Cotellic: Indications, Dosage, Precautions, Adverse Effects
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Cotellic - Product Information

Manufacture: Roche
Country: Canada
Condition: Melanoma, Metastatic
Class: Multikinase inhibitors
Form: Tablets
Ingredients: Cobimetinib Fumarate, Croscarmellose Sodium, Lactose Monohydrate, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol 3350 (macrogol 3350), Polyvinyl Alcohol, Talc, and Titanium Dioxide.

cobimetinib tablets

Summary Product Information

Route of
Administration
Dosage Form ⁄
Strength
Clinically Relevant Non–edicinal
Ingredients
oral tablet⁄20 mg
cobimetinib (as
cobimetinib
fumarate)
lactose monohydrate
For a complete listing see Dosage Forms,
Composition and Packaging section.

Indications and Clinical Use

COTELLIC(cobimetinib) is indicated for use in combination with vemurafenib for thetreatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Prior to initiation of treatment with COTELLIC in combination with vemurafenib, patientsmust have BRAF V600 mutation–positive melanoma tumour status confirmed by a validatedtest.

Effectiveness of COTELLIC in combination with vemurafenib is based on progression–freesurvival (PFS) and objective response rate (ORR) results. Prolongation of overall survival(OS) has not been demonstrated (see PART II, CLINICAL TRIALS).

Clinical data supporting the effectiveness of COTELLIC in combination with vemurafenib inpatients with a BRAF V600K mutation are limited (see PART II, CLINICAL TRIALS).There are no clinical data for other less common BRAF V600 mutations.

There are no clinical data to support the effectiveness of COTELLIC in combination withvemurafenib in patients with non–cutaneous malignant melanoma.

As COTELLIC is used in combination with vemurafenib, refer also to the ZELBORAF (vemurafenib) Product Monograph.

Pediatrics (<18 Years of Age)

The safety and efficacy of COTELLIC in children and adolescents have not been established (seeSpecial Populations, Pediatrics below

Contraindications

COTELLIC (cobimetinib) is contraindicated in:

  • Patients with known hypersensitivity to cobimetinib or any of the excipients. For acomplete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

Warnings and Precautions

Serious Warnings and Precautions

The following are clinically important adverse drug reactions, some of which were serious orlife-threatening, that were identified in clinical trials conducted with COTELLIC incombination with vemurafenib.

  • Left ventricular dysfunction (see Cardiovascular section below)
  • Hemorrhage, including major hemorrhage (see Hematologic section below)
  • Serous Retinopathy and Retinal Vein Occlusion (see Ophthalmologic section below)

COTELLIC has not been studied in patients with moderate and severe hepatic impairment(see Special Populations, Hepatic Impairment below).

COTELLIC should not be used concomitantly with a strong or moderate CYP3A inhibitor.(see Drug-Drug Interactions below, and DRUG INTERACTIONS).

COTELLIC in combination with vemurafenib should be prescribed and supervised by aqualified physician experienced in the use of anti-cancer agents.

General

COTELLIC should not be used in patients with wild–type BRAF melanoma. COTELLIC shouldnot be used in patients with unresectable or metastatic melanoma where the BRAF mutationalstatus is not known.

There are no clinical data to support the effectiveness of COTELLIC for the treatment of brainmetastases in patients with a BRAF V600 mutation–positive melanoma. Patients with active CNSlesions were excluded from the Phase III trial, and <1% of enrolled patients had previouslytreated brain metastases. A tissue distribution study conducted in rats demonstrated low levels ofcobimetinib in CNS tissues protected by the blood:brain barrier. COTELLIC is notrecommended for patients with BRAF V600 mutation–positive melanoma who have activeuntreated brain metastases (see DETAILED PHARMACOLOGY, Safety Pharmacology).

Drug–Drug Interactions

Concomitant use of COTELLIC and drugs that strongly or moderately inhibit CYP3A canincrease cobimetinib exposure. Strong or moderate CYP3A inhibitors should not be used whiletaking COTELLIC (see DRUG INTERACTIONS). If concomitant short–term use of a moderateCYP3A inhibitor is unavoidable for patients who are taking COTELLIC 60 mg, reduceCOTELLIC dose to 20 mg for the duration of inhibitor use. Carefully monitor patients for safety.After discontinuation of a moderate CYP3A inhibitor, resume COTELLIC at the previous dose.For patients who are taking a reduced dose of COTELLIC (40 or 20 mg daily), do not usemoderate CYP3A inhibitors (see DOSAGE AND ADMINISTRATION).

Carcinogenesis and Mutagenesis

Carcinogenicity studies have not been performed with cobimetinib (see TOXICOLOGY). In thePhase III trial, the incidence of second primary melanoma was 0.4% in the COTELLIC incombination with vemurafenib arm versus 2.6% in the placebo in combination with vemurafenibarm. In the Phase III trial, the incidence of basal cell carcinoma was 4% in the COTELLIC incombination with vemurafenib arm versus 2% in the placebo in combination with vemurafenib arm.

Cardiovascular

Patients with left ventricular ejection fraction (LVEF) either below institutional lower limit ofnormal or below 50%, symptomatic congestive heart failure of NYHA class 2 or higher, QTcF>450 msec, or uncontrolled hypertension ≥ Grade 2 were excluded from the Phase III study (seeADVERSE REACTIONS).

Concurrent cardiac conditions, medications that affect heart rate or ECG parameters, and needfor monitoring heart rate or ECGs should be considered when prescribing COTELLIC asclinically indicated.

Left Ventricular Dysfunction

The safety of COTELLIC has not been established in patients with decreased LVEF.In the Phase III study, all patients underwent evaluation of LVEF, either by echocardiography ormultiple gated ejection acquisition scan, at regular intervals during treatment. Decrease in LVEFfrom baseline has been reported in patients receiving COTELLIC (see ADVERSEREACTIONS). Reductions in LVEF of Grade 2 or higher severity were reported in 7% ofpatients in the COTELLIC in combination with vemurafenib arm versus 3% of patients in theplacebo in combination with vemurafenib arm. In the COTELLIC in combination withvemurafenib arm, median time to initial onset of decreased LVEF (all grades) was 4 months(range 1–7 months). Resolution was documented in 89% of patients who experienced an event ofdecreased LVEF with a median time to resolution of 2 (0–4) months.

