Cotellic (Cobimetinib)
MEK inhibitor for BRAF V600-mutated advanced melanoma, used in combination with vemurafenib
Quick Facts About Cotellic
Key Takeaways About Cotellic
- Combination therapy only: Cotellic must always be used together with vemurafenib – it is not approved as a standalone treatment for melanoma
- BRAF mutation required: Before starting treatment, a validated test must confirm the presence of a BRAF V600 mutation in the melanoma tumor
- Cyclic dosing: Take 60 mg (three tablets) once daily for 21 days, followed by a 7-day break, repeating this 28-day cycle continuously
- Eye monitoring essential: Cotellic can cause serous retinopathy and other vision problems; regular eye examinations are required during treatment
- Heart function checks: Your doctor will monitor your heart’s pumping ability (ejection fraction) before and during treatment, as Cotellic may reduce cardiac output
What Is Cotellic and What Is It Used For?
Cotellic (cobimetinib) is an anti-cancer medicine that targets the MEK protein, a key component of the signaling pathway that drives melanoma growth. It is used in combination with vemurafenib to treat adults whose melanoma has a BRAF V600 mutation and has spread to other parts of the body or cannot be surgically removed.
Melanoma is the most serious form of skin cancer, arising from the pigment-producing cells known as melanocytes. While early-stage melanoma can often be cured by surgical excision alone, advanced melanoma that has metastasized (spread) to distant organs or lymph nodes carries a significantly worse prognosis. Research has revealed that approximately 40–50% of cutaneous melanomas harbor mutations in the BRAF gene, most commonly at the V600 position, which leads to constitutive activation of the MAPK (mitogen-activated protein kinase) signaling pathway and uncontrolled cell proliferation.
Cotellic contains the active substance cobimetinib, a potent and highly selective reversible inhibitor of MEK1 and MEK2 (mitogen-activated extracellular signal-regulated kinase 1 and 2). MEK proteins occupy a critical position in the RAS/RAF/MEK/ERK signaling cascade, functioning as the intermediary between the upstream RAF kinases and the downstream ERK effectors that ultimately drive gene transcription, cell division, and survival. By blocking MEK, cobimetinib prevents the relay of growth signals even when the upstream BRAF protein is abnormally active.
The rationale for combining Cotellic with vemurafenib stems from the clinical observation that single-agent BRAF inhibitor therapy, while initially highly effective, frequently leads to acquired resistance within 6 to 12 months. This resistance often occurs through reactivation of the MAPK pathway via alternative signaling routes that bypass the BRAF blockade. By simultaneously inhibiting both BRAF (with vemurafenib) and MEK (with cobimetinib), the combination provides a more complete blockade of the MAPK pathway, resulting in deeper and more durable anti-tumor responses.
How Cotellic Works
The MAPK signaling pathway is one of the most important intracellular communication networks regulating cell growth, differentiation, and survival. In normal cells, growth factor signals from outside the cell activate RAS proteins at the cell membrane, which in turn activate RAF kinases (including BRAF), which then activate MEK, which finally activates ERK. ERK translocates to the cell nucleus and triggers gene expression programs that drive cell proliferation.
In BRAF V600-mutated melanoma, the mutant BRAF protein is constitutively active regardless of upstream signals, continuously driving MEK and ERK activation and fueling unchecked cancer cell growth. Vemurafenib specifically blocks this mutant BRAF protein. However, cancer cells can develop workarounds, reactivating MEK through alternative pathways. Cobimetinib addresses this by directly blocking MEK1 and MEK2, ensuring that even if cancer cells find a way around the BRAF blockade, the downstream signal is still interrupted.
The clinical efficacy of the Cotellic plus vemurafenib combination was demonstrated in the pivotal coBRIM phase III trial, which showed a significant improvement in progression-free survival (12.3 months versus 7.2 months with vemurafenib alone) and overall survival (22.3 months versus 17.4 months). These results established the combination as a standard-of-care regimen for BRAF V600-mutated unresectable or metastatic melanoma and led to regulatory approvals by both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA).
