Cotellic Drug Information

Unresectable or Metastatic Melanoma COTELLIC ® is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.

Histiocytic Neoplasms

COTELLIC®, as a single agent, is indicated for the treatment of adult patients with histiocytic neoplasms.

Patient Selection for Treatment of Melanoma Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with COTELLIC with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

The recommended dosage regimen of COTELLIC is 60 mg (three 20 mg tablets) orally taken once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Take COTELLIC with or without food. If a dose of COTELLIC is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose.

Dose Modifications Concurrent CYP3A Inhibitors

Do not take strong or moderate CYP3A inhibitors while taking COTELLIC. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for patients who are taking COTELLIC 60 mg, reduce COTELLIC dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume previous dose of COTELLIC 60 mg.

Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of COTELLIC (40 or 20 mg daily). Adverse Reactions Review the Full Prescribing Information for vemurafenib for recommended dose modifications. Table 1.

Recommended Dose Reductions for COTELLIC Table 2. Recommended Dose Modifications for COTELLIC for Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Unresectable or Metastatic Melanoma The safety of COTELLIC was evaluated in Trial 1, a randomized (1:1), double-blind, active-controlled trial in previously untreated patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma. All patients received vemurafenib 9 -day treatment cycle until disease progression or unacceptable toxicity.

Patients with abnormal liver function tests, history of acute coronary syndrome within 6 months, evidence of Class II or greater congestive heart failure (New York Heart Association), active central nervous system lesions, or evidence of retinal pathology were excluded from Trial 1. The demographics and baseline tumor characteristics of patients enrolled in Trial 1 are summarized in Clinical Studies. In Trial 1, 15% of patients receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC.

Among the 247 patients receiving COTELLIC, adverse reactions led to dose interruption or reductions in 55%. The most common (≥20%) adverse reactions with COTELLIC were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting. Table 3.

Incidence of Adverse Drug Reactions Occurring in ≥10% (All Grades) of Unresectable or Metastatic Melanoma Patients Receiving COTELLIC with Vemurafenib and at a Higher Incidence ≥5% for All Grades or ≥2% for Grades 3–4 incidence in patients receiving COTELLIC with vemurafenib compared with patients receiving vemurafenib as a single agent than Patients Receiving Vemurafenib in Trial 1 0 The following clinically relevant adverse reactions (all grades) of COTELLIC were reported with <10% incidence in Trial 1: Respiratory, thoracic and mediastinal disorders: Pneumonitis Table 4. Incidence of Laboratory Abnormalities Occurring in ≥10% (All Grades) or ≥2% (Grades 3–4) of Patients with Unresectable or Metastatic Melanoma in Trial 1 All the percentages are based on the number of patients who had a baseline result and at least one on-study laboratory test. The laboratory results are available for a total of 233~244 patients for COTELLIC, and 232~243 for vemurafenib, except where indicated. 0 Histiocytic Neoplasms The safety of COTELLIC was evaluated in Trial 2, a single-center single-arm trial in patients with histiocytic neoplasms.

The median treatment duration was 10.7 months. Table 5 presents adverse reactions in at least 15% of patients reported with histiocytic neoplasms treated with COTELLIC. Table 6 presents laboratory abnormalities of grades ≥3 reported in patients with histiocytic neoplasms treated COTELLIC.

One patient discontinued due to worsening of underlying dyspnea and hypoxia; one patient discontinued due to retinal vascular disorder; one patient discontinued due to hyponatremia; and the other patient discontinued due to pneumonia. Table 6. Incidence of Grade ≥3 Laboratory Abnormalities Occurring in Patients with Histiocytic Neoplasms Treated with COTELLIC in Trial 2 All the percentages are based on the number of patients who had a baseline result and at least one on-study laboratory test. 5

Postmarketing Experience

The following adverse reactions have been identified during post approval use of COTELLIC. 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. Immune system disorders: Sarcoidosis

Effect of Strong or Moderate CYP3A Inhibitors on COTELLIC Coadministration of COTELLIC with itraconazole (a strong CYP3A4 inhibitor) increased cobimetinib systemic exposure by 6.7-fold. Avoid concurrent use of COTELLIC and strong or moderate CYP3A inhibitors. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors including certain antibiotics (e.g., erythromycin, ciprofloxacin) is unavoidable for patients who are taking COTELLIC 60 mg, reduce COTELLIC dose to 20 mg.

After discontinuation of a moderate CYP3A inhibitor, resume COTELLIC at the previous dose. Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of COTELLIC (40 or 20 mg daily).

Effect of Strong or Moderate CYP3A Inducers on COTELLIC Coadministration of COTELLIC with a strong CYP3A inducer may decrease cobimetinib systemic exposure by more than 80% and reduce its efficacy. John's Wort.

Pregnancy Risk Summary Based on findings from animal reproduction studies and its mechanism of action, COTELLIC can cause fetal harm when administered to a pregnant woman. There are no available data on the use of COTELLIC during pregnancy. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg.

Advise pregnant women of the potential risk to a fetus. 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 Administration of cobimetinib to pregnant rats during the period of organogenesis resulted in increased post-implantation loss, including total litter loss, at exposures (AUC) of 0.9–1.4 times those in humans at the recommended dose of 60 mg.

Post-implantation loss was primarily due to early resorptions. Fetal malformations of the great vessels and skull (eye sockets) occurred at the same exposures.

Pediatric Use The safety and effectiveness of COTELLIC have not been established in pediatric patients. The safety and effectiveness of COTELLIC were assessed, but not established, in a multi-center, open-label, dose-escalation study in 55 pediatric patients aged 2 to 17 years with solid tumors. No new safety events were observed in pediatric patients in this trial.

Exposure in pediatric patients who received COTELLIC at the maximum tolerated dosage were lower than those previously observed in adults who received the approved recommended dosage. Juvenile Animal Data In a 4-week juvenile rat toxicology study, daily oral doses of 3 mg/kg (approximately 0.13–0.5 times the adult human AUC at the recommended dose of 60 mg) between postnatal Days 10–17 (approximately equivalent to ages 1–2 years in humans) were associated with mortality, the cause of which was not defined.

There is no information on overdosage of COTELLIC.