Cotellic 20 mg film-coated tablets

EMEA/H/C/xxxx/IG/1730. Implementation of PRAC recommendation (EPITT Np. 19961) - "Stomatitis" added to section 4.8 Undesirable effects and IIIB Leaflet Section 4. For tracked changes refer to the corresponding EU record.

EMEA/H/C/xxxx/IG/1730. Implementation of PRAC recommendation (EPITT Np. 19961) - "Stomatitis" added to section 4.8 Undesirable effects and IIIB Leaflet Section 4. For tracked changes refer to the corresponding EU record.

EMEA/H/C/003960/II/0025. EU SmPC: Section 4.2 Posology and method of administration, 4.8 Undesirable effects, 5.1 Pharmacodynamic properties and 5.2 Pharmacokinetic properties and IIIB Package leaflet updated to add information related to pediatrics. 

EMEA/H/C/003960/II/0025. EU SmPC: Section 4.2 Posology and method of administration, 4.8 Undesirable effects, 5.1 Pharmacodynamic properties and 5.2 Pharmacokinetic properties and IIIB Package leaflet updated to add information related to pediatrics. 

EMEA/H/C/003960/R/0019. Cotellic 5 year centralised licence renewal. Removal of cobimetinib from the List of Medicinal Products requiring additional monitoring (with corresponding removal of the inverted black triangle symbol from the PI). Furthermore an update to the PIL in line with the excipients guideline (EMA/CHMP/302620/2017) has been included and further minor updates to the SmPC/PIL an Annex II to align with the current QRD template.

COTELLIC, EMEA/H/C/003960/IB/0017

Shelf-life extension from 48 to 60 months for the finished drug product as packaged for sale.

7.       MARKETING AUTHORISATION HOLDER

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

10.     DATE OF REVISION OF THE TEXT

16 March 2018

4.2       Posology and method of administration

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 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.

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.

Creatine phosphokinase (CPK) elevations

Cotellic dosing does not need to be modified or interrupted to manage asymptomatic CPK elevations.

4.4     Special warnings and precautions for use

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 medications that increase the risk of bleeding (including antiplatelet or anticoagulant therapy). For management of haemorrhage please 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 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).

4.8       Undesirable effects

Table 3 Adverse drug reactions in patients treated with Cotellic in combination with vemurafenib in Study GO28141^{^}

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

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%). Higher frequencies in the Cotellic plus vemurafenib arm were observed for cerebral haemorrhage (1% vs 0%), gastrointestinal tract haemorrhage (4% vs 1%), reproductive system haemorrhage (2% vs <1%) and haematuria (3% vs 1%). 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 (12% of patients in the Cotellic plus vemurafenib arm vs 7% patients in the placebo plus vemurafenib arm). Most events resolved with no change in Cotellic dose. Grade 3‑4 events were experienced by 1% of patients in each arm. 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).The median time to first onset was 4.4 months (range 0.0 to 12.7 months) in the Cotellic plus vemurafenib arm.  

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).

4.8       Undesirable effects

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).

Table 3 Adverse drug reactions in patients treated with Cotellic in combination with vemurafenib in Study GO28141^{^}

^{^} 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.

^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

 

[...]

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

5.1     Pharmacodynamic properties

Table 5 Efficacy results from Study GO28141 (coBRIM) – Cut-off date 16 January 2015

NE = Not evaluable

^a Assessed and confirmed by the investigator (INV) using RECIST v1.1

^b Stratified analysis by geographic region and metastasis classification (disease stage)

^c Using Clopper-Pearson method

^d Using Hauck-Anderson method

^e 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 is 16 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 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 arm compared to the placebo plus vemurafenib arm. (Figure 1). The 1-year (75 %) and 2-year (48 %) OS estimates for the Cotellic plus vemurafenib arm were greater than those for placebo plus vemurafenib arm (64 % and 38 % respectively).

Figure 1 Kaplan-Meier curves of progression-free survival (INV) – intent to treat population (cut-off date: 16 January 2015)

Figure 21 Kaplan-Meier curves of final overall survival – Intent to treat population (cut-off date: 28 August 2015)

Figure 23 Forest plot for hazard ratios of progression-free survival subgroup analyses – intent to treat population (cut-off date: 16 January 2015)

Figure 42: Forest plot for hazard ratios of final overall survival subgroup analyses – Intent to treat 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 Aall functioning domains and most symptoms (appetite loss, constipation, insomnia, nausea and vomiting, dyspnoea, pain, fatigue) showed that the mean change from baseline was were similar between the two treatment arms and did not demonstrate a clinically meaningful change (all scores were ≥≤ 10 point increase or decreasechange from baseline).

Study NO25395 (BRIM7)

The efficacy of Cotellic was evaluated in Phase Ib Study, NO25395, which was designed to assess the safety, tolerability, pharmacokinetics and efficacy of Cotellic when added to vemurafenib for the treatment 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 with the majority (80%) being immunotherapy.

Results of the BRAFi naïve population from Study NO25395 were generally consistent with those from Study GO28141. The BRAFi‑naïve patients (n=63) attained an 87% objective response rate, including a complete response in 160% of patients. The median duration of response was 14.312.5 months. The median PFS for BRAFi‑naïve patients was 13.87 months, with median follow-up time of 20.612.7 months.

