation Recall: Severe cases have been reported. (
  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.
  ).
• Renal Failure: Measure serum creatinine before initiating ZELBORAF and monitor periodically during 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.
  ).
• Dupuytren's Contracture and plantar fascial fibromatosis: Events should be managed with dose reduction, treatment interruption, or treatment discontinuation. (
  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)].
  ).