Before starting Cotellic, your doctor will order a validated BRAF mutation test on your melanoma tissue. Only patients whose tumors carry a BRAF V600 mutation (most commonly V600E or V600K) are eligible for this treatment. Testing is performed using an approved diagnostic assay on a biopsy sample.
What Should You Know Before Taking Cotellic?
Before starting Cotellic, your doctor will assess your overall health including heart function, liver function, eye health, and muscle enzyme levels. You must not take Cotellic if you are allergic to cobimetinib or any of the tablet’s other ingredients. Several conditions and medications require special attention or monitoring.
Because cobimetinib affects a fundamental signaling pathway present in many cell types throughout the body, it has the potential to cause effects beyond the targeted cancer cells. A thorough medical evaluation before treatment helps identify patients who may be at increased risk for certain side effects and allows for appropriate baseline measurements that can be compared with results obtained during therapy.
Contraindications
You must not take Cotellic if:
- You are allergic (hypersensitive) to cobimetinib or any of the other ingredients in the tablet (including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate)
If you are unsure whether any of these apply to you, consult your doctor, pharmacist, or nurse before taking Cotellic.
Warnings and Precautions
Talk to your doctor, pharmacist, or nurse before taking Cotellic. Your medical team needs to be aware of the following potential complications so they can monitor you appropriately:
Bleeding: Cotellic can cause serious hemorrhage, particularly in the brain or gastrointestinal tract. Contact your doctor immediately if you experience unusual bleeding or any of these symptoms: headache, dizziness, weakness, blood in stools or black-colored stools, or bloody vomiting. The risk of bleeding may be increased in patients taking anticoagulants or antiplatelet medications concurrently.
Eye problems: Cotellic can cause visual disturbances, including serous retinopathy, a condition involving fluid accumulation beneath the retina. Symptoms include blurred vision, distorted vision, or partial loss of vision. Your doctor should perform an ophthalmological examination at baseline and at regular intervals during treatment, and immediately if you report any new or worsening visual symptoms. In clinical trials, serous retinopathy was reported in approximately 26% of patients receiving cobimetinib plus vemurafenib.
Heart problems: Cotellic can reduce the left ventricular ejection fraction (LVEF), which is the percentage of blood pumped out of the heart with each beat. Your doctor will perform echocardiography or multigated acquisition (MUGA) scans before starting treatment and at regular intervals to monitor cardiac function. Contact your doctor immediately if you experience palpitations, a racing or irregular heartbeat, dizziness, shortness of breath, fatigue, or swelling in the legs.
Liver problems: Cotellic may elevate certain liver enzymes (ALT, AST) in the blood, indicating liver stress. Your doctor will perform regular blood tests to monitor liver function throughout treatment. Dose reductions, treatment interruptions, or permanent discontinuation may be necessary depending on the severity of liver enzyme elevations.
Muscle problems: Cotellic can cause elevated creatine phosphokinase (CPK) levels, an enzyme found primarily in muscle tissue, the heart, and the brain. Elevated CPK may indicate muscle damage, and in rare cases, rhabdomyolysis (severe muscle breakdown) can occur. Your doctor will order blood tests to monitor CPK levels. Contact your doctor immediately if you experience muscle pain, muscle cramps, weakness, or dark or red-colored urine.
Diarrhea: Cotellic frequently causes diarrhea, which can range from mild to severe. Severe diarrhea can lead to dehydration and electrolyte imbalances. Contact your doctor immediately if you develop diarrhea, and follow their instructions on preventive and treatment measures, which may include adequate fluid intake and anti-diarrheal medications.
Pregnancy and Breastfeeding
If you are pregnant, breastfeeding, think you may be pregnant, or are planning to become pregnant, seek advice from your doctor or pharmacist before taking this medicine.
