COTELLIC 20mg tablets medication leaflet

Cotellic 20 mg film-coated tablets

Each film-coated tablet contains cobimetinib hemifumarate equivalent to 20 mg cobimetinib.

Each film-coated tablet contains 36 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet.

White, round film-coated tablets of approximately 6.6 mm diameter, with “COB” debossed on oneside.

Cotellic is indicated for use in combination with vemurafenib for the treatment of adult patients withunresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1).

Treatment with Cotellic in combination with vemurafenib should only be initiated and supervised by aqualified physician experienced in the use of anticancer medicinal products.

Before starting this treatment, patients must have BRAF V600 mutation-positive melanoma tumourstatus confirmed by a validated test (see sections 4.4 and 5.1).

The recommended dose of Cotellic is 60 mg (3 tablets of 20 mg) once daily.

Cotellic is taken on a 28 day cycle. Each dose consists of three 20 mg tablets (60 mg) and should betaken once daily for 21 consecutive days (Days 1 to 21-treatment period); followed by a 7-day break(Days 22 to 28-treatment break). Each subsequent Cotellic treatment cycle should start after the 7-daytreatment break has elapsed.

For information on the posology of vemurafenib, please refer to its SmPC.

Treatment with Cotellic should continue until the patient no longer derives benefit or until thedevelopment of unacceptable toxicity (see Table 1 below).

If a dose is missed, it can be taken up to 12 hours prior to the next dose to maintain the once-dailyregimen.

In case of vomiting after administration of Cotellic, the patient should not take an additional dose onthat day and treatment should be continued as prescribed the following day.

General dose modifications

The decision on whether to reduce the dose for either or both treatments should be based on theprescriber’s assessment of individual patient safety or tolerability. Dose modification of Cotellic isindependent of vemurafenib dose modification.

If doses are omitted for toxicity, these doses should not be replaced. Once the dose has been reduced,it should not be increased at a later time.

Table 1 below gives general Cotellic dose modification guidance.

Table 1 Recommended Cotellic dose modifications

Grade (CTC-AE)* Recommended Cotellic dose

Grade 1 or Grade 2 (tolerable) No dose reduction. Maintain Cotellic at a dose of60 mg once daily (3 tablets)

Grade 2 (intolerable) or Grade 3/41st Appearance Interrupt treatment until Grade ≤ 1, restart treatmentat 40 mg once daily (2 tablets)2nd Appearance Interrupt treatment until Grade ≤ 1, restart treatmentat 20 mg once daily (1 tablet)3rd Appearance Consider permanent discontinuation

*The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0(CTC-AE)

Dose modification advice for haemorrhage

Grade 4 events or cerebral haemorrhage: Cotellic treatment should be interrupted. Cotellic treatmentshould be permanently discontinued for haemorrhage events attributed to Cotellic.

Grade 3 events: Cotellic treatment should be interrupted during evaluation to avoid any potentialcontribution to the event. There is no data on the effectiveness of Cotellic dose modification forhaemorrhage events. Clinical judgment should be applied when considering restarting Cotellictreatment. Vemurafenib dosing can be continued when Cotellic treatment is interrupted, if clinicallyindicated.

Dose modification advice for left ventricular dysfunction

Permanent discontinuation of Cotellic treatment should be considered if cardiac symptoms areattributed to Cotellic and do not improve after temporary interruption.

Table 2 Recommended dose modifications for Cotellic in patients with left ventricular ejectionfraction (LVEF) decrease from baseline

Recommended LVEF value

LVEF Recommended Cotellic

Patient Cotellic dose followingvalue daily dosemodification treatment break≥ 50%(or 40-49%and < 10%

Continue atabsolute N/A N/Acurrent dosedecreasefrombaseline)1st occurrence: 40 mg

Asymptomatic< 40% < 10% absolute2nd(or 40-49% decrease from occurrence: 20 mgand ≥ 10% Interrupt baseline 3rd occurrence:absolute treatment for permanent discontinuationdecrease 2 weeks < 40%from (or ≥ 10% absolutebaseline) Permanent discontinuationdecrease frombaseline)1st occurrence: 40 mg

Asymptomatic and< 10% absolute 2nd occurrence: 20 mgdecrease fromrdbaseline 3 occurrence:

Interrupt permanent discontinuation

Symptomatic N/A treatment for Asymptomatic and4 weeks < 40%(or ≥ 10% absolute Permanent discontinuationdecrease frombaseline)

Symptomatic

Permanent discontinuationregardless of LVEF

N/A = Not Applicable

Vemurafenib treatment can be continued when Cotellic treatment is modified, if clinically indicated.

Dose modification advice for rhabdomyolysis and creatine phosphokinase (CPK) elevations

Rhabdomyolysis or symptomatic CPK elevations

Cotellic treatment should be interrupted. If rhabdomyolysis or symptomatic CPK elevations do notimprove within 4 weeks, Cotellic treatment should be permanently discontinued.

If severity is improved by at least one grade within 4 weeks, Cotellic could be restarted at a dosereduced by 20 mg, if clinically indicated. Patients should be closely monitored. Vemurafenib dosingcan be continued when Cotellic treatment is modified.

Asymptomatic CPK elevations

Grade 4: Cotellic treatment should be interrupted. If CPK elevations do not improve to Grade ≤3within 4 weeks following dose interruption, Cotellic treatment should be permanently discontinued.

If CPK improves to Grade ≤3 within 4 weeks, Cotellic could be restarted, if clinically indicated, at adose reduced by 20 mg and the patient should be closely monitored. Vemurafenib dosing can becontinued when Cotellic treatment is modified.

