Presentation and Status in Health Basket
Film Coated Tablets
63 X 20 mg
The recommended dose of Cobimetinib is 60 mg (3 tablets of 20 mg) once daily.
Cobimetinib 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 Cobimetinib treatment cycle should start after the 7-day treatment break has elapsed.
Duration of treatment: Treatment with Cobimetinib should continue until the patient no longer derives benefit or until the development of unacceptable toxicity.
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 Cobimetinib, 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 Cobimetinib 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.
For recommended Cobimetinib dose modifications: See prescribing information for full details.
For dose modification advice for left ventricular dysfunction: See prescribing information for full details.
For dosage in special populations: See prescribing information for full details.
Indicated for use in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Hypersensitivity to the active substance or to any of the excipients.
Before taking Cobimetinib in combination with vemurafenib, patients must have BRAF V600 mutationpositive 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. 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: 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.
Serous retinopathy: Serous retinopathy (fluid accumulation within the layers of the retina) has been observed in patients treated with MEK-inhibitors, including Cotellic. 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.
Left ventricular dysfunction: Decrease in LVEF from baseline has been reported in patients receiving Cotellic.
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.
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.
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.
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.
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.
Lactose intolerance: 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.
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.
QT prolongation: If during treatment the QTc exceeds 500 msec, please refer to the vemurafenib Prescribing Information sections 4.2 and 4.4.
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.
See prescribing information for full details.
Interaction studies have only been performed in adults.
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 CYP3A4 inhibitors: 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: Caution should be exercised if cobimetinib is coadministered 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.
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.
Pregnancy and Lactation
Pregnancy: There are no data from the use of Cotellic in pregnant women.
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.
See prescribing information for full details.
There is no experience with overdose in human clinical trials. In case of suspected overdose, cobimetinib should be withheld and supportive care instituted. There is no specific antidote for overdosage with cobimetinib.
Storage: Do not store above 30°C.