One patient in the Phase Ib study treated with COTELLIC in combination with vemurafenib atthe therapeutic dose developed Grade 3 congestive cardiomyopathy. COTELLIC waspermanently discontinued with documented improvement in LVEF from 25% to 36%approximately one month after the event.

COTELLIC is not recommended in patients with decreased LVEF (<50% or below theinstitutional lower limit of normal) at baseline. COTELLIC should be used with caution inpatients with conditions that could impair left ventricular function (see Monitoring andLaboratory Tests below). Decrease in LVEF from baseline can be managed using treatment interruption, dose reduction or with treatment discontinuation (see DOSAGE ANDADMINISTRATION).

Hypertension

In the Phase III study, hypertension was reported in 14% of patients receiving COTELLIC incombination with vemurafenib and in 8% of patients receiving placebo in combination withvemurafenib. Hypertension was observed at similar frequencies between patients with andwithout pre–existing hypertension. Grade 3 hypertension events were reported in 4% of patientstreated with COTELLIC in combination with vemurafenib compared with 3% of patients whoreceived placebo in combination with vemurafenib. A greater proportion of patients in theCOTELLIC in combination with vemurafenib arm compared to the placebo plus vemurafenibarm received treatment for hypertension (10% versus 5%, respectively) (see Monitoring andLaboratory Tests below)

Hematologic

Hemorrhage

Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area ororgan, can occur during treatment with COTELLIC.

In the Phase III trial, Grade 3–5 hemorrhagic events were experienced by 1.6 % in theCOTELLIC in combination with vemurafenib arm and 0.4% in the placebo in combination withvemurafenib arm. Bleeding events were reported more frequently in the COTELLIC incombination with vemurafenib arm than in the placebo in combination with vemurafenib arm (alltypes and grades 10% vs. 6%). Higher frequencies in the COTELLIC in combination withvemurafenib arm were observed for cerebral hemorrhage (1% vs. 0%), gastrointestinal tracthemorrhage (3% vs. <1%), reproductive system hemorrhage (2% vs.<1%), and hematuria (2%vs. 1%) (see Monitoring and Laboratory Tests below).

Hemorrhage can be managed using treatment interruption, dose reduction or with treatmentdiscontinuation (see DOSAGE AND ADMINISTRATION).

Hepatic

Hepatotoxicity can occur with COTELLIC. Liver laboratory test abnormalities Grade≥3 werereported more frequently in the Phase III study in patients who received COTELLIC incombination with vemurafenib than in patients who received placebo in combination withvemurafenib (20% vs. 15%, respectively) (see ADVERSE REACTIONS). One patient (0.4%)treated with COTELLIC in combination with vemurafenib versus none treated with placebo plusvemurafenib, developed concurrent elevations in alanine aminotransferase (ALT)>3 times theupper limit of normal (ULN) and bilirubin > 2 X ULN without evidence of cholestasis(significantly elevated serum alkaline phosphatase (ALP)). These events resolved withdiscontinuation of both drugs (see Monitoring and Laboratory Tests below).

Liver laboratory test abnormalities Grade ≥ 3 can be managed using treatment interruption, dose reduction or with treatment discontinuation (see DOSAGE AND ADMINISTRATION).

Immune

Grade 3 hypersensitivity events were reported in 3 patients (1.2%) in the COTELLIC incombination with vemurafenib arm compared with no such events in the placebo plusvemurafenib arm; all events required hospitalization and treatment with steroids.

Musculoskeletal and Connective Tissue Disorders

Serum Creatine Phosphokinase (CPK) Increased and Rhabdomyolysis

MEK inhibitors, including cobimetinib, have been associated with elevated CPK levels.Rhabdomyolysis may occur with COTELLIC.

In the Phase III trial, increases in serum CPK levels were observed with a higher frequency in theCOTELLIC in combination with vemurafenib compared with the placebo in combination withvemurafenib arm (all grades: 30% vs. 3%, Grade 3–4: 10% vs. <1%). The median time to firstincidence of Grade 3– CPK elevations was 0.5 (0 to 4) months in patients in the COTELLIC incombination with vemurafenib arm; the median time to complete resolution was 0.5 (0 to 11)months.

Elevation of serum CPK of more than 10 times the baseline value with a concurrent increase inserum creatinine of 1.5 times or greater compared to baseline occurred in 2.8% of patients in theCOTELLIC plus vemurafenib arm and in 0.4% of patients in the placebo plus vemurafenib arm.One event of rhabdomyolysis, with concurrent increases in blood CPK, was reported in eachtreatment arm (Grade 4 in the COTELLIC in combination with vemurafenib arm and Grade 3 inthe placebo in combination with vemurafenib arm) (see Monitoring and Laboratory Testsbelow).

Dose modification may be required depending on severity of symptoms and grade of CPKelevation (see DOSAGE AND ADMINISTRATION).

Ophthalmologic

Patients who have a history of or evidence of retinal pathology on ophthalmologic examinationthat is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion(RVO), or neovascular macular degeneration have not been studied.

Retinal Vein Occlusion

RVO developed in one patient (0.4%) in each arm of the Phase III study. The patient whodeveloped RVO while on treatment with COTELLIC in combination with vemurafenibexperienced blurred vision and was diagnosed with retinal ischemia. The event resolved afterinterruption of COTELLIC plus vemurafenib and treatment with both drugs was thenpermanently discontinued. Consider risk factors for RVO, including uncontrolled hypertension,diabetes, hypercholesterolemia, or glaucoma when prescribing COTELLIC

COTELLIC is not recommended in patients with a history of RVO. If retinal vein occlusion isdiagnosed, COTELLIC treatment should be permanently discontinued (see Monitoring andLaboratory Tests below; DOSAGE AND ADMINISTRATION).

Serous Retinopathy

Serous retinopathy (fluid accumulation within the layers of the retina) has been observed inpatients treated with MEK–nhibitors, including COTELLIC (see ADVERSE REACTIONS). Inthe Phase III study, serous retinopathy developed in 24% of patients in the COTELLIC incombination with vemurafenib arm compared with 2% of patients in the placebo in combinationwith vemurafenib arm. The majority of events were reported as chorioretinopathy or retinaldetachment. In the COTELLIC in combination with vemurafenib arm, the majority of serousretinopathy events were asymptomatic (52% of events reported were Grade 1). 11% of patientstreated with COTELLIC in combination with vemurafenib experienced symptomatic (i.e.≥Grade 2) serous retinopathy events.