Grade ≤3: After rhabdomyolysis has been ruled out, Cotellic dosing does not need to be modified.

Dose modification advice for Cotellic when used with vemurafenib

For Grade 1 and 2 liver laboratory abnormalities, Cotellic and vemurafenib should be continued at theprescribed dose.

Grade 3: Cotellic should be continued at the prescribed dose. The dose of vemurafenib may bereduced as clinically appropriate. Please refer to the vemurafenib SmPC.

Grade 4: Cotellic treatment and vemurafenib treatment should be interrupted. If liver laboratoryabnormalities improve to Grade ≤1 within 4 weeks, Cotellic should be restarted at a dose reduced by20 mg and vemurafenib at a clinically appropriate dose, per its SmPC.

Cotellic treatment and vemurafenib treatment should be discontinued if liver laboratory abnormalitiesdo not resolve to Grade ≤1 within 4 weeks or if Grade 4 liver laboratory abnormalities recur afterinitial improvement.

Grade ≤2 (tolerable) photosensitivity should be managed with supportive care.

Grade 2 (intolerable) or Grade ≥3 photosensitivity: Cotellic and vemurafenib should be interrupteduntil resolution to Grade ≤1. Treatment can be restarted with no change in Cotellic dose. Vemurafenibdosing should be reduced as clinically appropriate, please refer to its SmPC for further information.

Rash events may occur with either Cotellic or vemurafenib treatment. The dose of Cotellic and/orvemurafenib may be either temporarily interrupted and/or reduced as clinically indicated.

Additionally, for:

Grade ≤2 (tolerable) rash should be managed with supportive care. Cotellic dosing can be continuedwithout modification.

Grade 2 (intolerable) or Grade ≥3 acneiform rash: General dose modification recommendations in

Table 1 for Cotellic should be followed. Vemurafenib dosing can be continued when Cotellictreatment is modified (if clinically indicated).

Grade 2 (intolerable) or Grade ≥3 non-acneiform or maculopapular rash: Cotellic dosing can becontinued without modification if clinically indicated. Vemurafenib dosing may be either temporarilyinterrupted and/or reduced, please refer to its SmPC for further information.

If during treatment the QTc exceeds 500 msec, please refer to the vemurafenib SmPC (section 4.2) fordose modifications for vemurafenib. No dose modification of Cotellic is required when taken incombination with vemurafenib.

No dose adjustment is required in patients aged ≥65 years old.

No dose adjustment is recommended in patients with mild or moderate renal impairment based onpopulation pharmacokinetic analysis (see section 5.2). There are minimal data for Cotellic in patientswith severe renal impairment, therefore an effect cannot be excluded. Cotellic should be used withcaution in patients with severe renal impairment.

No dose adjustment is recommended in patients with hepatic impairment. Patients with severe hepaticimpairment may have increased plasma concentrations of unbound cobimetinib compared to patientswith normal hepatic function (see section 5.2). Liver laboratory abnormalities can occur with Cotellicand caution should be used in patients with any degree of hepatic impairment (see section 4.4).

The safety and efficacy of Cotellic in non-Caucasian patients have not been established.

The safety and efficacy of Cotellic in children and adolescents below 18 years of age have not beenestablished. Currently available data are described in sections 4.8, 5.1 and 5.2, but norecommendation on posology can be made.

Cotellic is for oral use. The tablets should be swallowed whole with water. They can be taken with orwithout food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Before taking Cotellic in combination with vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test.

Cotellic in combination with vemurafenib in patients who have progressed on a BRAF inhibitor

There are limited data in patients taking the combination of Cotellic with vemurafenib who haveprogressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will belower in these patients (see section 5.1). Therefore other treatment options should be considered beforetreatment with the combination in this prior BRAF inhibitor treated population. The sequencing oftreatments following progression on a BRAF inhibitor therapy has not been established.

Cotellic in combination with vemurafenib in patients with brain metastases

Limited data show that the safety of the combination of Cotellic and vemurafenib in patients with a

BRAF V600 mutation-positive melanoma which has metastasised to the brain is consistent with theknown safety profile of Cotellic in combination with vemurafenib. The efficacy of the Cotellic andvemurafenib combination in these patients has not been evaluated. The intracranial activity of Cotellicis unknown (see sections 5.1 and 5.2).

Haemorrhagic events, including major haemorrhagic events can occur (see section 4.8).

Caution should be used in patients with additional risk factors for bleeding, such as brain metastases,and/or in patients that use concomitant medicinal products that increase the risk of bleeding (includingantiplatelet or anticoagulant therapy). For management of haemorrhage please see section 4.2.

Serous retinopathy

Serous retinopathy (fluid accumulation within the layers of the retina) has been observed in patientstreated with MEK-inhibitors, including Cotellic (see section 4.8). The majority of events were reportedas chorioretinopathy or retinal detachment.

Median time to initial onset of serous retinopathy events was 1 month (range 0-9 months). Most eventsobserved in clinical studies were resolved, or improved to asymptomatic Grade 1, following doseinterruption or reduction.

Patients should be assessed at each visit for symptoms of new or worsening visual disturbances. Ifsymptoms of new or worsening visual disturbances are identified, an ophthalmologic examination isrecommended. If serous retinopathy is diagnosed, Cotellic treatment should be withheld until visualsymptoms improve to Grade ≤1. Serous retinopathy can be managed with treatment interruption, dosereduction or with treatment discontinuation (see Table 1 in section 4.2).

Decrease in LVEF from baseline has been reported in patients receiving Cotellic (see section 4.8).

Median time to initial onset of events was 4 months (1-13 months).