Among patients who had progressed on vemurafenib (n=66), the objective response rate was 15%. The median duration of response was 6.87 months. The median PFS for patients who had progressed on vemurafenib 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 at 1‑year was 83% (95% CI 73, 923) and 61% (95% CI 48, 74) at 2‑year28.5 months (95% CI 23.3-34.65). In patients who had progressed on BRAF inhibitor therapy, the median overall survival was 8.4 months (95% CI 6.7,-11.1). at 1‑year was 352% (95% CI 1923, 457) and 15% (95% CI 5, 25) at 2‑year.

6.3     Shelf life

2 years4 years.

10.     DATE OF REVISION OF THE TEXT

19 July 2016

4.4     Special warnings and precautions for use

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 (1‑7 13 months). 

4.8       Undesirable effects

Summary of the safety profile

The safety of Cotellic in combination with vemurafenib has been evaluated in 254 247 patients with advanced BRAF V600 mutated melanoma in Study GO28141.The median time to onset for theof first Grade ≥3 adverse events was 0.65 months in the Cotellic plus vemurafenib arm vs 0.8 months in the placebo plus vemurafenib arm.

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 in patients treated with Cotellic in combination with vemurafenib in Study GO28141

* 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.

^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

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: 130% vs 76%). Higher frequencies in the Cotellic plus vemurafenib arm were observed for cerebral haemorrhage (1% vs 0%), gastrointestinal tract haemorrhage (34% vs 1%), reproductive system haemorrhage (2% vs <1%) and haematuria (23% vs 1%).

The majority of events were Grade 1 or 2 and non-serious (912% of patients in the Cotellic plus vemurafenib arm vs 57% patients in the placebo plus vemurafenib arm). Grade 3‑45 events were experienced by 1%  and 0.4% of patients in each arm, respectively. The median time to first onset was 2.8 4.4 months (range 0.0 to 12.7 months) in the Cotellic plus vemurafenib arm.

Photosensitivity

Photosensitivity has been observed with a higher frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm (4147% vs 3135%).  The majority of events were Grades 1 or 2, with Grade ≥3 events occurring in 34% of patients in the Cotellic plus vemurafenib arm vs 0% in the placebo plus vemurafenib arm.

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 1113%).  Keratoacanthoma has been reported with a lower frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm (all Grade: 12% vs 89%). Hyperkeratosis has been reported with a lower frequency in the Cotellic plus vemurafenib vs placebo plus vemurafenib arm (all Grade: 1011% vs 2930%).

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

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

Special populations

Elderly patients

In the Phase III study with Cotellic in combination with vemurafenib in patients with unresectable or metastatic melanoma (n=254247), 1839 patients (74%) were <65 years of age, and 44 patients (187%) were 65‑74 years of age, 167 (67%) were 75‑84 years of age, and 4 patients (2%) were aged ³85 years. The proportion of patients experiencing adverse events (AE) was similar in the patients aged <65 years and those aged ³65 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.

10.     DATE OF REVISION OF THE TEXT

1 June 2016

4.2       Posology and method of administration

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).

The safety and efficacy of Cotellic has not been established in patients with hepatic impairment (see section 5.2). There are no pharmacokinetic data in patients with moderate or severe hepatic impairment.  Cotellic should be used with caution in patients with moderate to severe hepatic impairment.

 4.4     Special warnings and precautions for use

[....]

Drug-drug interactions: CYP3A4 inhibitors

Concurrent use of strong CYP3A inhibitors during treatment with Cotellic should be avoided. Caution should be exercised if a moderate CYP3A4 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).

[....]

4.5     Interaction with other medicinal products and other forms of interaction

[...]

Strong CYP3A4 inhibitors (see section 4.4.): Avoid concurrent use of strong CYP3A inhibitors during treatment with cobimetinib. Strong CYP3A4 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 CYP3A4 inhibitors (see section 4.4.): Caution should be exercised if cobimetinib is co-administered with moderate CYP3A inhibitors. Moderate CYP3A4 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 CYP3A4 inhibitors: Cobimetinib can be co-administered with mild inhibitors of CYP3A without dose adjustment.

[....]

4.8       Undesirable effects

[....]

Hepatic impairment

No dose adjustment is recommended in patients with hepatic impairment (see section 5.2).No pharmacokinetic data in subjects with hepatic impairment are available.

[...]

5.2     Pharmacokinetic properties

[....]

Hepatic impairment

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 severe hepatic impairment (Child Pugh C) and 10 healthy subjects. Systemic total cobimetinib exposures after a single dose were similar in subjects with mild or moderate hepatic impairment compared to healthy 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 be clinically significant. Unbound cobimetinib exposures were similar between subjects with mild and moderate hepatic impairment compared to subjects with normal hepatic function while subjects with severe hepatic impairment had approximately 2-fold higher exposures (see section 4.2).

No pharmacokinetic data in subjects with hepatic impairment are available.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20 November 2015

10.     DATE OF REVISION OF THE TEXT

01 June 2016