In the COTELLIC in combination with vemurafenib arm, for serous retinopathy events of allgrades, median time to initial onset was 1 month (range 0–9 months), and median time todocumented resolution was 6 months. Most symptomatic events were resolved, or improved toasymptomatic Grade 1, within a few months following dose interruption or reduction.Serous retinopathy can be managed with treatment interruption, dose reduction or with treatmentdiscontinuation (see Monitoring and Laboratory Tests below; DOSAGE ANDADMINISTRATION).

Sexual Function⁄Reproduction

There is no clinical information on the effect of COTELLIC on human fertility. No dedicatedfertility studies have been performed with cobimetinib in animals; however, effects onreproductive tissues observed in general toxicology studies conducted in animals suggest thatthere is potential for cobimetinib to impair fertility.

Based on findings in animals, COTELLIC may reduce fertility in females and males ofreproductive potential (see TOXICOLOGY).

Skin

Photosensitivity

Severe photosensitivity has been reported in association with COTELLIC when used withvemurafenib.

In the Phase III trial, Grade ≥ 3 events occurred in 3% of patients in the COTELLIC incombination with vemurafenib arm versus no patients in the placebo in combination withvemurafenib arm (see ADVERSE REACTIONS). There were no apparent trends in the time ofonset of Grade ≥ 3 events. Resolution of these events was documented for 6 of 8 (75%) patients.

During treatment, all patients should be advised to avoid sun exposure, and when outdoors towear protective clothing and to use a broad spectrum UVA⁄UVB sun screen and lip balm (SPF ≥30). Grade 2 (intolerable) or Grade ≥ 3 photosensitivity can be managed with treatmentinterruption, dose reduction or with treatment discontinuation (see Monitoring and LaboratoryTests below; DOSAGE AND ADMINISTRATION).

Rash

Severe rash has been reported in association with COTELLIC.

In the Phase III study, Grade 3 or 4 rash events were reported in approximately 16% of patientsin both treatment arms. Grade 3 or 4 dermatitis acneiform events were reported by 2.4% vs 1.7%of patients receiving COTELLIC in combination with vemurafenib vs placebo in combinationwith vemurafenib, respectively. Hospitalization for rash was required in 2.8% vs 1.7% of therespective arms. The median time to onset of Grade 3 or 4 rash events in the COTELLIC incombination with vemurafenib arm was 11 days; 93% of patients who reported a rash eventexperienced complete resolution with a median time to resolution of approximately 20 days.

Grade ≥ 3 rash can be managed using treatment interruption, dose reduction or with treatmentdiscontinuation (see Monitoring and Laboratory Tests below; DOSAGE ANDADMINISTRATION).

Ability to Drive and Use Machines

No studies on the effects on the ability to drive and to use machines have been performed.

Visual disturbances have been reported in some patients treated with COTELLIC during clinicaltrials (see Ophthalmologic and ADVERSE REACTIONS: Clinical Trial Adverse DrugReactions). Patients should be advised not to drive or operate machines if they experience visualdisturbances or any other adverse effects that may affect their ability.

Special Populations

Pregnant Women

COTELLIC is not recommended during pregnancy. There are no dataregarding the use of COTELLIC in pregnant women. Based on its mechanism of action andfindings from nonclinical reproduction studies, COTELLIC may cause fetal harm whenadministered to a pregnant woman.When administered to pregnant rats, cobimetinib causedembryolethality and fetal malformations of the great vessels and skull at clinically relevantexposures (see TOXICOLOGY). Females of childbearing potential should use two effectiveforms of contraception during treatment with COTELLIC and for at least three months followingtreatment discontinuation. If the patient becomes pregnant while taking COTELLIC, the patientshould be informed of the potential hazard to the fetus.

Nursing Women

It is not known whether COTELLIC is excreted in human breast milk.Because many drugs are excreted in human breast milk, a risk to the nursing infant cannot beexcluded. A decision should be made whether to discontinue nursing or to discontinueCOTELLIC therapy, taking into account the benefit of nursing for the infant and the benefit ofCOTELLIC for the mother.

Pediatrics (<18 Years of Age)

The safety and efficacy of COTELLIC in children andadolescents have not been established. In a nonclinical toxicology study, at exposures lower thanthose reported for adult humans administered the recommended dose of 60 mg, mortality wasseen in juvenile rats approximately equivalent in age to 1–2 year old humans, the cause of whichwas not defined (see ACTION AND CLINICAL PHARMACOLOGY; TOXICOLOGY).

Geriatrics (≥ 65 Years of Age)

Of the 254 patients with unresectable or metastatic melanomatreated with COTELLIC in combination with vemurafenib in the Phase III study, approximately74% were < 65, 17% were 65–74, and 8% were ≥ 75 years of age. Compared with patients < 65 years old, more patients ≥ 65 years old experienced AEs that led to discontinuation of thetreatment regimen (22% versus 10%) and to dose modification of the treatment regimen (57%versus 37%). Increased sensitivity of some geriatric patients cannot be ruled out (see ADVERSEREACTIONS).

Based on the population pharmacokinetic analysis, clearance of cobimetinib was lower in olderpatients, however this was not considered clinically significant (see ACTION AND CLINICALPHARMACOLOGY).

Gender

Based on the population pharmacokinetic analysis, gender does not have a clinically important effect on cobimetinib exposure (see ACTION AND CLINICAL PHARMACOLOGY).

Renal Impairment

No formal pharmacokinetic study of COTELLIC has been conducted inpatients with renal impairment. Based on the population pharmacokinetic analysis, no doseadjustment is recommended in patients with mild or moderate renal impairment. The safety andefficacy of COTELLIC have not been established in patients with severe renal impairment (seeACTION AND CLINICAL PHARMACOLOGY).

Hepatic Impairment

The safety and efficacy of COTELLIC in patients with hepatic impairment have not beenstudied. No pharmacokinetic studies of cobimetinib were conducted in patients with hepaticimpairment. As cobimetinib is metabolized and eliminated via the liver, patients with hepaticimpairment may have increased exposure and increased toxicities. No dosing recommendationshave been established for COTELLIC in patients with moderate to severe hepatic impairment.

