IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Review the Full Prescribing Information for ZELBORAF for information on the serious risks of ZELBORAF.

New Primary Malignancies

New primary malignancies, cutaneous and non-cutaneous, can occur with COTELLIC in combination with ZELBORAF and with ZELBORAF as a single agent.

Cutaneous Malignancies

• In Trial 1, the following cutaneous malignancies or premalignant conditions occurred in the COTELLIC with ZELBORAF arm and the ZELBORAF arm, respectively: cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA) (6% and 20%), basal cell carcinoma (4.5% and 2.4%), and second primary melanoma (0.8% and 2.4%). Among patients receiving COTELLIC with ZELBORAF, the median time to detection of first cuSCC/KA was 4 months (range: 2 to 11 months), and the median time to detection of basal cell carcinoma was 4 months (range: 27 days to 13 months). The time to onset in the 2 patients with second primary melanoma was 9 months and 12 months. 
• Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. No dose modifications are recommended for COTELLIC. Conduct dermatologic monitoring for 6 months following discontinuation of COTELLIC when administered with ZELBORAF.

Non-cutaneous Malignancies

• Based on its mechanism of action, ZELBORAF may promote growth and development of malignancies. 

• Monitor patients receiving COTELLIC, when administered with ZELBORAF, for signs or symptoms of non-cutaneous malignancies.

Other Malignancies

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

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.

Hemorrhage

Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with COTELLIC.

• In Trial 1, the incidence of Grade 3-4 hemorrhages was 1.2% in patients receiving COTELLIC with ZELBORAF and 0.8% in patients receiving ZELBORAF. Hemorrhage (all Grades) was 13% in patients receiving COTELLIC with ZELBORAF and 7% in patients receiving ZELBORAF.
• Withhold COTELLIC for Grade 3 hemorrhagic events. If improved to Grade 0 or 1 within 4 weeks, resume COTELLIC at a lower dose level. Discontinue COTELLIC for Grade 4 hemorrhagic events and any Grade 3 hemorrhagic events that do not improve.

Cardiomyopathy

• Cardiomyopathy, defined as symptomatic and asymptomatic decline in left ventricular ejection fraction (LVEF), can occur with COTELLIC. The safety of COTELLIC has not been established in patients with a baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50%.

• Grade 2 or 3 decrease in LVEF occurred in 26% of patients receiving COTELLIC with ZELBORAF and 19% of patients receiving ZELBORAF.

• Evaluate LVEF prior to initiation, 1 month after initiation, and every 3 months thereafter until discontinuation of COTELLIC. Manage events of left ventricular dysfunction through treatment interruption, reduction, or discontinuation. In patients restarting COTELLIC after a dose reduction or interruption, evaluate LVEF at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then as clinically indicated.

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.

Severe Dermatologic Reactions

COTELLIC:

• Severe rash and other skin reactions can occur with COTELLIC. In Trial 1, Grade 3 to 4 rash occurred in 16% of patients receiving COTELLIC with ZELBORAF and in 17% of patients receiving ZELBORAF, including Grade 4 rash in 1.6% of patients receiving COTELLIC with ZELBORAF and 0.8% of the patients receiving ZELBORAF.
• Interrupt, reduce the dose, or discontinue COTELLIC for severe dermatologic reactions.

ZELBORAF:

• 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.

Serous Retinopathy and Retinal Vein Occlusion

Ocular toxicities can occur with COTELLIC, including serous retinopathy (fluid accumulation under layers of the retina).

• Symptomatic and asymptomatic serous retinopathy was identified in 26% of patients receiving COTELLIC with ZELBORAF. The majority of these events were reported as chorioretinopathy (13%) or retinal detachment (12%).

• Perform an ophthalmologic evaluation at regular intervals and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt COTELLIC until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation.

QT Prolongation

• Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT substudy of ZELBORAF 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 with ZELBORAF 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 treatment with ZELBORAF if the QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias).

Hepatotoxicity

Hepatotoxicity can occur with COTELLIC in combination with ZELBORAF and with ZELBORAF as a single agent.