- Pregnancy: Cotellic is not recommended during pregnancy. Although human studies are lacking, based on its mechanism of action, cobimetinib may cause fetal harm or birth defects. If you become pregnant during treatment or within 3 months after your last dose, contact your doctor immediately
- Breastfeeding: It is not known whether cobimetinib passes into breast milk. Your doctor will discuss the benefits and risks of taking Cotellic while breastfeeding
- Contraception: Women of childbearing potential should use two effective methods of contraception (such as a condom or other barrier method, with spermicide if available) during treatment and for at least 3 months after the last dose. Discuss the most appropriate contraceptive methods with your doctor
Driving and Operating Machinery
Cotellic may impair your ability to drive and use machines. Avoid driving or operating machinery if you experience visual disturbances or other problems that could affect these abilities, such as dizziness or fatigue. If you are unsure whether it is safe, consult your doctor.
Children and Adolescents
Cotellic is not recommended for children and adolescents under 18 years of age. The safety and efficacy of cobimetinib have not been established in the pediatric population.
Cotellic tablets contain lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to certain sugars, contact your doctor before taking this medicine. This medicine also contains less than 1 mmol (23 mg) sodium per tablet, meaning it is essentially sodium-free.
How Does Cotellic Interact with Other Drugs?
Cobimetinib is primarily metabolized by the CYP3A4 enzyme. Strong CYP3A4 inhibitors (such as itraconazole and ritonavir) can significantly increase cobimetinib blood levels, while strong CYP3A4 inducers (such as rifampicin and carbamazepine) can substantially reduce them. Grapefruit juice should be avoided as it also inhibits CYP3A4.
Drug interactions are an important consideration with cobimetinib because changes in its blood concentration can affect both efficacy and safety. Cobimetinib is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 (CYP3A4) enzyme system. Co-administration with drugs that strongly inhibit or induce CYP3A4 can lead to clinically significant alterations in cobimetinib exposure. Always inform your doctor about all medications you are taking, including prescription drugs, over-the-counter medicines, herbal supplements, and vitamins.
Major Interactions
| Interacting Drug | Purpose | Effect on Cotellic |
|---|---|---|
| Itraconazole, voriconazole, posaconazole | Antifungal medications | Strong CYP3A4 inhibitors – increase cobimetinib levels significantly |
| Clarithromycin, erythromycin, telithromycin | Antibiotics | CYP3A4 inhibitors – increase cobimetinib levels |
| Ritonavir, cobicistat, lopinavir | HIV antivirals | Strong CYP3A4 inhibitors – increase cobimetinib levels significantly |
| Rifampicin | Antibiotic (tuberculosis) | Strong CYP3A4 inducer – decreases cobimetinib levels by up to 83% |
| Carbamazepine, phenytoin | Anticonvulsants (seizures) | Strong CYP3A4 inducers – decrease cobimetinib levels substantially |
| St. John’s Wort | Herbal remedy for depression | CYP3A4 inducer – may reduce cobimetinib efficacy |
| Diltiazem, verapamil | Blood pressure / heart medications | Moderate CYP3A4 inhibitors – may increase cobimetinib levels |
| Amiodarone | Heart rhythm medication | CYP3A4 inhibitor – may increase cobimetinib levels |
| Imatinib | Cancer treatment | Moderate CYP3A4 inhibitor – may increase cobimetinib levels |
Food Interactions
Grapefruit juice: You should avoid consuming grapefruit or grapefruit juice while taking Cotellic. Grapefruit contains compounds that inhibit CYP3A4 enzymes in the gut wall and liver, which can increase the amount of cobimetinib absorbed into the bloodstream. This elevated exposure may intensify side effects. Seville oranges and pomelos may have similar effects and should also be avoided.
Concomitant use of strong CYP3A4 inhibitors with Cotellic can increase cobimetinib exposure by approximately 6.7-fold. If short-term use (14 days or fewer) of a moderate CYP3A4 inhibitor is necessary, the cobimetinib dose should be reduced from 60 mg to 20 mg daily. Strong CYP3A4 inhibitors should be avoided. If a strong CYP3A4 inducer must be used, be aware that it may substantially reduce Cotellic efficacy.
What Is the Correct Dosage of Cotellic?
The recommended dosage of Cotellic is 60 mg (three 20 mg tablets) taken once daily for 21 consecutive days, followed by a 7-day treatment break. This 28-day cycle is repeated continuously. Cotellic should always be taken in combination with vemurafenib as directed by your doctor.
