4.1. Therapeutic indications

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

4.2. Posology and method of administration

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

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

Posology

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 be taken 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-day treatment break has elapsed.

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

Duration of treatment

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

Missed doses

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

Vomiting

In case of vomiting after administration of Cotellic, the patient should not take an additional dose on that 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 the prescriber's assessment of individual patient safety or tolerability. Dose modification of Cotellic is independent 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 of 60 mg once daily (3 tablets)

Grade 2 (intolerable) or Grade 3/4

1st Appearance

Interrupt treatment until Grade ≤ 1, restart treatment at 40 mg once daily (2 tablets)

2nd Appearance

Interrupt treatment until Grade ≤ 1, restart treatment at 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 treatment should be permanently discontinued for haemorrhage events attributed to Cotellic.

Grade 3 events: Cotellic treatment should be interrupted during evaluation to avoid any potential contribution to the event. There is no data on the effectiveness of Cotellic dose modification for haemorrhage events. Clinical judgment should be applied when considering restarting Cotellic treatment. Vemurafenib dosing can be continued when Cotellic treatment is interrupted, if clinically indicated.

Dose modification advice for left ventricular dysfunction

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

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

Patient

LVEF value

Recommended Cotellic dose modification

LVEF value following treatment break

Recommended Cotellic daily dose

Asymptomatic

≥ 50%

(or 40-49% and < 10% absolute decrease from baseline)

Continue at current dose

N/A

N/A

< 40%

(or 40-49% and ≥ 10% absolute decrease from baseline)

Interrupt treatment for 2 weeks

< 10% absolute decrease from baseline

1st occurrence: 40 mg

2nd occurrence: 20 mg

3rd occurrence: permanent discontinuation

< 40%

(or ≥ 10% absolute decrease from baseline)

Permanent discontinuation

Symptomatic

N/A

Interrupt treatment for 4 weeks

Asymptomatic and < 10% absolute decrease from baseline

1st occurrence: 40 mg

2nd occurrence: 20 mg

3rd occurrence: permanent discontinuation

Asymptomatic and < 40%

(or ≥ 10% absolute decrease from baseline)

Permanent discontinuation

Symptomatic regardless of LVEF

Permanent discontinuation

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 not improve 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 dose reduced by 20 mg, if clinically indicated. Patients should be closely monitored. Vemurafenib dosing can 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 ≤3 within 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 a dose reduced by 20 mg and the patient should be closely monitored. Vemurafenib dosing can be continued 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

Liver laboratory abnormalities

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

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

Grade 4: Cotellic treatment and vemurafenib treatment should be interrupted. If liver laboratory abnormalities improve to Grade ≤1 within 4 weeks, Cotellic should be restarted at a dose reduced by 20 mg and vemurafenib at a clinically appropriate dose, per its SmPC.

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

Photosensitivity

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

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

Rash

Rash events may occur with either Cotellic or vemurafenib treatment. The dose of Cotellic and/or vemurafenib 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 continued without 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 Cotellic treatment is modified (if clinically indicated).

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

QT prolongation

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

Special populations

Elderly patients

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

Renal impairment

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

Hepatic impairment

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

Non-Caucasian patients

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

Paediatric population

The safety and efficacy of Cotellic in children and adolescents below 18 years of age have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on posology can be made.

Method of administration

Cotellic is for oral use. The tablets should be swallowed whole with water. They can be taken with or without food.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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 have progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be lower in these patients (see section 5.1). Therefore other treatment options should be considered before treatment with the combination in this prior BRAF inhibitor treated population. The sequencing of treatments 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 the known safety profile of Cotellic in combination with vemurafenib. The efficacy of the Cotellic and vemurafenib combination in these patients has not been evaluated. The intracranial activity of Cotellic is unknown (see sections 5.1 and 5.2).

Haemorrhage

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 (including antiplatelet 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 patients treated with MEK-inhibitors, including Cotellic (see section 4.8). The majority of events were reported as chorioretinopathy or retinal detachment.

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

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

Left ventricular dysfunction

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 first month of treatment and at least every 3 months or as clinically indicated until treatment discontinuation. Decrease in LVEF from baseline can be managed using treatment interruption, dose reduction or with treatment discontinuation (see section 4.2).