• The incidences of Grade 3 or 4 liver laboratory abnormalities in Trial 1 among patients receiving COTELLIC with ZELBORAF compared with patients receiving ZELBORAF were 11% vs 5% for alanine aminotransferase, 8% vs 2.1% for aspartate aminotransferase, 1.6% vs 1.2% for total bilirubin, and 7% vs 3.3% for alkaline phosphatase.
• Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF.
• Monitor liver laboratory tests, including transaminases, alkaline phosphatase, and bilirubin, before initiation of COTELLIC in combination with ZELBORAF and monthly during treatment, or more frequently as clinically indicated. Manage Grade 3 or 4 liver laboratory abnormalities with dose interruption, reduction, or discontinuation of COTELLIC and ZELBORAF.

Concurrent Administration with Ipilimumab

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

Rhabdomyolysis

Rhabdomyolysis can occur with COTELLIC.

• In Trial 1, Grade 3 or 4 creatine phosphokinase (CPK) elevations, including asymptomatic elevations over baseline, occurred in 14% of patients receiving COTELLIC with ZELBORAF and 0.5% of patients receiving ZELBORAF.

• Obtain baseline serum CPK and creatinine levels prior to initiating COTELLIC, periodically during treatment, and as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, dose interruption or discontinuation of COTELLIC may be required.

Severe Photosensitivity

Photosensitivity, including severe cases, can occur with COTELLIC in combination with ZELBORAF and with ZELBORAF as a single agent.

• In Trial 1, photosensitivity was reported in 47% of patients receiving COTELLIC with ZELBORAF: 43% of patients with Grades 1 or 2 photosensitivity and the remaining 4% with Grade 3 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. Manage intolerable Grade ≥2 photosensitivity with dose modifications.  

Other Ophthalmologic Reactions

• Uveitis, blurry vision and photophobia can occur in patients treated with ZELBORAF.
• Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

Embryo-Fetal Toxicity

• Based on its mechanism of action and findings from animal reproduction studies, COTELLIC can cause fetal harm when administered to a pregnant woman. 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 COTELLIC and ZELBORAF and for 2 weeks after the final dose of COTELLIC or ZELBORAF (whichever is taken later).

Radiation Sensitization and Radiation Recall

• Radiation sensitization and recall, in some cases severe, have been reported in patients treated with radiation prior to, during, or subsequent to ZELBORAF. Fatal cases have been reported in patients with visceral organ involvement.
• Monitor patients closely when ZELBORAF is administered concomitantly or sequentially with radiation treatment.

Renal Failure

• Renal failure, including acute interstitial nephritis and acute tubular necrosis, can occur with ZELBORAF.
• Measure serum creatinine before initiation of ZELBORAF and periodically during treatment.

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 have also been reported.
• Events should be managed with dose reduction, treatment interruption, or treatment discontinuation.

USE IN SPECIFIC POPULATIONS: Lactation

Because of the potential for serious adverse reactions in a breastfed infant, including malignancy, severe dermatologic reactions, QT prolongation, hepatotoxicity, photosensitivity, and ophthalmologic toxicity from ZELBORAF, advise women not to breastfeed during treatment with COTELLIC and ZELBORAF and for 2 weeks after the final dose of COTELLIC or ZELBORAF (whichever is taken later).

DRUG INTERACTIONS

COTELLIC:

• Avoid concurrent use of strong or moderate CYP3A inhibitors.
• Avoid concurrent use of strong or moderate CYP3A inducers including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and St. John’s Wort.

ZELBORAF:

• Avoid coadministration with strong CYP3A4 inhibitors or strong inducers and replace these drugs with alternative drugs when possible.
• Avoid concomitant use with drugs having a narrow therapeutic window that are predominantly metabolized by CYP1A2.
• Avoid concurrent use of P-glycoprotein (P-gp) substrates known to have narrow therapeutic indices.

Most Common Adverse Reactions for COTELLIC

The most common (≥20%) adverse reactions with COTELLIC were diarrhea (60%), photosensitivity reaction (46%), nausea (41%), pyrexia (28%) and vomiting (24%). The most common (≥5%) Grade 3-4 laboratory abnormalities were increased GGT (21%), increased CPK (14%), hypophosphatemia (12%), increased ALT (11%), lymphopenia (10%), increased AST (8%), increased alkaline phosphatase (7%), and hyponatremia (6%).

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see both Full COTELLIC Prescribing Information and Full ZELBORAF Prescribing Information for additional Important Safety Information.