LVEF should be evaluated before initiation of treatment to establish baseline values, then after the firstmonth of treatment and at least every 3 months or as clinically indicated until treatmentdiscontinuation. Decrease in LVEF from baseline can be managed using treatment interruption, dosereduction or with treatment discontinuation (see section 4.2).

All patients restarting treatment with a dose reduction of Cotellic should have LVEF measurementstaken after approximately 2 weeks, 4 weeks, 10 weeks and 16 weeks, and then as clinically indicated.

Patients with a baseline LVEF either below institutional lower limit of normal (LLN) or below 50%have not been studied.

Liver laboratory abnormalities can occur when Cotellic is used in combination with vemurafenib andwith vemurafenib as a single agent (please refer to its SmPC).

Liver laboratory abnormalities, specifically increases in alanine aminotransferase (ALT), aspartateaminotransferase (AST), and alkaline phosphatase (ALP), have been observed in patients treated with

Cotellic plus vemurafenib (see section 4.8).

Liver value abnormalities should be monitored by liver laboratory tests before initiation ofcombination treatment and monthly during treatment, or more frequently as clinically indicated (seesection 4.2).

Grade 3 liver laboratory abnormalities should be managed with vemurafenib treatment interruption ordose reduction. Manage Grade 4 liver laboratory abnormalities with treatment interruption, dosereduction or with treatment discontinuation of both Cotellic and vemurafenib (see section 4.2).

Rhabdomyolysis and CPK elevations

Rhabdomyolysis has been reported in patients receiving Cotellic (see section 4.8).

If rhabdomyolysis is diagnosed, Cotellic treatment should be interrupted and CPK levels and othersymptoms monitored until resolution. Depending on the severity of rhabdomyolysis, dose reduction ortreatment discontinuation may be required (see section 4.2).

Grade 3 and 4 CPK elevations, including asymptomatic elevations over baseline, also occurred inpatients receiving Cotellic with vemurafenib in clinical studies (see section 4.8). The median time tofirst occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 11 days to 10 months); themedian time to complete resolution was 16 days (range: 2 days to 15 months).

Serum CPK and creatinine levels should be measured before initiation of treatment, to establishbaseline values, and then monitored monthly during treatment, or as clinically indicated. If serum CPKis elevated, check for signs and symptoms of rhabdomyolysis or other causes. Depending on theseverity of symptoms or CPK elevation; treatment interruption, dose reduction or treatmentdiscontinuation may be required (see section 4.2).

Cases of Grade ≥3 and serious diarrhoea have been reported in patients treated with Cotellic.

Diarrhoea should be managed with anti-diarrhoeal agents and supportive care. For Grade ≥3 diarrhoeathat occurs despite supportive care, Cotellic and vemurafenib should be withheld until diarrhoea hasimproved to Grade ≤1. If Grade ≥3 diarrhoea recurs, the dose of Cotellic and vemurafenib should bereduced (see section 4.2).

Drug-drug interactions: CYP3A inhibitors

Concurrent use of strong CYP3A inhibitors during treatment with Cotellic should be avoided. Cautionshould be exercised if a moderate CYP3A inhibitor is co-administered with Cotellic. If concomitantuse with a strong or moderate CYP3A inhibitor is unavoidable, patients should be carefully monitoredfor safety and dose modifications applied if clinically indicated (see Table 1 in section 4.2).

If during treatment the QTc exceeds 500 msec, please refer to the vemurafenib SmPC sections 4.2 and4.4.

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucosegalactose malabsorption should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Effects of other medicinal products on cobimetinib

Cobimetinib is metabolized by CYP3A and cobimetinib AUC increased approximately 7 fold in thepresence of a strong CYP3A inhibitor (itraconazole) in healthy subjects. The magnitude of interactioncould potentially be lower in patients.

Strong CYP3A inhibitors (see section 4.4.)

Avoid concurrent use of strong CYP3A inhibitors during treatment with cobimetinib. Strong CYP3Ainhibitors include, but are not limited to ritonavir, cobicistat, telaprevir, lopinavir, itraconazole,voriconazole, clarithromycin, telithromycin, posaconazole, nefazodone and grapefruit juice. Ifconcomitant use of a strong CYP3A inhibitor is unavoidable, patients should be carefully monitoredfor safety. For strong CYP3A inhibitors used short-term (7 days or less), consider interruptingcobimetinib therapy during the duration of inhibitor use.

Moderate CYP3A inhibitors (see section 4.4.)

Caution should be exercised if cobimetinib is co-administered with moderate CYP3A inhibitors.

Moderate CYP3A inhibitors include, but are not limited to, amiodarone, erythromycin, fluconazole,miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, imatinib. Whencobimetinib is co-administered with a moderate CYP3A inhibitor, patients should be carefullymonitored for safety.

Mild CYP3A inhibitors

Cobimetinib can be co-administered with mild inhibitors of CYP3A without dose adjustment.

Co-administration of cobimetinib with a strong CYP3A inducer was not assessed in a clinical study,however, a reduction in cobimetinib exposure is likely. Therefore, concomitant use of moderate andstrong CYP3A inducers (e.g. carbamazepine, rifampicin, phenytoin, and St. John’s Wort) should beavoided. Alternative agents with no or minimal CYP3A induction should be considered. Given thatcobimetinib concentrations are likely to be significantly reduced when co-administered with moderateto strong CYP3A inducers, patient’s efficacy may be compromised.

P-glycoprotein inhibitors

Cobimetinib is a substrate of P-glycoprotein (P-gp). Concomitant administration of P-gp inhibitorssuch as ciclosporin and verapamil may have the potential to increase plasma concentrations ofcobimetinib.

