Special Warning : אזהרת שימוש

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 Prescribing Information).

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 Prescribing Information 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’.

Effects on Driving

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.