Monitoring and Laboratory Tests

Prior to initiation of treatment with COTELLIC in combination with vemurafenib, patients musthave BRAF V600 mutation–positive melanoma tumour status confirmed by a validated test

Left ventricular ejection fraction should be evaluated before initiation of treatment to establishbaseline values, then after the first month of treatment and at least every 3 months or as clinicallyindicated until treatment discontinuation (see DOSAGE AND ADMINISTRATION). Allpatients restarting treatment with a dose reduction of COTELLIC should have LVEFmeasurements taken at approximately 2 weeks, 4 weeks, 10 weeks and 16 weeks, and then asclinically indicated.

Monitor ECG before initiating treatment and routinely during treatment with COTELLIC, whenadministered with vemurafenib (see also ACTION AND CLINICAL PHARMACOLOGY).

Blood pressure should be monitored at regular intervals during treatment, with control ofhypertension as clinically indicated.

Ophthalmological evaluation, including retinal evaluation, should be performed before initiationof treatment and at regular intervals during treatment, if clinically indicated, and at any time thata patient reports new or worsening visual disturbances (see DOSAGE AND ADMINISTRATION).

Dermatologic evaluation should be performed before initiation of treatment and at regularintervals during treatment (see DOSAGE AND ADMINISTRATION). Patients should beinstructed to inform their healthcare professionals of the occurrence of any skin changes.

Dermatologic monitoring should continue for 6 months following discontinuation of treatment.

Patients should be assessed for signs and symptoms of bleeding events during treatment.Complete blood counts should be determined before initiation of treatment and periodicallyduring treatment, or as clinically indicated (see ADVERSE REACTIONS; DOSAGE ANDADMINISTRATION).

Monitor for liver value abnormalities by liver laboratory tests before initiation of combinationtreatment and monthly during treatment, or more frequently as clinically indicated (seeADVERSE REACTIONS; DOSAGE AND ADMINISTRATION).

Serum CPK and creatinine levels should be evaluated before initiation of treatment, periodicallyduring treatment, and as clinically indicated. For Grade ≥ 3 CPK elevations, evaluation ofcausality should include an assessment for rhabdomyolysis and other causes, including cardiacinjury (see ADVERSE REACTIONS; DOSAGE AND ADMINISTRATION)

Assess serum chemistry before initiation of treatment and periodically during treatment perinstitution guidelines or as clinically indicated (see ADVERSE REACTIONS)

Adverse Reactions

Because clinical trials are conducted under very specific conditions the adverse reactionrates observed in the clinical trials may not reflect the rates observed in practice andshould not be compared to the rates in the clinical trials of another drug. Adverse drugreaction information from clinical trials is useful for identifying drug–elated adverseevents and for approximating rates.

Adverse Drug Reaction Overview

Study G028141

The safety of COTELLIC in combination with vemurafenib has been evaluated in a safetypopulation of 254 patients with previously untreated BRAF V600 mutated unresectable locallyadvanced or metastatic melanoma in the Phase III study GO28141 comparing COTELLIC incombination with vemurafenib to placebo in combination with vemurafenib. For patients in theCOTELLIC in combination with vemurafenib arm, the median duration of COTELLIC exposurewas 179 days and the median duration of vemurafenib exposure was 183 days.

The frequency of adverse events (AEs) was similar for both arms (approximately 98%). Themost common AEs (≥ 20%) that occurred with greater frequency in the COTELLIC incombination with vemurafenib arm were diarrhea, rash, nausea, blood CPK increased,photosensitivity reaction, pyrexia, ALT increased, AST increased, and vomiting. The mostcommon AEs (≥ 20%) that occurred with greater frequency in the placebo in combination withvemurafenib arm compared with the COTELLIC in combination with vemurafenib arm,respectively, were arthralgia (40% vs 33%), alopecia (29% vs 14%) and hyperkeratosis (28% vs10%). Fatigue was observed at similar frequencies in both arms.

The median time to onset of first Grade ≥ 3 AEs was 0.5 months in the COTELLIC incombination with vemurafenib arm vs. 0.8 months in the placebo in combination withvemurafenib arm.

Serious adverse events (SAEs) were reported in 30% of patients treated with COTELLIC incombination with vemurafenib compared with 25% of patients treated with placebo incombination with vemurafenib. SAEs reported in ≥ 1% of patients treated with COTELLIC incombination with vemurafenib included pyrexia, dehydration, rash, rash maculo–papular, ALTincreased, AST increased, atrial fibrillation, chorioretinopathy, diarrhea, hypersensitivity, andretinal detachment.

Adverse events leading to permanent discontinuation of the combination were documented in10.6% of patients receiving COTELLIC in combination with vemurafenib compared with7.1%% of patients receiving placebo in combination with vemurafenib. In patients treatedwith COTELLIC in combination with vemurafenib, the most common AEs resulting inpermanent discontinuation of the combination were increased AST (2.0%), increased GGT(1.2%), increased ALT (1.6%), rash (1.6%), pyrexia (1.2%), and retinal detachment (1.2%).

Adverse events led to dose interruption or reduction of the combination in 42.1% of patientstreated with COTELLIC in combination with vemurafenib versus 32.6% treated with placebo incombination with vemurafenib. The most common reasons cited for dose interruption orreduction of the combination of COTELLIC and vemurafenib versus placebo and vemurafenib,respectively, were diarrhea (7.9% vs 2.5%), pyrexia (5.9% vs 2.9%), vomiting (5.1% vs4.6%), chorioretinopathy (5.1% vs 0%), rash maculo–papular (4.7% vs 4.2%), and rash (4.3% vs5%).

Geriatrics (≥ 65 Years of Age)

Adverse events for which patients ≥ 65 were more likely to havedose modification in the COTELLIC in combination with vemurafenib arm were reflective ofthose which resulted in dose modification in the total study population. However, there was ahigher incidence of dose modification for adverse events overall in patients ≥ 65 relative to those<65, and for specific AEs including diarrhea, vomiting, asthenia, pyrexia, dehydration, ASTincreased, chorioretinopathy, and retinal detachment.