Effects of cobimetinib on other medicinal products

CYP3A and CYP2D6 substrates

A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations ofmidazolam (a sensitive CYP3A substrate) and dextromethorphan (a sensitive CYP2D6 substrate) werenot altered in the presence of cobimetinib.

CYP1A2 substrates

In vitro, cobimetinib is a potential inducer of CYP1A2 and may therefore reduce the exposure ofsubstrates of this enzyme e.g., theophylline. No clinical DDI studies have been conducted to assess theclinical relevance of this finding.

In vitro, cobimetinib is a moderate inhibitor of BCRP (Breast Cancer Resistance Protein). No clinical

DDI studies have been conducted to assess this finding, and clinically relevant inhibition of intestinal

BCRP cannot be ruled out.

Other anti-cancer agents

Vemurafenib

There is no evidence of any clinically significant drug-drug interaction between cobimetinib andvemurafenib in unresectable or metastatic melanoma patients and therefore no dose adjustments isrecommended.

Effects of cobimetinib on drug transport systems

In vitro studies show that cobimetinib is not a substrate of the liver uptake transporters OATP1B1,

OATP1B3 and OCT1, however, it weakly inhibits these transporters. The clinical relevance of thesefindings has not been investigated.

Interaction studies have only been performed in adults.

Women of childbearing potential should be advised to use two effective contraceptive methods, suchas a condom or other barrier method (with spermicide, if available) during treatment with Cotellic andfor at least three months following treatment discontinuation.

There are no data from the use of Cotellic in pregnant women. Studies in animals have shownembryolethality and foetal malformations of the great vessels and skull (see section 5.3). Cotellicshould not be used during pregnancy unless clearly necessary and after a careful consideration of theneeds of the mother and the risk to the foetus.

It is not known whether cobimetinib is excreted in human breast milk. A risk to the newborns/infantscannot be excluded. A decision should be made whether to discontinue breast-feeding or discontinue

Cotellic therapy, taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

There are no data in humans for cobimetinib. In animals, no fertility studies have been performed, butadverse effects were seen on reproductive organs (see section 5.3). The clinical relevance of this isunknown.

Cotellic has minor influence on the ability to drive or use machines. Visual disturbances have beenreported in some patients treated with cobimetinib during clinical studies (see sections 4.4 and 4.8).

Patients should be advised not to drive or use machines if they experience visual disturbances or anyother adverse effects that may affect their ability.

The safety of Cotellic in combination with vemurafenib has been evaluated in 247 patients withadvanced BRAF V600 mutated melanoma in Study GO28141.The median time to onset for the first

Grade ≥3 adverse events was 0.6 months in the Cotellic plus vemurafenib arm vs 0.8 months in theplacebo plus vemurafenib arm.

The safety of Cotellic in combination with vemurafenib has also been evaluated in 129 patients withadvanced BRAF V600 mutated melanoma in Study NO25395. The safety profile of Study NO25395was consistent with that observed in Study GO28141.

In Study GO28141, the most common adverse reactions (>20%) observed with a higher frequency inthe Cotellic plus vemurafenib arm were diarrhoea, rash, nausea, pyrexia, photosensitivity reaction,increased alanine aminotransferase, increased aspartate aminotransferase, increased blood creatinephosphokinase, and vomiting. The most common adverse reactions (>20%) observed with a higherfrequency in the placebo plus vemurafenib arm were arthralgia, alopecia, and hyperkeratosis. Fatiguewas observed at similar frequencies in both arms.

Please refer to the vemurafenib SmPC for complete descriptions of all undesirable effects associatedwith vemurafenib treatment.

Adverse drug reactions (ADRs) are based on results from a multi-centre, randomised, double-blind,placebo-controlled, Phase III Study (GO28141) that evaluated the safety and efficacy of Cotellic incombination with vemurafenib as compared to vemurafenib alone in previously untreated BRAF V600mutation-positive patients with unresectable locally advanced (Stage IIIc) or metastatic melanoma(Stage IV).

ADR frequencies are based upon the safety analysis of patients treated with cobimetinib plusvemurafenib with a median follow up of 11.2 months (data cut-off date of 19 September 2014).

ADRs which were reported in melanoma patients are listed below by MedDRA body system organclass, frequency and grade of severity. The following convention has been used for the classificationof frequency:

Very common ≥ 1/10

Common ≥ 1/100 to < 1/10

Uncommon ≥ 1/1,000 to < 1/100

Rare ≥ 1/10,000 to < 1/1,000

Very rare < 1/10,000

Table 3 lists adverse reactions considered associated with the use of Cotellic. Within each frequencygrouping, ADRs are presented in order of decreasing severity and were reported according to NCI-

CTCAE v 4.0 (common toxicity criteria) for assessment of toxicity in Study GO28141.

Table 3 Adverse drug reactions (ADRs) in patients treated with Cotellic in combination withvemurafenib in Study GO28141^

System organ class Very Common Common Uncommon

Neoplasms benign, Basal cell carcinoma,malignant and Cutaneous squamousunspecified (incl. cysts cell carcinoma**,and polyps) Keratoacanthoma**

Blood and lymphatic Anaemiasystem disorders

Metabolism and nutrition Dehydration,disorders Hypophosphataemia,

Hyponatremia,

Eye disorders Serous retinopathya, Visual impairment

Blurred vision

Vascular disorders Hypertension,

Haemorrhage*

Respiratory, thoracic and Pneumonitismediastinal disorders

Gastrointestinal Diarrhoea, Nausea,disorders Vomiting, Stomatitis

Skin and subcutaneous Photosensitivityb, Rash,tissue disorders Rash maculo-papular,

Dermatitis acneiform,

Hyperkeratosis**,

Pruritus c, Dry skin c

Musculoskeletal and Rhabdomyolysis***connective tissuedisorders

General disorders and Pyrexia, Chills, Oedemaadministration site peripheralcconditions

Investigations Blood CPK increased, Ejection fraction

ALT increased, AST decreased, Bloodincreased, Gamma- bilirubin increased

Glutamyltransferase(GGT) increased, Blood

ALP increased^ Data cut-off date of 19 September 2014

* Please refer to the paragraph Haemorrhage in the “Description of selected adverse reactions” section

** Please refer to the paragraph Cutaneous squamous cell carcinoma, keratoacanthoma and hyperkeratosis inthe “Description of selected adverse reactions” section.

