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.

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 960 mg twice daily on Days 1–28 and received either COTELLIC 60 mg once daily (n=247) or placebo (n=246) on Days 1–21 of each 28-day treatment cycle until disease progression or unacceptable toxicity. In the COTELLIC plus vemurafenib arm, 66% percent of patients were exposed for greater than 6 months and 24% of patients were exposed for greater than 1 year.

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. The most common adverse reactions resulting in permanent discontinuation were liver laboratory abnormalities defined as increased aspartate aminotransferase (AST) (2.4%), increased gamma glutamyltransferase (GGT) (1.6%) and increased alanine aminotransferase (ALT) (1.6%); rash (1.6%); pyrexia (1.2%); and retinal detachment (2%). Among the 247 patients receiving COTELLIC, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of COTELLIC were rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase (CPK) (4.9%). 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 Adverse reactions COTELLIC + Vemurafenib (n=247) Placebo + Vemurafenib (n=246) All Grades NCI CTCAE, v4.0. (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) GASTROINTESTINAL DISORDERS Diarrhea 60 6 31 1 Nausea 41 1 25 1 Vomiting 24 1 13 1 Stomatitis Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation 14 1 8 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Photosensitivity reaction Includes solar dermatitis, sunburn, photosensitivity reaction 46 4 35 0 Acneiform dermatitis 16 2 11 1 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Pyrexia 28 2 23 0 Chills 10 0 5 0 VASCULAR DISORDERS Hypertension 15 4 8 2 Hemorrhage Includes hemorrhage, rectal hemorrhage, melena, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, hematochezia, gingival bleeding, metrorrhagia, uterine hemorrhage, hemorrhagic ovarian cyst, menometrorrhagia, menorrhagia, vaginal hemorrhage, hemoptysis, pulmonary, cerebral, subarachnoid hemorrhage, subgaleal hematoma, hematuria, epistaxis, contusion, traumatic hematoma, ecchymosis, purpura, nail bed bleeding, ocular, eye, conjunctival, and retinal hemorrhage 13 1 7 <1 EYE DISORDERS Vision impaired Includes vision blurred, visual acuity reduced, visual impairment 15 <1 4 0 Chorioretinopathy 13 <1 <1 0 Retinal detachment Includes retinal detachment, detachment of retinal pigment epithelium, detachment of macular retinal pigment epithelium 12 2 <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. Laboratory COTELLIC + Vemurafenib Placebo + Vemurafenib All Grades NCI CTCAE v4.0. Grades 3–4 All Grades Grades 3–4 % % % % AST - aspartate aminotransferase, ALT - alanine aminotransferase, GGT - gamma-glutamyltransferase Chemistry Increased creatinine 100 3.3 100

Increased

AST 73 8 44

Increased

ALT 68 11 55 5 Increased alkaline phosphatase 71 7 56

Increased creatine phosphokinase Increase creatine phosphokinase, n=213 for

COTELLIC and 217 for vemurafenib. 79 14 16

Hypophosphatemia 68 12 38 6 Increased

GGT 65 21 61 17 Hyponatremia 38 6 33

Hypoalbuminemia 42 0.8 20 0.4 Hypokalemia 25 4.5 17 3.3 Hyperkalemia 26

2.9 15

Hypocalcemia 24 0.4 10 1.7 Hematology Anemia 69 2.5 57 3.3 Lymphopenia

Lymphopenia, n=185 for COTELLIC, and 181 for vemurafenib. 73 10 55 8 Thrombocytopenia 18 0 10 0 Histiocytic Neoplasms The safety of COTELLIC was evaluated in Trial 2, a single-center single-arm trial in patients with histiocytic neoplasms . In Trial 2, 26 patients with histiocytic neoplasms received COTELLIC 60 mg once daily for 21 days on, then 7 days off, in a 28-day treatment cycle. 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. In Trial 2, 4 patients (15%) receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of 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 5 Incidence of Adverse Reactions Reported Occurring in ≥15% (All Grades) or Any Percentage (Grade ≥3) in Patients with Histiocytic Neoplasms Treated with COTELLIC in Trial 2 Body Systems Adverse reactions All Grades NCI CTCAE v4.0. (%) (n=26) Grades ≥3 (%) (n=26) GASTROINTESTINAL DISORDERS Diarrhea 62 8 Nausea 46 0 Dyspepsia Gastritis, and gastroesophageal reflux disease. 27 0 Vomiting 27 0 Dry Mouth 15 0 Oral pain Oral dysesthesia and oropharyngeal pain. 15 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Malaise 42 0 Edema Facial edema, edema genital, edema peripheral, periorbital edema, and lymphoedema. 42 4 Pain 15 0 INFECTIONS AND INFESTATIONS Infections Influenza like illness, mucosal infection, paronychia, pharyngitis, pneumonia, bronchitis, sepsis, sinusitis, skin infection, tooth infection, upper respiratory tract infection., and urinary tract infection. 62 23 Urinary tract infection 23 8 Pulmonary infections Pneumonia and bronchitis. 19 12 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Fall 15 4 INVESTIGATIONS Decreased Ejection Fraction 19 12 RENAL AND URINARY Acute kidney injury 15 12 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Dyspnea 27 15 Cough 15 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Acneiform dermatitis 65 0 Dry skin 31 0 Maculo-papular rash 31 0 Pruritus 31 4 VASCULAR DISORDERS Hemorrhage Epistaxis, contusion, purpura, hematoma, and rectal hemorrhage. 19 0 Hypertension 15 4 The following clinically relevant adverse reactions (all grades) of COTELLIC were reported with <15% incidence in Trial 2: Eye disorders : Vision blurred (12%), retinal vascular disorder (4%) and retinopathy (4%). Gastrointestinal disorders : Stomatitis (12%) Nervous system disorders : Headache (12%) Respiratory, thoracic, and mediastinal disorders : Hypoxia (12%), pulmonary edema (4%), and respiratory failure (8%). 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. Grades 3–4 NCI CTCAE v4.0 % AST - aspartate aminotransferase, ALT - alanine aminotransferase Chemistry Increased blood creatine phosphokinase 27 Hyponatremia 18 Hypokalemia 12 Increased blood creatinine 9 Increased AST 9 Hypocalcemia 9 Increased ALT 5 Hematology Lymphopenia 27 Leukopenia 9 Anemia 8 Neutropenia 5

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. Avoid concurrent use of COTELLIC and strong or moderate CYP3A inducers including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and St. 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.