All patients restarting treatment with a dose reduction of Cotellic should have LVEF measurements taken 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

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

Liver laboratory abnormalities, specifically increases in alanine aminotransferase (ALT), aspartate aminotransferase (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 of combination treatment and monthly during treatment, or more frequently as clinically indicated (see section 4.2).

Grade 3 liver laboratory abnormalities should be managed with vemurafenib treatment interruption or dose reduction. Manage Grade 4 liver laboratory abnormalities with treatment interruption, dose reduction 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 other symptoms monitored until resolution. Depending on the severity of rhabdomyolysis, dose reduction or treatment discontinuation may be required (see section 4.2).

Grade 3 and 4 CPK elevations, including asymptomatic elevations over baseline, also occurred in patients receiving Cotellic with vemurafenib in clinical studies(see section 4.8). The median time to first occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 11 days to 10 months); the median 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 establish baseline values, and then monitored monthly during treatment, or as clinically indicated. If serum CPK is elevated, check for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation; treatment interruption, dose reduction or treatment discontinuation may be required (see section 4.2).

Diarrhoea

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 diarrhoea that occurs despite supportive care, Cotellic and vemurafenib should be withheld until diarrhoea has improved to Grade ≤1. If Grade ≥3 diarrhoea recurs, the dose of Cotellic and vemurafenib should be reduced (see section 4.2).

Drug-drug interactions: CYP3A inhibitors

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

QT prolongation

If during treatment the QTc exceeds 500 msec, please refer to the vemurafenib SmPC sections 4.2 and 4.4.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, 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'.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on cobimetinib

CYP3A inhibitors

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

Strong CYP3A inhibitors (see section 4.4.)

Avoid concurrent use of strong CYP3A inhibitors during treatment with cobimetinib. Strong CYP3A inhibitors include, but are not limited to ritonavir, cobicistat, telaprevir, lopinavir, itraconazole, voriconazole, clarithromycin, telithromycin, posaconazole, nefazodone and grapefruit juice. If concomitant use of a strong CYP3A inhibitor is unavoidable, patients should be carefully monitored for safety. For strong CYP3A inhibitors used short-term (7 days or less), consider interrupting cobimetinib 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. When cobimetinib is co-administered with a moderate CYP3A inhibitor, patients should be carefully monitored for safety.

Mild CYP3A inhibitors

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

CYP3A inducers

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 and strong CYP3A inducers (e.g. carbamazepine, rifampicin, phenytoin, and St. John's Wort) should be avoided. Alternative agents with no or minimal CYP3A induction should be considered. Given that cobimetinib concentrations are likely to be significantly reduced when co-administered with moderate to 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 inhibitors such as ciclosporin and verapamil may have the potential to increase plasma concentrations of cobimetinib.

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 of midazolam (a sensitive CYP3A substrate) and dextromethorphan (a sensitive CYP2D6 substrate) were not altered in the presence of cobimetinib.

CYP1A2 substrates

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

BCRP substrates

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 and vemurafenib in unresectable or metastatic melanoma patients and therefore no dose adjustments is recommended.

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 these findings has not been investigated.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception

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

Pregnancy

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

Breast-feeding

It is not known whether cobimetinib is excreted in human breast milk. A risk to the newborns/infants cannot 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 of therapy for the woman.

Fertility

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

4.7. Effects on ability to drive and use machines

Cotellic has minor influence on the ability to drive or use machines. Visual disturbances have been reported 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 any other adverse effects that may affect their ability.

4.8. Undesirable effects

Summary of the safety profile

The safety of Cotellic in combination with vemurafenib has been evaluated in 247 patients with advanced 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 the placebo plus vemurafenib arm.