*** Please refer to the paragraph Rhabdomyolysis in the “Description of selected adverse reactions” section.a Includes both chorioretinopathy and retinal detachment events indicative of serous retinopathy (see section 4.4)b Combined figure includes reports of photosensitivity reaction, sunburn, solar dermatitis, actinic elastosisc ADRs identified in a cobimetinib monotherapy study (ML29733; US study). However, these were also reported

ADRs for cobimetinib plus vemurafenib combination in clinical trials conducted in patients with unresectable ormetastatic melanoma.

Bleeding events have been reported more frequently in the Cotellic plus vemurafenib arm than in theplacebo plus vemurafenib arm (all types and Grades: 13% vs 7%). The median time to first onset was6.1 months in the Cotellic plus vemurafenib arm.

The majority of events were Grade 1 or 2 and non-serious. Most events resolved with no change in

Cotellic dose. Major haemorrhagic events (including intracranial and gastrointestinal tracthaemorrhage) were reported in the post-marketing setting. The risk of haemorrhage may be increasedwith concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, treat as clinicallyindicated (see section 4.2 and 4.4).

Rhabdomyolysis has been reported in the post-marketing setting. Signs or symptoms ofrhabdomyolysis warrant an appropriate clinical evaluation and treatment as indicated, along with

Cotellic dose modification or discontinuation according to the severity of the adverse reaction (seesection 4.2 and 4.4).

Photosensitivity has been observed with a higher frequency in the Cotellic plus vemurafenib arm vsplacebo plus vemurafenib arm (47% vs 35%). The majority of events were Grades 1 or 2, with

Grade ≥3 events occurring in 4% of patients in the Cotellic plus vemurafenib arm vs 0% in the placeboplus vemurafenib arm.

There were no apparent trends in the time of onset of Grade ≥3 events. Grade ≥3 photosensitivityevents in the Cotellic plus vemurafenib arm were treated with primary topical medicinal products inconjunction with dose interruptions of both cobimetinib and vemurafenib (see section 4.2).

No evidence of phototoxicity was observed with Cotellic as a single agent.

Cutaneous squamous cell carcinoma, keratoacanthoma and hyperkeratosis

Cutaneous squamous cell carcinoma has been reported with a lower frequency in the Cotellic plusvemurafenib arm vs placebo plus vemurafenib arm (all Grade: 3% vs 13%). Keratoacanthoma hasbeen reported with a lower frequency in the Cotellic plus vemurafenib arm vs placebo plusvemurafenib arm (all Grade: 2% vs 9%). Hyperkeratosis has been reported with a lower frequency inthe Cotellic plus vemurafenib vs placebo plus vemurafenib arm (all Grade: 11% vs 30%).

Serous retinopathy

Cases of serous retinopathy have been reported in patients treated with Cotellic (see section 4.4.) Forpatients reporting new or worsening visual disturbances, an ophthalmologic examination isrecommended. Serous retinopathy can be managed with treatment interruption, dose reduction or withtreatment discontinuation (see Table 1 in section 4.2).

Decrease in LVEF from baseline has been reported in patients receiving Cotellic (see section 4.4).

LVEF should be evaluated before initiation of treatment to establish baseline values, then after the firstmonth of treatment and at least every 3 months or as clinically indicated until treatmentdiscontinuation. Decrease in LVEF from baseline can be managed using treatment interruption, dosereduction or with treatment discontinuation (see section 4.2).

Liver laboratory abnormalities, specifically ALT, AST, and ALP have been observed in patientstreated with Cotellic in combination with vemurafenib (see section 4.4).

Liver laboratory tests should be monitored before initiation of combination treatment and monthlyduring treatment, or more frequently if clinically indicated (see section 4.2).

Blood creatine phosphokinase increase

Asymptomatic increases in blood CPK levels were observed with a higher frequency in the Cotellicplus vemurafenib arm vs placebo plus vemurafenib arm in Study GO28141 (see section 4.2 and 4.4).

One event of rhabdomyolysis was observed in each treatment arm of the study with concurrentincreases in blood CPK.

Table 4 provides the frequency of measured liver laboratory abnormalities and elevated creatinephosphokinase for all Grades and Grades 3-4.

Table 4 Liver function and other laboratory tests observed in the Phase III Study GO28141

Changes in reported Cobimetinib plus Placebo plus vemurafeniblaboratory data vemurafenib (n = 246)(n = 247) (%)(%)

All Grades Grades 3-4 All Grades Grades 3-4

Liver function test

Increased ALP 69 7 55 3

Increased ALT 67 11 54 5

Increased AST 71 7 43 2

Increased GGT 62 20 59 17

Increased blood bilirubin 33 2 43 1

Other laboratory abnormalities

Increased blood CPK 70 12 14 <1

In the Phase III study with Cotellic in combination with vemurafenib in patients with unresectable ormetastatic melanoma (n=247), 183 patients (74%) were <65 years of age, and 44 patients (18%) were65-74 years of age, 16 (6%) were 75-84 years of age, and 4 patients (2%) were aged 85 years. Theproportion of patients experiencing adverse events (AE) was similar in the patients aged 65 years andthose aged 65 years. Patients ≥65 years were more likely to experience serious adverse events(SAEs) and experience AEs leading to discontinuation of cobimetinib than those 65 years.