Clinical Trial Adverse Drug Reactions

The table below summarizes the adverse drug reacti1ns (ADRs) occurring in ≥ 5% higherincidence (All Grades) or in ≥ 2% higher incidence (Grades 3–5) of patients treated withCOTELLIC in combination with vemurafenib in the Phase III study. The following categoriesof frequency have been used: very common (≥1⁄10), common (≥1⁄100 to <1⁄10), uncommon(≥1⁄1,000 to <1⁄100), rare (≥1⁄10,000 to <1⁄1000), very rare (<1⁄10,000).

Table 1 Adverse Reactions of All Grades (Incidence ≥ 5% over the control arm) orGrade 3–4 (Incidence ≥ 2% over the control arm)
ADRs Phase III study: GO28141 Frequencyaa
(All Grades)
COTELLIC + vemurafenib
(n = 254)
Placebo + vemurafenib
(n = 239)
All grades
(%)
Grade 3–4
(%)
All grades
(%)
Grade 3–4
(%)
Eye Disorders
Chorioretinopathy 12 <1 <1 very common
Vision Blurred 9 2 common
Retinal Detachment 8 2 common
Gastrointestinal
disorders
Diarrhea 57 6 28 very common
Nausea 39 1 24 1 very common
Vomiting 21 1 12 1 very common
General disorders and
administration site
conditions
Pyrexia 26 2 22 very common
Investigations
Decreased Ejection 7 1 3 1 common
Fraction
Metabolism and
nutrition disorders
Dehydration 4 2 1 common
Hypophosphatemia 4 2 <1 common
Hyponatremia 4 2 <1 <1 common
Neoplasms benign,
malignant and
unspecified
Basal Cell Carcinoma 4 4 2 2 common
Skin and subcutaneous
tissue disorders
Photosensitivityb 41 3 31 very common
Vascular Disorders
Hypertension 14 4 8 3 very common

aBased on the Phase III study GO28141 adverse events of all grades

bCombined figure includes reports of photosensitivity reaction, sunburn, solar dermatitis, actinic elastosis

The following ADRs (all grades) were reported with <5% greater incidence in the COTELLICarm than the control arm in study GO28141:

Cardiac disorders: Atrial fibrillation (3% in COTELLIC plus vemurafenib arm vs. <1% in theplacebo plus vemurafenib arm).

Eye Disorders

Visual impairment (3% in COTELLIC plus vemurafenib arm vs. 0% in theplacebo plus vemurafenib arm)

Immune System Disorders

Hypersensitivity (2% in COTELLIC plus vemurafenib arm vs. <1%in the placebo plus vemurafenib arm)

Respiratory, Thoracic and Mediastinal Disorders

Pneumonitis (1% in COTELLIC plusZELBORAF arm vs. <1% in the placebo plus ZELBORAF arm)

Skin and Subcutaneous Tissue Disorders

Rash (39% in COTELLIC plus vemurafenib arm vs.36% in the placebo plus vemurafenib arm), rash maculo–papular (15% vs. 15%, respectively),dermatitis acneiform (13% vs. 9%)

Further Information on Selected Adverse Reactions

Cutaneous Squamous Cell Carcinoma, Keratoacanthoma and Hyperkeratosis

Cutaneous squamous cell carcinoma has been reported with a lower frequency in the COTELLICplus vemurafenib vs. placebo plus vemurafenib arm (all grades: 3% vs. 11%). Keratoacanthomahas been reported with a lower frequency in the COTELLIC plus vemurafenib vs. placebo plusvemurafenib arm (all grades: 1% vs. 8%). Hyperkeratosis has been reported with a lowerfrequency in the COTELLIC plus vemurafenib vs. placebo plus vemurafenib arm (all grades:10% vs. 28%)

Abnormal Hematologic and Clinical Chemistry Findings

Table 2 Incidence of Laboratory Abnormalities Occurring in ≥ 10% (All Grades) or≥ 2% (Grades 3–4) of Patients in Study GO28141
Phase III Study: GO28141
Laboratory Test COTELLIC + vemurafenib Placebo + vemurafenib
All Gradesa
(%)
Grades 3–4a
(%)
All Gradesa
(%)
Grades 3–4a
(%)
Chemistry
Increased creatinine 99 3 98 1
Increased AST 69 7 42 2
Increased ALT 66 10 53 5
Increased alkaline phosphatase 69 7 54 3
Increased creatine phosphokinase 65 10 13 <1
Hypophosphatemia 61 10 35 6
Increased GGT 60 19 59 17
Hyponatremia 36 6 31 2
Hypokalemia 24 5 16 3
Hypocalcemia 24 1 13 1
Hematology
Anemia 67 2 56 3
Lymphopenia b 65 9 48 8
Thrombocytopenia 16 0 10 0

AST – aspartate aminotransferase, ALT – alanine aminotransferase, GGT – gamma–glutamyltransferase

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 248–252 patients for COTELLIC, and 235–237 for vemurafenib, except whereindicated.

aNCI CTCAE v4.0

bLymphopenia, n=207 for COTELLIC, and 195 for vemurafenib

Drug Interactions

Overview

Cobimetinib is a substrate of CYP3A. A drug interaction was observed when cobimetinib wasadministered with a strong CYP3A inhibitor. Related findings and precautions are discussedfurther below.

Drug–Drug Interactions

Agents That May Increase Cobimetinib Plasma Concentrations
CYP3A Inhibitors

Cobimetinib is metabolized by CYP3A. Co–administration of itraconazole (a strong CYP3Ainhibitor) 200 mg once daily for 14 days with a single 10 mg cobimetinib dose administered onDay 4 increased mean cobimetinib AUC (90% CI) by 6.7–fold (5.6, 8.0) and mean Cmax (90%CI) by 3.2–fold (2.7, 3.7). Strong CYP3A inhibitors including, but not limited to: clarithromycin,itraconazole, ketoconazole, lopinavir, posaconazole, ritonavir, and voriconazole should not beused concomitantly with COTELLIC.

