ZELBORAF: Package Insert and Label Information

ZELBORAF- vemurafenib tablet, film coated
Genentech, Inc.

1 INDICATIONS AND USAGE

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)].

1.2 Erdheim-Chester Disease

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

2 DOSAGE AND ADMINISTRATION

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

For New Primary Cutaneous Malignancies: No dose modifications are recommended.

For Other Adverse Reactions:

Permanently discontinue ZELBORAF 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 [see Warnings and Precautions (5.5)]

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

Upon recovery to Grade 0–1, restart ZELBORAF 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.

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.

3 DOSAGE FORMS AND STRENGTHS

Tablet: 240 mg.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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.

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)].

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)].

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 ADVERSE REACTIONS

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

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.

Table 1 Adverse Reactions Reported in ≥ 10% of Unresectable or Metastatic Melanoma Patients Treated with ZELBORAF *
ADRs Trial 1: Treatment-Naïve Patients Trial 2: Patients with Failure of at Least One Prior Systemic Therapy
ZELBORAFn=336 Dacarbazinen=287 ZELBORAFn=132
All Grades(%) Grade 3(%) All Grades(%) Grade 3(%) All Grades (%) Grade 3 (%)
*
Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.
Grade 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.
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

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.

Table 2 Change from Baseline to Grade 3/4 Liver Laboratory Abnormalities in Trial 1*
Parameter Change From Baseline to Grade 3/4
ZELBORAF (%) Dacarbazine (%)
*
For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.
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

Erdheim-Chester Disease (ECD)

This section describes adverse reactions identified from analyses of Trial 4 [see Clinical Studies (14)]. In Trial 4, 22 patients with BRAF V600 mutation-positive ECD received ZELBORAF 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 ZELBORAF.

In Trial 4, the most commonly reported adverse reactions (> 50%) in patients with BRAF V600 mutation- positive ECD treated with ZELBORAF 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 ZELBORAF *
Trial 4: Patients with ECD
n=22
Body SystemAdverse Reactions All Grades (%) Grade 3-4 (%)
*
Adverse drug reactions, graded using NCI-CTCAE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.
Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.
Skin and subcutaneous tissue disorders
Rash maculo-papular 59 18
Alopecia 55
Hyperkeratosis 50 5
Dry skin 45
Photosensitivity reaction 41
Palmar-plantar erythrodysaesthesia syndrome 41
Pruritus 36
Actinic keratosis 32 5
Keratosis pilaris 32
Rash papular 23
Musculoskeletal and connective tissue disorders
Arthralgia 82 14
General disorders and administration site conditions
Fatigue 55 5
Gastrointestinal disorders
Diarrhea 50
Nausea 32
Vomiting 23
Nervous system disorders
Peripheral sensory neuropathy 36
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
Skin papilloma 55
Seborrhoeic keratosis 41
SCC of skin 36 36
Melanocytic nevus 23 _
Cardiac disorders
Electrocardiogram QT interval prolonged 55 5
Respiratory, thoracic and mediastinal disorders
Cough 36
Vascular disorders
Hypertension 36 23
Injury, poisoning and procedural complications
Sunburn 23

Clinically relevant adverse reactions reported in < 20% of ECD patients treated with ZELBORAF 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
Change From Baseline to Grade 3
Parameter Vemurafenib (%)
AST 0
ALT 9.1
Alkaline phosphatase 4.5
Bilirubin 0
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