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

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

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

Tabulated list of adverse reactions

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 in combination with vemurafenib as compared to vemurafenib alone in previously untreated BRAF V600 mutation-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 plus vemurafenib 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 organ class, frequency and grade of severity. The following convention has been used for the classification of 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 frequency grouping, 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 with vemurafenib in Study GO28141^

System organ class

Very Common

Common

Uncommon

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Basal cell carcinoma, Cutaneous squamous cell carcinoma**, Keratoacanthoma**

Blood and lymphatic system disorders

Anaemia

Metabolism and nutrition disorders

Dehydration, Hypophosphataemia, Hyponatremia, Hyperglycaemia

Eye disorders

Serous retinopathya, Blurred vision

Visual impairment

Vascular disorders

Hypertension, Haemorrhage*

Respiratory, thoracic and mediastinal disorders

Pneumonitis

Gastrointestinal disorders

Diarrhoea, Nausea, Vomiting

Stomatitis

Skin and subcutaneous tissue disorders

Photosensitivityb, Rash, Rash maculo-papular, Dermatitis acneiform, Hyperkeratosis**, Pruritusc, Dry skinc

Musculoskeletal and connective tissue disorders

Rhabdomyolysis***

General disorders and administration site conditions

Pyrexia, Chills, Oedema peripheralc

Investigations

Blood CPK increased, ALT increased, AST increased, Gamma-Glutamyltransferase (GGT) increased, Blood ALP increased

Ejection fraction decreased, Blood bilirubin 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 in the “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 elastosis

c 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 or metastatic melanoma.

Description of selected adverse reactions

Haemorrhage

Bleeding events have been reported more frequently in the Cotellic plus vemurafenib arm than in the placebo plus vemurafenib arm (all types and Grades: 13% vs 7%). The median time to first onset was 6.1 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 tract haemorrhage) were reported in the post-marketing setting. The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, treat as clinically indicated (see section 4.2 and 4.4).

Rhabdomyolysis

Rhabdomyolysis has been reported in the post-marketing setting. Signs or symptoms of rhabdomyolysis warrant an appropriate clinical evaluation and treatment as indicated, along with Cotellic dose modification or discontinuation according to the severity of the adverse reaction (see section 4.2 and 4.4).

Photosensitivity

Photosensitivity has been observed with a higher frequency in the Cotellic plus vemurafenib arm vs placebo 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 placebo plus vemurafenib arm.

There were no apparent trends in the time of onset of Grade ≥3 events. Grade ≥3 photosensitivity events in the Cotellic plus vemurafenib arm were treated with primary topical medicinal products in conjunction 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 plus vemurafenib arm vs placebo plus vemurafenib arm (all Grade: 3% vs 13%). Keratoacanthoma has been reported with a lower frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm (all Grade: 2% vs 9%). Hyperkeratosis has been reported with a lower frequency in the 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.) For patients reporting new or worsening visual disturbances, an ophthalmologic examination is recommended. Serous retinopathy can be managed with treatment interruption, dose reduction or with treatment discontinuation (see Table 1 in section 4.2).

Left ventricular dysfunction

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 first month of treatment and at least every 3 months or as clinically indicated until treatment discontinuation. Decrease in LVEF from baseline can be managed using treatment interruption, dose reduction or with treatment discontinuation (see section 4.2).

Laboratory abnormalities

Liver laboratory abnormalities

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

Liver laboratory tests should be monitored before initiation of combination treatment and monthly during 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 Cotellic plus 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 concurrent increases in blood CPK.

Table 4 provides the frequency of measured liver laboratory abnormalities and elevated creatine phosphokinase 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 laboratory data

Cobimetinib plus vemurafenib

(n = 247)

(%)

Placebo plus vemurafenib

(n = 246)

(%)

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

Special populations

Elderly patients

In the Phase III study with Cotellic in combination with vemurafenib in patients with unresectable or metastatic melanoma (n=247), 183 patients (74%) were <65 years of age, and 44 patients (18%) were 65-74 years of age, 16 (6%) were 75-84 years of age, and 4 patients (2%) were aged ≥85 years. The proportion of patients experiencing adverse events (AE) was similar in the patients aged <65 years and those 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.

Paediatric population

The safety of Cotellic in children and adolescents has not been fully established. The safety of Cotellic was assessed in a multi-centre, open-label, dose-escalation study in 55 paediatric patients aged 2 to 17 years with solid tumours. The safety profile of Cotellic in these patients was consistent with that in the adult population (see section 5.2).

Renal impairment

No pharmacokinetic trial in subjects with renal impairment has been conducted. Dose adjustment is not recommended for mild to moderate renal impairment based on the results of the population pharmacokinetic analysis. There are minimal data for Cotellic in patients with severe renal impairment. Cotellic should be used with caution in patients with severe renal impairment.

Hepatic impairment

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

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4.9. Overdose

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 for overdosage with cobimetinib.