Co–administration of cobimetinib with a moderate CYP3A inhibitor has not been assessed in aclinical drug interaction study. Simulations with a physiologically–based pharmacokineticsmodel suggest that moderate inhibitors of CYP3A could increase cobimetinib AUC by 3–4 foldand Cmax by ~2–fold. The concomitant use of moderate CYP3A inhibitors including, but notlimited to: amiodarone, delavirdine, diltiazem, erythromycin, fluconazole, fosamprenavir,imatinib, miconazole, and verapamil should be avoided. If concomitant short term (14 days orless) use of a moderate CYP3A inhibitor is unavoidable for patients who are taking COTELLIC60 mg, patients should be carefully monitored for safety and dose should be reduced to 20 mg forthe duration of inhibitor use. After discontinuation of a moderate CYP3A inhibitor, resumeCOTELLIC at the previous dose. For patients who are taking a reduced dose of COTELLIC (40or 20 mg daily), do not use moderate CYP3A inhibitors (see DOSAGE ANDADMINISTRATION).

Agents That May Decrease Cobimetinib Plasma Concentrations

Effect of CYP3A Inducers

Cobimetinib is metabolized by CYP3A and cobimetinib exposures may be lower in the presenceof CYP3A inducers. Co–administration of cobimetinib with a strong or moderate CYP3A inducerhas not been assessed in a clinical drug interaction study. Simulations with a physiologicallybasedpharmacokinetics model suggest that strong and moderate inducers of CYP3A coulddecrease cobimetinib AUC by 83% and 72%, respectively, and Cmax by ~63%. The concomitantuse of strong and moderate CYP3A inducers including, but not limited to: bosentan,carbamazepine, efavirenz, etravirine, modafinil, phenytoin, and rifampin should be avoided.

Acid Reducing Agents

Coadministration of a proton pump inhibitor, rabeprazole 20 mg once daily for 5 days, with asingle dose of 20 mg COTELLIC under fed and fasted conditions did not result in a clinicallyimportant change in cobimetinib exposure.

Drugs That May Have Their Plasma Concentrations Altered by Cobimetinib

CYP Substrates

In vitro data indicate that cobimetinib is an inhibitor of CYP3A and CYP2D6, and an inducer ofCYP3A. Coadministration of cobimetinib 60 mg once daily for 13 days followed by coadministrationwith a single 30 mg dose of dextromethorphan (sensitive CYP2D6 substrate) anda single 2 mg dose of midazolam (sensitive CYP3A substrate) to 20 patients with solid tumorsdid not change dextromethorphan or midazolam systemic exposure. Therefore, cobimetinib isnot an inducer or inhibitor of CYP3A or inhibitor of CYP2D6 at the clinically relevant dose.

Effects Between Cobimetinib and Vemurafenib

There is no evidence of any clinically significant drug–drug interaction between cobimetinib andvemurafenib in unresectable or metastatic melanoma patients.

In Vitro Studies With Drug Transporters

In vitro studies demonstrate that cobimetinib is a substrate of the efflux transporter P–glycoprotein(P–gp), but is not a substrate of the breast cancer resistance protein (BCRP), organicanion transporting polypeptide (OATP1B1 or OATP1B3) or organic cation transporter OCT1.

Co–administration of cobimetinib with P–gp inhibitors such as cyclosporine and verapamil mayincrease cobimetinib plasma concentrations.

In vitro studies indicate that cobimetinib is an inhibitor of BCRP. The relevance of this in vitro finding has not been investigated clinically. Cobimetinib may alter the gastrointestinal absorptionof drugs which are BCRP substrates.

Cobimetinib did not inhibit the transport activities of Pndash;gp, OATP1B1, OATP1B3, OAT1,OAT3, OCT1 or OCT2 at clinically relevant concentrations in vitro.

Drug–Food Interactions

Grapefruit, grapefruit juice, and products containing grapefruit extract may increase cobimetinibplasma concentrations and should be avoided.

Drug–Herb Interactions

Interactions with herbal products have not been established. St. John’s wort (Hypericum perforatum) is an inducer of CYP3A that may decrease cobimetinib plasma concentrations andshould be avoided.

Dosage and Administration

Dosing Considerations

Also refer to the Product Monograph for ZELBORAF(vemurafenib), which is used incombination with COTELLIC.

Recommended Dose and Dosage Adjustment

Standard Dosage

The recommended dose of COTELLIC is 60 mg (three 20 mg tablets) once daily. COTELLIC istaken on a 28 day cycle. Each COTELLIC dose consists of three 20 mg tablets (60 mg) andshould be taken once daily for 21 consecutive days (days 1 to 21 – treatment period); followed bya 7 day break in COTELLIC treatment (days 22 to 28 – treatment break). Each subsequentCOTELLIC treatment cycle should start after the 7–day treatment break has elapsed.

Each dose of three 20 mg tablets (60 mg) can be taken with or without food (see ACTION ANDCLINICAL PHARMACOLOGY: Pharmacokinetics, Absorption). COTELLIC tablets should beswallowed whole with a glass of water.

Duration of Treatment

Treatment with COTELLIC should continue until the patient no longer derives benefit or untilthe development of unacceptable toxicity.

Missed Dose

If a dose of COTELLIC is missed, it can be taken up to 12 hours prior to the next dose tomaintain the once–daily regimen. Both doses should not be taken at the same time.

Vomiting

In case of vomiting after COTELLIC administration, the patient should not take an additionaldose of COTELLIC on that day, and treatment should be continued as prescribed the followingday.

Dose Modification Recommendations

COTELLIC dose modification should be based on the physicians assessment of individualpatient safety or tolerability. Dose modification of COTELLIC is independent of vemurafenibdose modification.

COTELLIC monotherapy should not be initiated in patients for the treatment of advancedmelanoma.

If doses are omitted for toxicity; missed doses should not be replaced.

Once the dose has been reduced, it should not be increased at a later time.

Recommended COTELLIC Dose Modifications for Concomitant DrugsIf concomitant short term (14 days or less) use of a moderate CYP3A inhibitor is unavoidable forpatients who are taking COTELLIC 60 mg, patients should be carefully monitored for safety anddose should be reduced to 20 mg for the duration of inhibitor use. After discontinuation of amoderate CYP3A inhibitor, resume previous dose of COTELLIC 60 mg.

Recommended COTELLIC Dose Modifications for Adverse Drug ReactionsTable 3 below gives general COTELLIC dose modification advice, and Table 4 givesCOTELLIC dose modification advice for specified Adverse Drug Reactions.

