cobimetinib (Rx)

Brand and Other Names:Cotellic
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 20 mg

Melanoma

Indicated for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib

60 mg PO qDay for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity

Vemurafenib: 960 mg PO BID on days 1-28 of an every 28-day cycle

Dosage Modifications

New primary malignancies (cutaneous and noncutaneous): No dosage modification 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 necessary

Renal impairment

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

Coadministration with CYP3A inhibitors

  • Do not take strong or moderate CYP3A inhibitors while taking cobimetinib
  • If concurrent short-term (≤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 PO qDay
  • Second dose reduction: 20 mg PO qDay
  • Subsequent modification: Permanently discontinue cobimetinib if unable to tolerate 20-mg dose

Hemorrhage

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

Cardiomyopathy

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

Retinopathy or retinal vein occlusion

  • Serous retinopathy: Withhold for up to 4 wk; 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 wk
  • Retinal vein occlusion: Permanently discontinue

Hepatoxicity

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

Rhabdomyolysis and elevated CPK

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

Photosensitivity

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

Other adverse events

  • Grade 2 (intolerable) adverse reactions or any grade 3
    • Withhold for up to 4 wk; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 wk
  • 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 prior to 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

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Interactions

Interaction Checker

and cobimetinib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            Adverse reactions are listed for all grades, unless otherwise stated

            Data listed below are based on combination of cobimetinib plus vemurafenib

            >10%

            Increased creatinine (99.6%)

            Increased CPK (79%)

            Increased AST (73%)

            Lymphopenia (73%)

            Increased alkaline phosphatase (71%)

            Anemia (69%)

            Increased ALT (68%)

            Hypophosphatemia (68%)

            Increased GGT (65%)

            Diarrhea (60%)

            Photosensitivity (46%)

            Hypoalbuminemia (42%)

            Nausea (41%)

            Hyponatremia (38%)

            Pyrexia (28%)

            Hyperkalemia (26%)

            Hypokalemia (25%)

            Hypocalcemia (24%)

            Vomiting (24%)

            Thrombocytopenia (18%)

            Acneiform dermatitis (16%)

            Hypertension (15%)

            Vision impaired (15%)

            Alopecia (15%)

            Stomatitis (14%)

            Hemorrhage (13%)

            Chorioretinopathy (13%)

            Retinal detachment (12%)

            Hyperkeratosis (11%)

            Grades 3-4

            • Increased GGT (21%)
            • Increased CPK (14%)
            • Hypophosphatemia (12%)
            • Increased ALT (11%)

            1-10%

            Chills (10%)

            Erythema (10%)

            Grades 3-4

            • Lymphopenia (10%)
            • Increased AST (8%)
            • Increased alkaline phosphatase (7%)
            • Hyponatremia (6%)
            • Diarrhea (6%)
            • Hypokalemia (4.5%), Hyperkalemia (2.9%)
            • Photosensitivity (4%)
            • Hypertension (4%)
            • Increased creatinine (3.3%)
            • Anemia (2.5)
            • Acneiform dermatitis (2%)
            • Pyrexia (2%)
            • Retinal detachment (2%)
            • Nausea (1%) Vomiting (1%)
            • Stomatitis (1%) Hemorrhage (1%)

            <1%

            Grades 3-4

            • Vision impaired
            • Chorioretinopathy
            • Hypoalbuminemia
            • Hypocalcemia
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            Warnings

            Contraindications

            None

            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 prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose (see Dosage Modifications)

            Major hemorrhagic events reported; monitor for signs and symptoms of bleeding (see Dosage Modifications)

            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 (see Dosage Modifications)

            May cause severe dermatologic reactions; monitor for severe rashes (see Dosage Modifications)

            Serous retinopathy and retinal vein occlusion reported; perform an ophthalmological evaluation at regular intervals and for any visual disturbances (see Dosage Modifications)

            Hepatotoxicity reported; monitor liver laboratory tests during treatment and as clinically indicated (see Dosage Modifications)

            Monitor CPK periodically and as clinically indicated for signs and symptoms of rhabdomyolysis (see Dosage Modifications)

            Severe photosensitivity may occur; advise patients to avoid sun exposure (see Dosage Modifications)

            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 (see Dosage Modifications)
            • Coadministration with a strong CYP3A inducer may decrease cobimetinib systemic exposure by more than 80% and reduce its efficacy
            • Also see Dosage Modification
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            Pregnancy

            Pregnancy

            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

            Advise pregnant women of the potential risk to a fetus

            Contraception: Advise females of reproductive potential to use effective contraception during treatment with and for 2 weeks after the final dose

            Infertility: Based on findings in animals, cobimetinib may reduce fertility in females and males of reproductive potential

            Lactation

            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

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2

            MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation

            BRAF V600E and K mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2

            Cobimetinib and vemurafenib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations

            Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model

            Absorption

            Bioavailability: 46%

            Peak plasma time: 2.4 hr

            Peak plasma concentration: 273 ng/mL

            AUC: 4340 ng·h/mL

            Distribution

            Protein bound: 95%

            Vd: 806 L

            Metabolism

            CYP3A oxidation and UGT2B7 glucuronidation are the major metabolic pathways for cobimetinib

            Elimination

            Half-life: 44 hr

            Clearance: 13.8 L/hr

            Excretion: 76% feces (6.6% unchanged); 17.8% urine (1.6% unchanged)

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            Administration

            Instructions

            May take with or without food

            Missed or vomited dose: Resume dosing with the next scheduled dose

            Storage

            Store at room temperature below 30°C (86°F)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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