Drug information of Cobimetinib

Cobimetinib


Cobimetinib is a cancer medicine that interferes with the growth and spread of cancer cells in the body.
Cobimetinib is used to treat a certain type of metastatic melanoma (skin cancer) that has spread to other parts of the body and cannot be removed with surgery. Cobimetinib is usually given together with another medicine called vemurafenib (Zelboraf).
Cobimetinib is used only if your tumor has a specific genetic marker, for which your doctor will test

Mechanism of effect

Cobimetinib is a potent and selective inhibitor of the mitogen-activated extracellular kinase (MEK) pathway (Larkin 2014); it reversibly inhibits MEK1 and MEK2, which are upstream regulators of the extracellular signal-related kinase (ERK) pathway. The ERK pathway promotes cellular proliferation. MEK1 and MEK2 are part of the BRAF pathway, which is activated by BRAF V600E and K mutations. Vemurafenib targets a different kinase in the RAS/RAF/MEK/ERK pathway; when cobimetinib and vemurafenib are used in combination, increased apoptosis and reduced tumor growth occurs

Pharmacokinetics

Distribution
806 L
Metabolism
Hepatic; via CYP3A4 oxidation and UGT2B7 glucuronidation.
Excretion
Feces (76%; ~7 as unchanged drug); Urine (~18%; ~2% as unchanged drug)
Time to Peak
Median: 2.4 hours (range: 1 to 24 hours)
Half life
Mean: 44 hours (range: 23 to 70 hours)

Drug indications

Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation (in combination with vemurafenib)

Dosage

Usual Adult Dose for Melanoma - Metastatic
60 mg orally once a day for first 21 days of each 28-day cycle until disease progression or unacceptable toxicity

Drug contraindications

None
Safety and efficacy have not been established in patients younger than 18 years

Side effects

>10%
Cardiovascular: Decreased left ventricular ejection fraction, hypertension
Dermatologic: Skin photosensitivity, acneiform eruption
Endocrine & metabolic: Hypophosphatemia, increased gamma-glutamyl transferase, hypoalbuminemia, hyponatremia, hyperkalemia, hypokalemia, hypocalcemia
Gastrointestinal: Diarrhea, nausea, vomiting, stomatitis (includes aphthous stomatitis, mucositis, and oral mucosa ulcer)
Hematologic & oncologic: Lymphocytopenia, anemia, thrombocytopenia, hemorrhage ( includes bruise, ecchymoses, epistaxis, gingival hemorrhage, hematemesis, hematochezia, hemoptysis, hemorrhoidal bleeding, hypermenorrhea, melena, menometrorrhagia, nail bed bleeding, pulmonary hemorrhage, purpura, rectal hemorrhage, rupture of ovarian cyst, subarachnoid hemorrhage, subgaleal hematoma, traumatic hematoma, uterine hemorrhage, and vaginal hemorrhage)
Hepatic: Increased serum AST, increased serum alkaline phosphatase, increased serum ALT
Neuromuscular & skeletal: Increased creatine phosphokinase
Ophthalmic: Visual impairment (includes blurred vision, decreased visual acuity), chorioretinopathy, retinal detachment (includes detachment of macular retinal pigment epithelium and retinal pigment epithelium detachment)
Renal: Increased serum creatinine
Miscellaneous: Fever
1%
 to 10%
Central nervous system: Chills
Dermatologic: Skin rash
Gastrointestinal: Gastrointestinal hemorrhage
Genitourinary: Genitourinary tract hemorrhage, hematuria
Hematologic & oncologic: Keratoacanthoma, squamous cell carcinoma of skin, basal cell carcinoma
Hepatic: Abnormal bilirubin levels
<1%, postmarketing, and/or case reports: Cerebral hemorrhage, malignant melanoma (second primary), malignant neoplasm (noncutaneous)

Conivaptan
CYP3A4 Inducers (Moderate), CYP3A4 Inducers (Strong), CYP3A4 Inhibitors (Moderate),
CYP3A4 Inhibitors (Strong),

Alerts

Avoid grapefruit juice

Hypertension has been observed with cobimetinib in combination with vemurafenib, including grades 3 or 4 hypertension

Points of recommendation

To make sure cobimetinib is safe for you, tell your doctor if you have:
-heart disease, heart rhythm disorder
-a history of eye problems (especially a problem with your retina)
-liver or kidney disease
-skin problems not related to melanoma
-a muscle disorder
-a bleeding or blood clotting disorder such as hemophilia
-a condition for which you take a blood thinner such as warfarin (Coumadin, Jantoven)

Do not use cobimetinib if you are pregnant. It could harm the unborn baby. Tell your doctor if you become pregnant during treatment. Use effective birth control while you are using this medication and for at least 2 weeks after your last dose.
3-It is not known whether cobimetinib passes into breast milk or if it could harm a nursing baby. Do not breast-feed while taking cobimetinib, and for 2 weeks after your last dose

Cobimetinib is given in a 28-day treatment cycle. You may need to use the medicine only during the first 21 days of each cycle. Your doctor will determine how long to treat you with cobimetinib

Do not change your doses or medication schedule without your doctor's advice

You may take cobimetinib with or without food

Check your skin on a regular basis while you are using cobimetinib. Tell your doctor if you notice any new skin symptoms such as redness, sores that will not heal, a new wart, or a mole that has changed in size or color

Your heart function may need to be checked with an electrocardiograph or ECG (sometimes called an EKG) while you are using this medicine. You may also need regular vision examinations

Store at room temperature away from moisture and heat

If a dose is missed, it can be taken up to 12 hours prior to the next dose to maintain the once-daily regimen

In case of vomiting after administration of a dose, the patient should not take an additional dose on that day and therapy should be continued the following day


Pregnancy level

D

Based on findings from animal reproduction studies and its mechanism of action, cobimetinib can cause fetal harm when administered to a pregnant woman
Infertility: Based on findings in animals, cobimetinib may reduce fertility in females and males of reproductive potential

Breast feeding warning

Unknown if distributed in human breast milk
Because of the potential for serious adverse reactions in a breastfed infant, advise women not to breastfeed during treatment and for 2 weeks after the final dose

Drug forms

Cotellic

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