Cotellic follows a carefully designed cyclic dosing schedule intended to balance anti-tumor efficacy with tolerability. The 21-day-on, 7-day-off regimen allows the body periodic recovery from the continuous MEK inhibition while maintaining therapeutic drug levels during the active treatment phase. Always take this medicine exactly as your doctor or pharmacist has told you.
Adults
Standard Adult Dosage
Take 3 tablets (60 mg total) once daily for 21 consecutive days. After 21 days, do not take any Cotellic tablets for 7 days. During this 7-day break, continue taking vemurafenib as instructed by your doctor. Start the next 21-day treatment period after the 7-day break. Each complete cycle is 28 days.
| Period | Days | Cotellic Dose | Vemurafenib |
|---|---|---|---|
| Treatment period | Days 1–21 | 60 mg (3 tablets) once daily | Continue as prescribed |
| Rest period | Days 22–28 | No Cotellic | Continue as prescribed |
How to take the tablets: Swallow the tablets whole with a glass of water. Cotellic can be taken with or without food. Do not crush, chew, or break the tablets.
Dose modifications: If you experience side effects, your doctor may decide to lower your dose, temporarily interrupt treatment, or permanently discontinue Cotellic. Dose reductions typically follow a stepwise approach: from 60 mg (3 tablets) to 40 mg (2 tablets) to 20 mg (1 tablet) once daily. Always follow your doctor’s instructions regarding dose adjustments.
Children
Cotellic is not recommended for use in children and adolescents under 18 years of age. There is no relevant clinical data supporting its use in pediatric patients.
Elderly
No dose adjustment is required specifically for elderly patients. However, older adults may be more susceptible to certain side effects, particularly cardiac events and dehydration from diarrhea. Close monitoring is recommended, and dose adjustments should be made based on individual tolerability.
Missed Dose
What to Do If You Miss a Dose
If it is more than 12 hours before your next scheduled dose, take the missed dose as soon as you remember it. If it is less than 12 hours until your next dose, skip the missed dose and take the next one at the usual time. Do not take a double dose to compensate for a missed dose.
Vomiting After a Dose
If you vomit after taking Cotellic, do not take an additional dose on that day. Continue taking Cotellic as normal the next day at your usual time.
Overdose
If you take more Cotellic than prescribed, contact your doctor or go to the nearest emergency department immediately. Bring the medicine package and this information with you. There is no specific antidote for cobimetinib overdose. Treatment is supportive and symptomatic.
It is important to continue taking Cotellic for as long as your doctor prescribes it. Do not stop treatment without discussing it with your doctor first, even if you feel better or experience side effects. Your doctor will determine whether treatment adjustments or discontinuation are appropriate based on your clinical response and tolerability.
What Are the Side Effects of Cotellic?
Like all medicines, Cotellic can cause side effects, although not everybody gets them. The most common side effects include diarrhea, skin rash, nausea, fever, increased sun sensitivity, elevated liver enzymes, and vision problems. Serious side effects include severe bleeding, reduced heart function, rhabdomyolysis, and serous retinopathy.
Side effects of Cotellic are typically managed through dose modifications (reduction, interruption, or discontinuation), supportive care, and close monitoring. It is important to also read the patient information leaflet for vemurafenib, as the two medicines are used together and each can cause its own set of side effects. If you experience any side effects, your doctor will determine the most appropriate course of action.
Serious Side Effects
Contact your doctor immediately if you experience any of the following serious side effects:
Cotellic can cause serious hemorrhage, particularly in the brain or gastrointestinal tract. Symptoms may include: severe headache, dizziness or weakness; bloody vomiting; abdominal pain; red- or black-colored stools. Seek immediate medical attention if any of these occur.
Cotellic can cause serous retinopathy, a condition involving fluid accumulation under the retina. Symptoms include: blurred vision, distorted vision, partial or complete vision loss, or other visual changes. Report any visual symptoms to your doctor promptly for ophthalmological evaluation.