Table 3 Recommended COTELLIC Dose Modifications
Grade (CTC–AE) Recommended COTELLIC dosage
Grade 1 or Grade 2 (tolerable) No dose reduction
Grade 2 (intolerable) or Grade 3⁄4
1st Appearance Interrupt treatment until grade ≤1, restart treatment at 40 mg once
daily [First dose reduction]
2nd Appearance Interrupt treatment until grade ≤1, restart treatment at 20 mg once
daily [Second dose reduction]
3rd Appearance Permanently discontinue COTELLIC

The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CT–CAE)

Table 4 Recommended COTELLIC Dose Modifications for Specified Adverse Drug
Reactions
Adverse Drug Reaction Dose Modification for COTELLIC
Rhabdomyolysis and
CPK elevations
Grade 4
CPK
elevations
or
Any CPK
elevation
and myalgia
Withhold COTELLIC for up to 4 weeks
–If improved to Grade 3 or lower, resume at the next lower
dose level.
–If not improved within 4 weeks, permanently discontinue.
Liver Laboratory
Abnormalities and
Hepatotoxicity
First
Occurrence
Grade 4
Withhold COTELLIC for up to 4 weeks.
–If improved to Grade 0 or 1, then resume at the next lower
dose level.
–If not improved to Grade 0 or 1 within 4 weeks,
permanently discontinue.
Recurrent
Grade 4
Permanently discontinue COTELLIC.
Retinal vein occlusion
(RVO)
Permanently discontinue COTELLIC.
Adverse Drug Reaction Dose Modification for COTELLIC
Serous Retinopathy Withhold COTELLIC for up to 4 weeks.
–If improved to Grade 0 or 1, then resume at the next lower dose level.
–If not improved to Grade 0 or 1 within 4 weeks, permanently discontinue
Photosensitivity Grade ≤ 2
(tolerable)
Should be managed with supportive care.
Grade 2
(intolerable),
Grade ≥ 3
COTELLIC should be interrupted until resolution to Grade ≤ 1.
Treatment can be restarted with no change in COTELLIC dose.
Rash Grade ≤ 2
(tolerable)
rash
Should be managed with supportive care.
Grade 2,
(intolerable)
or Grade ≥ 3
Acneiform rash: Follow general dose modification table
recommendations in Table 3 for COTELLIC.
Non–acneiform or maculopapular rash: COTELLIC dosing canbe continued without modification (if clinically indicated).
Asymptomatic, absolute
decrease in LVEF from
baseline of greater than
10% and less than
institutional lower limit
of normal (LLN)
Withhold COTELLIC for 2 weeks; repeat LVEF
Resume at next lower dose if all of the following are present:
–LVEF ≥ LLN and
– Absolute decrease from baseline LVEF is ≤ 10%
Permanently discontinue if any of the following are present
–LVEF ≤ LLN or
– Absolute decrease from baseline LVEF > 10%
Symptomatic LVEF
decrease from baseline
Withhold COTELLIC for up to 4 weeks, repeat LVEF.
Resume at next lower dose if all of the following are present:
–Symptoms resolve and
– LVEF is ≥ LLN and
– Absolute decrease from baseline LVEF is ≤10% or less
Permanently discontinue if any of the following are present:
– Symptoms persist, or
– LVEF –Absolute decrease from baseline LVEF > 10%
Hemorrhage Grade 3 Withhold COTELLIC for up to 4 weeks.
Resume COTELLIC at the next lower dose level if improved to
Grade 0 or 1 and if clinically appropriate and improved. If not
improved within 4 weeks or if clinically indicated, permanently
discontinue.
Grade 4 Permanently discontinue COTELLIC.

Elderly

No dose adjustment of COTELLIC is required in patients ≥ 65 years of age.

Renal Impairment

No dose adjustment is recommended in patients with mild or moderate renal impairment, basedon population pharmacokinetic analysis. The safety and efficacy of COTELLIC have not beenestablished in patients with severe renal impairment (see ACTION AND CLINICALPHARMACOLOGY: Pharmacokinetics, Special Populations and Conditions).

Hepatic Impairment

The safety and efficacy of COTELLIC in patients with moderate and severe hepatic impairmenthas not been studied. (see ACTION AND CLINICAL PHARMACOLOGY: Pharmacokinetics,Special Populations and Conditions). No dosing recommendations can be made for COTELLICin patients with moderate to severe hepatic impairment.

Overdosage

There is no experience with overdose in human clinical trials. In case of suspected overdose,COTELLIC should be withheld and supportive care instituted. There is no specific antidote foroverdose with COTELLIC.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

The mitogen–activated protein kinase (MAPK) pathway, which includes themitogen⁄extracellular signal–regulated kinases (MEKs), is a key signaling pathway that regulatescell proliferation, cell cycle regulation, cell survival, angiogenesis, and cell migration.

COTELLIC is an orally available, highly selective inhibitor that targets MEK1⁄2. It has shownhigh inhibitory potency in biochemical and cell based assays, as well as broad anti–tumouractivity in vivo in xenograft tumour models, including those that are mutated for BRAF andKRAS. In vitro, cobimetinib inhibited MEK1 and MEK2 with IC50 values of 0.95 nM and 199nM, respectively.

By dual targeting of the MAPK pathway with BRAF and MEK inhibitors, the combination ofvemurafenib and COTELLIC inhibits MAPK pathway reactivation through MEK1⁄2, resulting instronger inhibition of signaling, greater tumour cell apoptosis and enhanced tumour responses inpre–clinical models compared to vemurafenib alone.

Cardiac Electrophysiology

Serial ECG recordings were performed in 13 patients who received COTELLIC at a dose of 60mg⁄day (21 days on–treatment, 7 days off–treatment) as part of a non–randomized,open–label study. ECG recordings were performed on Day 21 (pre–dose, 1.5 h, 3 h, & 6 h) of Cycle 1, andstatistically significant decreases in heart rate from pretreatment baseline were observed with amaximum mean decrease of −10.7 bpm (95% CI −17.6, −3.8) at 1.5 h post–dosing. Statisticallysignificant mean increases from baseline in the PR interval and QRS duration were observed atall time points on Day 21. The maximum mean increase in the PR interval was 15.0 ms (95% CI6.4, 23.6) at 3 h post–dosing and the maximum mean increase in the QRS duration was 5.8 ms(95% CI 1.0, 10.7) at 1.5 h post–dosing. For the QTcF interval, the maximum mean increasefrom baseline was 1.2 ms (95% CI −6.2, 8.5).

