Cobimetinib

Cobimetinib is used to treat melanoma.

Cobimetinib is available under the following different brand names: Cotellic.

Dosages of Cobimetinib:

Dosage Forms and Strengths

Tablet

• 20 mg

Dosage Considerations – Should be Given as Follows:

Melanoma

• Indicated for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib
• 60 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity
• Vemurafenib: 960 mg orally twice daily on days 1-28 of an every 28-day cycle

Dosage Modifications

• New primary malignancies (cutaneous and noncutaneous): No dosage modification is required
• Avoid concurrent use of cobimetinib and strong or moderate CYP3A inducers including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and St. John's Wort

Hepatic impairment

• Mild-to-severe (Child-Pugh A to C): No dosage adjustment is necessary

Renal impairment

• Mild-to-moderate (CrCl 30-89 mL/minute): No dosage adjustment necessary
• Severe (CrCl less than 30 mL/minute): Safety and efficacy not established

Coadministration with CYP3A inhibitors

• Do not take strong or moderate CYP3A inhibitors while taking cobimetinib
• If concurrent short-term (up to 14 days) use of moderate CYP3A inhibitors is unavoidable for patients taking cobimetinib 60 mg, reduce dose to 20 mg; after the moderate CYP3A inhibitor is discontinued, resume previous cobimetinib dose
• Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of cobimetinib (40 or 20 mg daily)

Dose reductions

• First dose reduction: 40 mg orally once daily
• Second dose reduction: 20 mg orally once daily
• Subsequent modification: Permanently discontinue cobimetinib if unable to tolerate a 20-mg dose

Hemorrhage

• Grade 3: Withhold cobimetinib for up to 4 weeks; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 weeks
• Grade 4: Permanently discontinue

Cardiomyopathy

• Asymptomatic
  • Definition: Absolute decrease in LVEF from baseline of greater than 10% and less than the institutional lower limit of normal (LLN) Withhold cobimetinib for 2 weeks; repeat LVEF
  • Resume at next lower dose if all of the following are present: LVEF is greater than or equal to LLN and absolute decrease from baseline LVEF is up to 10%
  • Permanently discontinue if any of the following are present: LVEF is 10%
• Symptomatic LVEF decrease from baseline
  • Withhold cobimetinib for 4 weeks; repeat LVEF
  • Resume at next lower dose if all of the following are present:
  • Symptoms resolve and LVEF is greater than or equal to LLN and absolute decrease from baseline LVEF is up to 10%
  • Permanently discontinue if any of the following are present:
  • Symptoms persist, or LVEF is 10%

Dermatologic reactions

• Grade 2 (intolerable) or grades 3 or 4: Withhold or reduce the dose

Retinopathy or retinal vein occlusion

• Serous retinopathy: Withhold for up to 4 weeks; if signs and symptoms improve, resume at the next lower dose level; permanently discontinue if not improved or symptoms recur at the lower dose within 4 weeks
• Retinal vein occlusion: Permanently discontinue

Hepatoxicity

• First occurrence grade 4: Withhold for up to 4 weeks; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 weeks
• Recurrent grade 4: Permanently discontinue

Rhabdomyolysis and elevated CPK

• Grade 4 creatine phosphokinase (CPK) elevation or any CPK elevation plus myalgia: Withhold for up to 4 weeks; if improved to up to grade 3, resume at the next lower dose level; permanently discontinue if not improved within 4 weeks

Photosensitivity

• Grade 2 (intolerable), grades 3 or 4: Withhold for up to 4 weeks; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 weeks

Other adverse events

• Grade 2 (intolerable) adverse reactions or any grade 3
  • Withhold for up to 4 weeks; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 weeks
• The first occurrence of any grade 4 adverse reaction
  • Withhold until adverse reaction improves to grade 0 or 1 and then resume at the next lower dose level, OR
  • Permanently discontinue
• Recurrent grade 4 adverse reaction
  • Permanently discontinue

Dosage Considerations

• Confirm the presence of BRAF V600E or V600K mutation in tumor specimens before initiation of treatment
• Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics
• Safety and efficacy not established in pediatric patients

Side effects of Cobimetinib may include.