The safety of Cotellic in children and adolescents has not been fully established. The safety of Cotellicwas assessed in a multi-centre, open-label, dose-escalation study in 55 paediatric patients aged 2 to17 years with solid tumours. The safety profile of Cotellic in these patients was consistent with that inthe adult population (see section 5.2).

No pharmacokinetic trial in subjects with renal impairment has been conducted. Dose adjustment isnot recommended for mild to moderate renal impairment based on the results of the populationpharmacokinetic analysis. There are minimal data for Cotellic in patients with severe renalimpairment. Cotellic should be used with caution in patients with severe renal impairment.

No dose adjustment is recommended in patients with hepatic impairment (see section 5.2).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EE02

Cobimetinib is a reversible, selective, allosteric, oral inhibitor that blocks the mitogen-activatedprotein kinase (MAPK) pathway by targeting the mitogen-activated extracellular signal-regulatedkinase (MEK) 1 and MEK 2 which results in inhibition of phosphorylation of the extracellular signal-regulated kinase (ERK) 1 and ERK 2. Therefore, cobimetinib blocks the cell proliferation induced bythe MAPK pathway through inhibition of the MEK1/2 signalling node.

In the preclinical models, the combination of cobimetinib and vemurafenib showed that bysimultaneously targeting mutated BRAF V600 proteins and MEK proteins in melanoma cells, thecombination of the two products inhibits MAPK pathway reactivation through MEK1/2, resulting in astronger inhibition of intracellular signalling and decreased tumour cell proliferation

There is limited data on the safety and no data on efficacy of Cotellic in combination withvemurafenib in patients with central nervous system metastasis. There is no data in patients with non-cutaneous malignant melanoma.

Study GO28141 (coBRIM)

Study GO28141 is a multi-centre, randomised, double-blind, placebo-controlled, Phase III study toevaluate the safety and efficacy of Cotellic in combination with vemurafenib as compared tovemurafenib plus placebo, in previously untreated patients with BRAF V600 mutation-positiveunresectable locally advanced (Stage IIIc) or metastatic melanoma (Stage IV).

Only patients with ECOG performance status 0 and 1 were enrolled in Study GO28141. Patients with

ECOG performance status 2 or higher were excluded from the study.

Following confirmation of a BRAF V600 mutation, using the cobas® 4800 BRAF V600 mutation test,495 previously untreated patients with unresectable locally advanced or metastatic melanoma wererandomised to receive either:

* Placebo once daily on Days 1-21 of each 28-day treatment cycle and 960 mg vemurafenib twicedaily on Days 1-28, or

* Cotellic 60 mg once daily on Days 1-21 of each 28-day treatment cycle and 960 mgvemurafenib twice daily on Days 1-28

Progression-free survival (PFS) as assessed by the investigator (INV) was the primary endpoint.

Secondary efficacy endpoints included overall survival (OS), objective response rate, duration ofresponse (DoR) as assessed by INV and PFS as assessed by an independent review facility (IRF).

Key baseline characteristics included: 58% of patients were male, median age was 55 years (range 23to 88 years), 60% had metastatic melanoma stage M1c and the proportion of patients with elevated

LDH was 46.3% in the cobimetinib plus vemurafenib arm and 43.0% in the placebo plus vemurafenibarm.

In Study GO28141, there were 89 patients (18.1%) aged 65-74, 38 patients (7.7%) aged 75-84 and5 patients (1.0%) aged 85 years and older.

Efficacy results are summarized in Table 5.

Table 5 Efficacy results from Study GO28141 (coBRIM)

Cotellic + vemurafenib P l a c e b o + v e m u r a f e n i b

N=247 N=248

Primary Endpointa, f

Progression-Free Survival (PFS)

Median (months) 12.3 7.2(95 % CI) (9.5, 13.4) (5.6, 7.5)

Hazard ratio (95% CI) b 0.58 (0.46; 0.72)

Key Secondary Endpointsa, f,

Overall Survival (OS)g

Median (months) 22.3 17.4(95 % CI) (20.3, NE) (15.0, 19.8)0.70 (95% CI: 0.55, 0.90)

Hazard ratio (95% CI)b(p-value = 0.0050e)

Objective response rate172 (69.6%) 124 (50.0%)(ORR)(95% CI) for ORRc (63.5%, 75.3%) (43.6%, 56.4%)

Difference in ORR % (95% CI) d 19.6 (11.0, 28.3)

Best Overall Response (BOR)

Complete Response 39 (15.8%) 26 (10.5%)

Partial Response 133 (53.8%) 98 (39.5%)

Stable disease 44 (17.8%) 92 (37.1%)

Duration of Response (DoR)

Median DoR (months) 13 9.2(95% CI) for median (11.1, 16.6) (7.5, 12.8)

NE = Not evaluablea Assessed and confirmed by the investigator (INV) using RECIST v1.1b Stratified analysis by geographic region and metastasis classification (disease stage)c Using Clopper-Pearson methodd Using Hauck-Anderson methode The OS p-value (0.0050) crossed the pre-specified boundary (p value <0.0499)f The data cut-off date for this updated PFS analysis and the secondary endpoints of ORR, BOR and DoR is16 January 2015. The median follow up was 14.2 months.g The data cut-off date for the final OS analysis is 28 August 2015 and median follow-up was 18.5 months.

The primary analysis for Study GO28141 was conducted with a data cut-off date of 09 May 2014.