Side Effect Frequency Guide
Very Common
May affect more than 1 in 10 people
- Diarrhea
- Skin rash (including acne-like rash)
- Increased sensitivity to sunlight (photosensitivity)
- Nausea and vomiting
- Fever (pyrexia)
- Chills
- Increased liver enzymes (shown in blood tests)
- Abnormal creatine phosphokinase levels (shown in blood tests)
- Eye problems (serous retinopathy, blurred vision)
- High blood pressure (hypertension)
- Anemia (low red blood cell count)
- Bleeding events
- Abnormal skin thickening
- Peripheral edema (swelling, usually in the legs)
- Itching or dry skin
- Mouth sores or inflammation (stomatitis)
Common
May affect up to 1 in 10 people
- New skin cancers (basal cell carcinoma, squamous cell carcinoma, keratoacanthoma)
- Dehydration
- Decreased blood phosphate or sodium levels
- Increased blood sugar levels
- Increased bilirubin (may cause yellowing of skin or eyes)
- Pneumonitis (lung inflammation that can cause breathing difficulties)
- Decreased heart pumping function (reduced LVEF)
- Serious bleeding (intracranial or gastrointestinal)
Uncommon
May affect up to 1 in 100 people
- Rhabdomyolysis (severe muscle breakdown with dark urine, muscle pain, weakness)
Heart Problems
Cotellic can reduce the amount of blood pumped by your heart (decreased left ventricular ejection fraction). This is a common side effect affecting up to 1 in 10 patients. Symptoms may include feeling dizzy, short of breath, tired, or experiencing palpitations, a racing or irregular heartbeat, or swelling in the legs. Your doctor will monitor your heart function with echocardiograms or MUGA scans before and during treatment. Treatment may need to be interrupted or permanently discontinued if the ejection fraction drops below certain thresholds.
Muscle Problems
Elevated creatine phosphokinase (CPK) levels are very common with Cotellic treatment. While most CPK elevations are asymptomatic and manageable, in rare cases they can indicate rhabdomyolysis, a potentially life-threatening condition involving the breakdown of skeletal muscle tissue. Breakdown products released into the bloodstream can damage the kidneys. Seek immediate medical attention if you notice muscle pain, cramps, weakness, or dark or reddish-colored urine.
It is important to report suspected side effects after the medicine has been authorized. This allows continued monitoring of the benefit-risk balance. Healthcare professionals and patients can report suspected adverse reactions to their national medicines regulatory agency.
How Should You Store Cotellic?
Store Cotellic out of the sight and reach of children. Do not use after the expiry date printed on the blister and carton. No special storage conditions are required. Do not dispose of medicines in wastewater or household waste.
Proper storage of Cotellic is essential to maintain the medicine’s integrity and effectiveness. The following guidelines should be observed:
- Keep out of sight and reach of children at all times
- Check the expiry date: Do not use Cotellic after the expiry date stated on the blister and outer carton after “EXP.” The expiry date refers to the last day of that month
- Storage conditions: This medicine does not require any special storage conditions. Store at room temperature
- Disposal: Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer needed. These measures help protect the environment
Cotellic film-coated tablets are white, round, with “COB” engraved on one side. Each package contains 63 tablets (3 blisters of 21 tablets each), providing exactly one complete 21-day treatment cycle per package.
What Does Cotellic Contain?
Each Cotellic film-coated tablet contains cobimetinib hemifumarate equivalent to 20 mg of cobimetinib. The tablets also contain inactive ingredients including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
Understanding the complete composition of Cotellic is important, particularly for patients with known allergies or intolerances to specific excipients.
Active Substance
The active substance is cobimetinib. Each film-coated tablet contains cobimetinib hemifumarate equivalent to 20 mg cobimetinib. Cobimetinib hemifumarate is the salt form used in the pharmaceutical formulation, which enhances the drug’s stability and bioavailability.
Inactive Ingredients
Tablet core: lactose monohydrate, microcrystalline cellulose (E460), croscarmellose sodium (E468), and magnesium stearate (E470b).
Film coating: polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, and talc (E553b).