Pharmacokinetics

The pharmacokinetic parameters for cobimetinib were determined in cancer patients and healthysubjects in Phase I studies.

Absorption

Following oral dosing of 60 mg in cancer patients, cobimetinib showed a moderaterate of absorption with a median Tmax of 2.4 hours. The mean steady–state Cmax and AUC0–24 were b273 ng⁄mL and 4340 ng.h⁄mL respectively. The mean accumulation ratio at steady state wasapproximately 2.4–fold.

Cobimetinib has linear pharmacokinetics in the dose range of ~3.5 mg to 100 mg.

The absolute bioavailability of cobimetinib was 45.9% (90% CI: 39.7%, 53.1%) in healthysubjects. A human mass balance study was conducted in healthy subjects, and showed thatcobimetinib was extensively metabolized and eliminated in feces. The fraction absorbed was~88% indicating high absorption and first pass metabolism.

Following a single dose of 20 mg cobimetinib with food (high–fat meal), median tmax value (6.00hours) was extended compared to the fasted state (median tmax = 2.03 hours) in healthy subjects.Although absorption was slower in the fed state, exposure (AUC and Cmax) to cobimetinib wasgenerally similar with or without food.

Distribution

Cobimetinib is 94.8% bound to human plasma proteins in vitro. In vitro,cobimetinib is more highly bound to alpha–1 acid glycoprotein. No preferential binding to humanred blood cells was observed (blood–to–plasma ratio 0.93).

The volume of distribution was 1050 L in healthy subjects given an IV dose of 2 mg. Theapparent volume of distribution was 806 L in cancer patients based on populationpharmacokinetic analysis.

Metabolism

Cobimetinib and its metabolites were characterized in a mass balance study inhealthy subjects.

On average, 94% of the dose was recovered within 17 days. Cobimetinib was extensivelymetabolized to several metabolites, and eliminated in feces.

Oxidation by CYP3A and glucuronidation by UGT2B7 appear to be the major pathways ofcobimetinib metabolism. Following oral administration of a single 20 mg radiolabeledcobimetinib dose, cobimetinib (parent compound) was the predominant moiety in plasma,followed by the glycine conjugate of the hydrolyzed cobimetinib and the glucuronide conjugatewhere each of them accounted for greater than 10% of the plasma radioactivity at timepoints upto 48 hour post–dose. No other metabolites greater than 10% of total circulating radioactivity orhuman specific metabolites were observed in plasma. Unchanged drug in feces and urineaccounted for 6.6% and 1.6% of the administered dose, respectively, indicating that cobimetinibis primarily metabolized with very little renal elimination.

Excretion

Following IV administration of a 2 mg dose of cobimetinib, the mean plasmaclearance (CL) was 10.7 L⁄hr. The mean apparent CL following oral dosing of 60 mg in cancerpatients was 13.8 L⁄hr and the mean elimination half–life was 43.6 hours (range: 23.1 to 69.6hours).

Following oral administration of a single 20 mg radiolabeled cobimetinib dose, 76.5% of thedose was recovered in the feces and 17.8% of the dose was recovered in the urine.

Special Populations and Conditions

Based on a population pharmacokinetic analysis, gender, race, ethnicity, baseline ECOG, mildand moderate renal impairment did not affect the pharmacokineticsof cobimetinib. Baseline ageand baseline body weight were identified as statistically significant covariates on cobimetinibclearance and volume of distribution respectively. However, sensitivity analysis suggests neitherof these covariates had clinically significant impact on steady state exposure.

Pediatrics

No studies have been conducted to investigate the pharmacokinetics of cobimetinibin pediatric patients (see TOXICOLOGY).

Geriatrics

Based on the population pharmacokinetic analysis including 133 patients ≥ 65 yearsof age, age was a significant covariate influencing cobimetinib clearance, which decreased withincreasing age, however this was not considered clinically significant.

Gender

Based on a population pharmacokinetic analysis including 210 women and 277 men,gender does not have a clinically important effect on the exposure of cobimetinib.

Hepatic Insufficiency

No pharmacokinetic studies of cobimetinib were conducted in patientswith hepatic impairment. As cobimetinib is metabolized and eliminated via the liver, patientswith hepatic impairment may have increased exposure.

Renal Insufficiency

Based on pre–clinical data and the human mass balance study, cobimetinibis mainly metabolized, with minimal renal elimination. No formal pharmacokinetic study hasbeen conducted in patients with renal impairment.

A population pharmacokinetic analysis using data from 151 patients with mild renal impairment(creatinine clearance – CRCL 60 to less than 90 mL⁄min), 48 patients with moderate renalimpairment (CRCL 30 to less than 60 mL⁄min), and 286 patients with normal renal function(CRCL greater than or equal to 90 mL⁄min), showed that CRCL had no meaningful influence onexposure of cobimetinib.

Mild to moderate renal impairment does not influence cobimetinib exposure based on thepopulation pharmacokinetic analysis. There are insufficient data available for patients withsevere renal impairment or end stage renal disease.

Storage and Stability

Store between 15–30°C.

Keep in a safe place out of the reach and sight of children.

Special Handling Instructions

This medicine should not be used after the expiry date (EXP) shown on the pack

Disposal of Unused ⁄Expired Medicines

The release of pharmaceuticals in the environment should be minimized. Medicines should notbe disposed of via wastewater and disposal through household waste should be avoided. Useestablished “collection systems,” if available in your location.

Dosage Forms, Composition and Packaging

Dosage Form ⁄ Composition

Each COTELLIC film–coated tablet contains 20 mg cobimetinib (22.2 mg as cobimetinibfumarate salt). Non–medicinal ingredients (alphabetical order) include: croscarmellose sodium,lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film–coatingmixture includes (alphabetical order): polyethylene glycol 3350 (macrogol 3350), polyvinylalcohol, talc, and titanium dioxide.

Packaging

COTELLIC tablets are supplied as white, round, film–coated 20 mg tablets with COB debossedon one side. COTELLIC is available in PVC⁄PVDC blister packs containing 63 film–coatedtablets (21 tablets per blister card and 3 blister cards per carton).