Significant improvement in the primary endpoint, investigator-assessed PFS, was observed in patientsassigned to the Cotellic plus vemurafenib arm compared to the placebo plus vemurafenib arm (HR0.51 (0.39; 0.68); p-value < 0.0001). The median estimate for investigator-assessed PFS was 9.9months for the Cotellic plus vemurafenib arm vs. 6.2 months for the placebo plus vemurafenib arm.

The median estimate for independent review of PFS was 11.3 months for the Cotellic plusvemurafenib arm vs. 6.0 months for the placebo plus vemurafenib arm (HR 0.60 (0.45; 0.79); p-value= 0.0003). The objective response rate (ORR) in the Cotellic plus vemurafenib arm was 67.6% vs44.8% in the placebo plus vemurafenib arm. The difference in ORR was 22.9 % (p-value<0.0001).

The final OS analysis for Study GO28141 was conducted with a data-cut off date of 28 August 2015.

Significant improvement in OS was observed in patients assigned to the Cotellic plus vemurafenib armcompared to the placebo plus vemurafenib arm (Figure 1). The 1-year (75 %) and 2-year (48 %) OSestimates for the Cotellic plus vemurafenib arm were greater than those for placebo plus vemurafenibarm (64 % and 38 % respectively).

Figure 1 Kaplan-Meier curves of final overall survival - Intent to treat population (cut-off date:

28 August 2015)

Figure 2: Forest plot for hazard ratios of final overall survival subgroup analyses - Intent totreat population (cut-off date: 28 August 2015)

Global health status/health-related quality of life by patient-report were measured using the EORTC

Quality of Life Questionnaire - Core 30 (QLQ-C30). Scores for all functioning domains and mostsymptoms (appetite loss, constipation, nausea and vomiting, dyspnoea, pain, fatigue) showed that themean change from baseline was similar between the two treatment arms and did not demonstrate aclinically meaningful change (all scores were ≤ 10 point change from baseline).

Study NO25395 (BRIM7)

The efficacy of Cotellic was evaluated in Phase Ib Study, NO25395, which was designed to assess thesafety, tolerability, pharmacokinetics and efficacy of Cotellic when added to vemurafenib for thetreatment of patients with BRAFV600 mutation-positive (as detected by the cobas® 4800 BRAF V600

Mutation Test), unresectable or metastatic melanoma.

This study treated 129 patients with Cotellic and vemurafenib: 63 were BRAF inhibitor (BRAFi)therapy naïve and 66 patients had previously progressed on prior vemurafenib therapy. Among the 63

BRAFi naïve patients, 20 patients had received prior systemic therapy for advanced melanoma withthe majority (80%) being immunotherapy.

Results of the BRAFi naïve population from Study NO25395 were generally consistent with thosefrom Study GO28141. The BRAFi-naïve patients (n=63) attained an 87% objective response rate,including a complete response in 16% of patients. The median duration of response was 14.3 months.

The median PFS for BRAFi-naïve patients was 13.8 months, with median follow-up time of20.6 months.

Among patients who had progressed on vemurafenib (n=66), the objective response rate was 15%. Themedian duration of response was 6.8 months. The median PFS for patients who had progressed onvemurafenib was 2.8 months, with median follow-up time of 8.1 months.

In patients who were naive to BRAF inhibitor therapy, the median overall survival was 28.5 months(95% CI 23.3-34.6). In patients who had progressed on BRAF inhibitor therapy, the median overallsurvival was 8.4 months (95% CI 6.7-11.1).

A phase I/II, multi-centre, open-label, dose-escalation study was conducted in paediatric patients (< 18years, n=55) to evaluate the safety, efficacy and pharmacokinetics of Cotellic. The study includedpaediatric patients with solid tumours with known or potential RAS/RAF/MEK/ERK pathwayactivation, for which standard therapy has proven to be ineffective or intolerable or for which nocurative standard-of-care treatment options exist. Patients were treated with up to 60 mg of Cotellicorally once daily on Days 1-21 of each 28-day cycle. Overall response rate was low with only 2 partialresponses (3.6%).

Following oral dosing of 60 mg in cancer patients, cobimetinib showed a moderate rate of absorptionwith a median Tmax of 2.4 hours. The mean steady-state Cmax and AUC0-24 were 273 ng/mL and4340 ng.h/mL respectively. The mean accumulation ratio at steady state was approximately 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 healthy subjects.

A human mass balance study was conducted in healthy subjects, and showed that cobimetinib wasextensively metabolised and eliminated in faeces. The fraction absorbed was ~88% indicating highabsorption and first pass metabolism.

The pharmacokinetics of cobimetinib are not altered when administered in the fed state (high-fat meal)compared with the fasted state in healthy subjects. Since food does not alter the pharmacokinetics ofcobimetinib, it can be administered with or without food.

Cobimetinib is 94.8% bound to human plasma proteins in vitro. No preferential binding to human redblood cells was observed (blood to plasma ratio 0.93).

The volume of distribution was 1050 L in healthy subjects given an intravenous dose of 2 mg. Theapparent volume of distribution was 806 L in cancer patients based on population pharmacokineticanalysis.

Cobimetinib is a substrate of P-gp in vitro. The transport across the blood brain barrier is unknown.

Oxidation by CYP3A and glucuronidation by UGT2B7 appear to be the major pathways ofcobimetinib metabolism. Cobimetinib is the predominant moiety in plasma. No oxidative metabolitesgreater than 10% of total circulating radioactivity or human specific metabolites were observed inplasma. Unchanged medicinal product in faeces and urine accounted for 6.6% and 1.6% of theadministered dose, respectively, indicating that cobimetinib is primarily metabolised with minimalrenal elimination. In vitro data indicate cobimetinib is not an inhibitor of OAT1, OAT3 or OCT2.

