Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
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 mutationpositive tumour status confirmed by a validated test.
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.
The safety and efficacy of the combination of Cotellic and vemurafenib have not been evaluated in patients with a BRAF V600 mutation-positive melanoma which has metastasised to the brain. The intracranial activity of cobimetinib is currently 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 medications that increase the risk of bleeding (including antiplatelet or anticoagulant therapy). For management of haemorrhage please see section 4.2.
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 trials 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).
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 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 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 trials (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).
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).
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, congenital lactase deficiency or glucose-galactose malabsorption should consult with their physician and discuss whether the benefits outweigh the risks on an individual basis.
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).
If during treatment the QTc exceeds 500 msec, please refer to the vemurafenib SmPC sections 4.2 and 4.4.
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 coadministered 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.
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.
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.
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.
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.
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.
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.
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.
Interaction studies have only been performed in adults.
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.
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.
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.
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.
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 trials (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.
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.
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 NCICTCAE v 4.0 (common toxicity criteria) for assessment of toxicity in Study GO28141.
Table 3. Adverse drug reactions in patients treated with Cotellic in combination with vemurafenib in Study GO28141^:
Common: Basal cell carcinoma, Cutaneous squamous cell carcinoma**, Keratoacanthoma**
Very Common: Anaemia
Common: Dehydration, Hypophosphataemia, Hyponatremia, Hyperglycaemia
Very Common: Serous retinopathya, Blurred vision
Common: Visual impairment
Very Common: Hypertension, Haemorrhage*
Common: Pneumonitis
Very Common: Diarrhoea, Nausea, Vomiting
Very Common: Photosensitivityb, Rash, Rash maculo-papular, Dermatitis acneiform, Hyperkeratosis**
Uncommon: Rhabdomyolysis***
Very Common: Pyrexia, Chills
Very Common: Blood CPK increased, ALT increased, AST increased, Gamma-Glutamyltransferase (GGT) increased, Blood ALP increased
Common: 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
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 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 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 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%).
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).
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).
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).
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 |
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.
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.
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. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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