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Cotellic is a brand name for Cobimetinib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 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).
Verbatim from this product's EMA label. Tap a section to expand.
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. 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).
3 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.
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.
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).
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. 0 (common toxicity criteria) for assessment of toxicity in Study GO28141.
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.
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. 2). 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).
2. 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.
1.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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.
4 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. 5 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 […]
12 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**, Pruritus c, Dry skin c 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. 4) 13 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%).
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. 4). Rhabdomyolysis Rhabdomyolysis has been reported in the post-marketing setting. 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 […]
2). 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.
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). 8). 2). Grade 3 liver laboratory abnormalities should be managed with vemurafenib treatment interruption or dose reduction.
2). 8). If rhabdomyolysis is diagnosed, Cotellic treatment should be interrupted and CPK levels and other symptoms monitored until resolution. 2). 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.
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 […]