Cobimetinib and its metabolites were characterised in a mass balance study in healthy subjects. Onaverage, 94% of the dose was recovered within 17 days. Cobimetinib was extensively metabolised andeliminated in faeces.

Following intravenous administration of a 2 mg dose of cobimetinib, the mean plasma clearance (CL)was 10.7 L/hr. The mean apparent CL following oral dosing of 60 mg in cancer patients was 13.8 L/hr.

The mean elimination half-life following oral dosing of cobimetinib was 43.6 hours (range: 23.1 to69.6 hours). Therefore, it may take up to 2 weeks following treatment cessation for cobimetinib to becompletely removed from systemic circulation.

Based on a population pharmacokinetic analysis, gender, race, ethnicity, baseline ECOG, mild andmoderate renal impairment did not affect the pharmacokinetic of cobimetinib. Baseline age andbaseline body weight were identified as statistically significant covariates on cobimetinib clearanceand volume of distribution respectively. However, sensitivity analysis suggests neither of thesecovariates had clinically significant impact on steady state exposure.

Gender does not have an effect on the exposure of cobimetinib, based on a populationpharmacokinetic analysis including 210 women and 277 men.

Age does not have an effect on the exposure of cobimetinib, based on a population pharmacokineticanalysis including 133 patients ≥ 65 years of age.

Based on preclinical data and the human mass balance study, cobimetinib is mainly metabolised, withminimal renal elimination. No formal pharmacokinetic study has been conducted in patients with renalimpairment.

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 renal impairment(CRCL 30 to less than 60 mL/min), and 286 patients with normal renal function (CRCL greater thanor equal to 90 mL/min), showed that CRCL had no meaningful influence on exposure of cobimetinib.

Mild to moderate renal impairment does not influence cobimetinib exposure based on the populationpharmacokinetic analysis. There are minimal data for Cotellic in patients with severe renalimpairment.

The pharmacokinetics of cobimetinib were evaluated in 6 subjects with mild hepatic impairment(Child Pugh A), 6 subjects with moderate hepatic impairment (Child Pugh B), 6 subjects with severehepatic impairment (Child Pugh C) and 10 healthy subjects. Systemic total cobimetinib exposuresafter a single dose were similar in subjects with mild or moderate hepatic impairment compared tohealthy subjects, while subjects with severe hepatic impairment had lower total cobimetinib exposures(AUC0-∞ geometric mean ratio of 0.69 compared to healthy subjects) which is not considered to beclinically significant. Unbound cobimetinib exposures were similar between subjects with mild andmoderate hepatic impairment compared to subjects with normal hepatic function while subjects withsevere hepatic impairment had approximately 2-fold higher exposures (see section 4.2).

The maximum tolerated dose (MTD) in paediatric patients with cancer for the tablet and suspensionformulations were declared at 0.8 mg/kg/day and 1.0 mg/kg/day, respectively. The geometric mean(CV%) steady state exposures in paediatric patients at the declared MTD of 1.0 mg/kg/day(suspension formulation) was Cmax,ss 142 ng/mL (79.5%) and AUC0-24,ss 1862 ng.h/mL (87.0%), whichis approximately 50% lower than in adults at a dose of 60 mg once daily.

Carcinogenicity studies have not been conducted with cobimetinib. Standard genotoxicity studies withcobimetinib were negative.

No dedicated fertility studies in animals have been performed with cobimetinib. In toxicology studies,degenerative changes were observed in reproductive tissues including increased apoptosis/necrosis ofcorpora lutea and seminal vesicle, epididymal and vaginal epithelial cells in rats, and epididymalepithelial cells in dogs. The clinical relevance of this is unknown.

When administered to pregnant rats, cobimetinib caused embryolethality and foetal malformations ofthe great vessels and skull at systemic exposures similar to human exposure at recommended dose.

Cardiovascular safety of cobimetinib in combination with vemurafenib has not been evaluated in vivo.

In vitro, cobimetinib produced moderate hERG ion channel inhibition (IC50= 0.5 µM [266 ng/mL]),which is approximately 18 fold higher than peak plasma concentrations (Cmax) at the 60 mg to bemarketed dose (unbound Cmax=14 ng/mL [0.03 µM]).

Toxicity studies in rats and dogs identified generally reversible degenerative changes in the bonemarrow, gastrointestinal tract, skin, thymus, adrenal gland, liver, spleen, lymph node, kidney, heart,ovary, and vagina at plasma exposures below clinical efficacious levels. Dose limiting toxicitiesincluded skin ulcerations, surface exudates, and acanthosis in the rat and chronic active inflammationand degeneration of the oesophagus associated with varying degrees of gastroenteropathy in dogs.

In a repeat dose toxicity study in juvenile rats, cobimetinib systemic exposures were 2 to11 fold higheron post natal day 10 than on post natal day 38 when exposures were similar to those in adult rats. Injuvenile rats, cobimetinib administration resulted in similar changes as seen in the pivotal toxicitystudies in adults, including reversible degenerative changes in the thymus and liver, decreased spleenand thyroid/parathyroid weights, increased phosphorus, bilirubin and red blood cell mass anddecreased triglycerides. Mortality occurred in juvenile animals at a dose (3 mg/kg) which did not leadto mortalities in adult animals.

Lactose monohydrate

Microcrystalline cellulose (E460)

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc (E553b)

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

Transparent PVC/PVDC blister containing 21 tablets. Each pack contains 63 tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/15/1048/001

Date of first authorisation: 20 November 2015

Date of latest renewal: 25 June 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.