• Increased creatinine
• Increased CPK
• Increased AST
• Low white blood cells (lymphopenia)
• Increased alkaline phosphatase
• Anemia
• Increased ALT
• Low phosphates (hypophosphatemia)
• Increased GGT
• Diarrhea
• Sensitivity to light
• Low albumin levels (hypoalbuminemia)
• Nausea
• Low sodium levels (hyponatremia)
• Fever
• High or low potassium (hyperkalemia or hypokalemia)
• Low calcium levels (hypocalcemia)
• Vomiting
• Low platelets (thrombocytopenia)
• Acne
• High blood pressure (hypertension)
• Vision impaired
• Hair loss
• Inflammation of the mouth and lips
• Hemorrhage
• Chorioretinopathy
• Retinal detachment
• Hyperkeratosis
• Hypophosphatemia
• Chills
• Redness

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

• Cobimetinib has severe interactions with at least 49 different drugs.
• Cobimetinib has serious interactions with at least 37 different drugs.
• Moderate interactions of cobimetinib include:
  • cenobamate
  • cholera vaccine
  • dengue vaccine
  • duvelisib
  • elagolix
  • encorafenib
  • fedratinib
  • istradefylline
  • siponimod
  • stiripentol
  • tecovirimat
• Cobimetinib has no listed mild interactions with other drugs.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

Warnings

• This medication contains cobimetinib. Do not take Cotellic if you are allergic to cobimetinib or any ingredients contained in this drug.
• Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Contraindications

• None

Effects of Drug Abuse

• No information is available.

Short-Term Effects

• See "What Are Side Effects Associated with Using Cobimetinib?"

Long-Term Effects

• See "What Are Side Effects Associated with Using Cobimetinib?"

Cautions

• Refer to the Dosage Modification section for instructions on withholding, decreasing, or permanently discontinuing cobimetinib in the event of adverse reactions
• New primary malignancies can occur; monitor for new malignancies before initiation of therapy, while on therapy, and for up to 6 months following the last dose
• Major hemorrhagic events reported; monitor for signs and symptoms of bleeding
• The risk of cardiomyopathy is increased in patients receiving cobimetinib with vemurafenib compared with vemurafenib as a single agent; safety has not been established in patients with decreased LVEF; evaluate LVEF before treatment, after 1 month of treatment, then q3 months thereafter during treatment
• May cause severe dermatologic reactions; monitor for severe rashes
• Serous retinopathy and retinal vein occlusion reported; perform an ophthalmological evaluation at regular intervals and for any visual disturbances
• Hepatotoxicity reported; monitor liver laboratory tests during treatment and as clinically indicated
• Monitor CPK periodically and as clinically indicated for signs and symptoms of rhabdomyolysis
• Severe photosensitivity may occur; advise patients to avoid sun exposure
• Can cause fetal harm; advise females of reproductive potential of the potential risk to a fetus and to use effective contraception

Drug interactions overview

• Coadministration with itraconazole (a strong CYP3A4 inhibitor) increased cobimetinib systemic exposure by 6.7-fold
• Avoid coadministration with moderate or strong CYP3A4 inhibitors or inducers; if unable to avoid short-term use of moderate CYP3A4 inhibitors, reduce cobimetinib dose
• Coadministration with a strong CYP3A inducer may decrease cobimetinib systemic exposure by more than 80% and reduce its efficacy
• Also, see Dosage Modification

Pregnancy and Lactation

• Based on findings from animal reproduction studies and its mechanism of action, cobimetinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9- to 1.4-times those observed in humans at the recommended human dose of 60 mg. Pregnant women should be advised of the potential risk to a fetus.
• Females of reproductive potential are advised to use effective contraception during treatment with cobimetinib and for 2 weeks after the final dose.
• Based on findings in animals, cobimetinib may reduce fertility in females and males of reproductive potential. It is unknown if cobimetinib is distributed in human breast milk. Because of the potential for serious adverse reactions in a breastfed infant, women are advised not to breastfeed during treatment with cobimetinib and for 2 weeks after the final dose.