The film coating serves to protect the tablet core, make the tablet easier to swallow, and improve its stability. Titanium dioxide provides the white color of the tablet.
Marketing Authorization Holder
Cotellic is manufactured by Roche Pharma AG, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany. The marketing authorization is held by Roche Registration GmbH at the same address. For additional information about this medicine, contact the local representative of the marketing authorization holder in your country.
Frequently Asked Questions About Cotellic
Cotellic (cobimetinib) is an oral MEK inhibitor used in combination with vemurafenib to treat adults with unresectable or metastatic melanoma that has a BRAF V600 mutation. It works by blocking MEK1 and MEK2 proteins in the MAPK signaling pathway, which cancer cells use to grow and divide. When combined with vemurafenib (which blocks the mutated BRAF protein), the two drugs provide a more complete blockade of this pathway, slowing or stopping melanoma growth more effectively than either drug alone.
The most common side effects (affecting more than 1 in 10 patients) include diarrhea, skin rash, increased sun sensitivity, nausea, fever, elevated liver enzymes, vomiting, high blood pressure, anemia, vision problems (serous retinopathy), and abnormal creatine phosphokinase levels. Serious side effects that require immediate medical attention include bleeding (especially in the brain or stomach), decreased heart function, rhabdomyolysis (muscle breakdown), and severe diarrhea causing dehydration.
The recommended dose is 60 mg (three 20 mg tablets) taken once daily for 21 consecutive days, followed by a 7-day break. This 28-day cycle is repeated continuously. Tablets should be swallowed whole with water and can be taken with or without food. During the 7-day break from Cotellic, you should continue taking vemurafenib as directed by your doctor.
No, Cotellic is specifically approved for use only in combination with vemurafenib. It should not be used as a single agent. The combination targets two different points in the MAPK signaling pathway (MEK and BRAF), providing more effective tumor suppression than either drug alone. Before starting treatment, a validated test must confirm the presence of a BRAF V600 mutation in the melanoma.
If you miss a dose and it is more than 12 hours before your next scheduled dose, take the missed dose as soon as you remember. If it is less than 12 hours until your next dose, skip the missed dose and take the next one at the usual time. Never take a double dose to make up for a missed dose. If you vomit after taking Cotellic, do not take an extra dose that day; continue with your normal schedule the next day.
No, you should avoid grapefruit juice and grapefruit products while taking Cotellic. Grapefruit inhibits the CYP3A4 enzyme that metabolizes cobimetinib, which can increase the amount of the drug in your blood and raise the risk of side effects. Seville oranges and pomelos may have similar effects and should also be avoided. Discuss any dietary concerns with your doctor or pharmacist.
References
- European Medicines Agency (EMA). Cotellic (cobimetinib) – Summary of Product Characteristics. Last updated 2025. Available at: EMA – Cotellic EPAR
- U.S. Food and Drug Administration (FDA). Cotellic (cobimetinib) Prescribing Information. Genentech, Inc. Available at: FDA – Cotellic Label
- Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876. doi:10.1056/NEJMoa1408868
- Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF V600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-1260. doi:10.1016/S1470-2045(16)30122-X
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Melanoma: Cutaneous. Version 2.2025.
- World Health Organization (WHO). WHO Model List of Essential Medicines – 23rd list, 2023. Geneva: World Health Organization.
- European Society for Medical Oncology (ESMO). Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(12):1884-1901.
- British National Formulary (BNF). Cobimetinib – drug monograph. National Institute for Health and Care Excellence (NICE). Available at: BNF – NICE
Editorial Team
Medical Content
iMedic Medical Editorial Team
Licensed specialist physicians with expertise in oncology, dermatology, and clinical pharmacology. All content follows international evidence-based guidelines.
Medical Review
iMedic Medical Review Board
Independent panel of medical experts who review all content for accuracy, completeness, and adherence to current clinical guidelines from EMA, FDA, NCCN, and ESMO.
This article was written by our medical editorial team and independently reviewed by our medical review board. All medical claims are supported by peer-reviewed evidence at Evidence Level 1A. Last reviewed: .