Cotellic (cobimetinib fumarate)

Dosage of cobimetinib fumarate is expressed in terms of cobimetinib.

If adverse reactions occur, consider interruption of therapy, dosage reduction, and/or permanent discontinuance of cobimetinib. If dosage modification of cobimetinib is necessary, an initial dosage reduction to 40 mg once daily is recommended. If further dosage reduction is necessary, reduce the dosage to 20 mg once daily. Dosages less than 20 mg once daily are not recommended; permanently discontinue the drug if the 20-mg daily dosage is not tolerated.

Cobimetinib fumarate is administered orally without regard to meals.

Store below 30degreesC.

No dosing information is available for this tab.

Cobimetinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A and uridine diphosphate-glucuronosyltransferase (UGT) 2B7. In vitro, cobimetinib is a substrate of CYP3A and P-glycoprotein (P-gp). In vitro studies also indicate that cobimetinib may inhibit CYP isoenzymes 3A and 2D6. In vitro, cobimetinib does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, and 2C19 or induce CYP isoenzymes 1A2, 2B6, and 3A4 at clinically relevant concentrations. Cobimetinib also does not inhibit P-gp in vitro at clinically relevant concentrations.

In vitro studies indicate that cobimetinib is not a substrate or inhibitor of breast cancer resistance protein (BCRP), organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, and OAT3 at clinically relevant concentrations.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Cobimetinib/Strong & Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of cobimetinib.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of cobimetinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of strong or moderate CYP3A4 inducers in patients receiving therapy with cobimetinib.(1) Consider the use of alternatives with little to no induction potential.

DISCUSSION: Based upon simulations, coadministration of cobimetinib with a strong CYP3A4 inducer may decrease cobimetinib exposure by 83%, with a moderate CYP3A4 inducer by 73%, leading to a reduction in efficacy.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, cenobamate, encorafenib, enzalutamide, ivosidenib, lorlatinib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(1-3)

Cobimetinib/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of cobimetinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from cobimetinib, including hemorrhage, cardiomyopathy, dermatologic reactions, retinopathy, hepatotoxicity, or rhabdomyolysis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with cobimetinib.(1) Consider alternatives with no or minimal enzyme inhibition. The manufacturer of cobimetinib states an alternative to a strong or moderate CYP3A4 inhibitor in patients taking cobimetinib 20 mg or 40 mg daily is recommended.(1) The manufacturer of itraconazole states avoid concomitant use during and 2 weeks after itraconazole treatment.(2,3)

DISCUSSION: In a study, itraconazole 200 mg once daily for 14 days followed by a single dose of cobimetinib 10 mg increased mean cobimetinib area-under-curve (AUC) 6.7-fold (90% CI 5.6, 8.0).(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Cobimetinib; Olaparib; Sonidegib/Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of cobimetinib, olaparib, and sonidegib.(1-4)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase systemic exposure and the risk for adverse effects from cobimetinib, olaparib, or sonidegib.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid the use of moderate CYP3A4 inhibitors in patients receiving cobimetinib, olaparib, or sonidegib.(1-4) For patients taking cobimetinib 60 mg daily, if concurrent short term use (14 days or less) of a moderate CYP3A4 inhibitor cannot be avoided, reduce cobimetinib dose to 20 mg daily. After discontinuation of the moderate CYP3A4 inhibitor resume the previous 60 mg dose. Patients who are taking cobimetinib 40 mg or 20 mg daily should not receive a moderate or strong CYP3A4 inhibitor.(1) If concomitant use with olaparib cannot be avoided, reduce the olaparib dose. Dosage adjustments are specific to the formulation of olaparib.(2,3) Reduce the dosage of the CAPsule formulation to 200 mg (four 50 mg CAPsules) taken twice daily.(2) Reduce the dosage of the TABlet formulation to 150 mg (one 150 mg TABlet) twice daily). If the CYP3A4 inhibitor is discontinued, resume the dose of olaparib taken prior to initiation of the CYP3A4 inhibitor after 3 to 5 half-lives.(3) If sonidegib and a moderate CYP3A4 inhibitor must be used, administer the moderate CYP3A4 inhibitor for less than 14 days and monitor closely for adverse effects, particularly musculoskeletal adverse reactions.(4)

DISCUSSION: In an interaction study, itraconazole (a strong CYP3A4 inhibitor) given 200 mg once daily for 14 days followed by a single dose of cobimetinib 10 mg increased mean cobimetinib AUC 6.7-fold (90% CI 5.6, 8.0). Subsequent simulations showed that predicted steady-state concentrations of cobimetinib at a reduced daily dose of 20 mg given with short term use of a moderate CYP3A4 inhibitor were similar to observed steady-state concentrations at the 60 mg dose without an inhibitor.(1) In simulations using physiologically-based pharmacokinetic (PBPK) models, concurrent use of fluconazole, a moderate CYP3A4 inhibitor, may increase the area-under-curve (AUC) of olaparib by 2.2-fold.(2,3) Based upon PBPK simulations, sonidegib mean steady-state AUC would increase 1.8-fold if administered with a moderate CYP3A4 inhibitor for 14 days and would further increase to 2.8-fold if the moderate CYP3A4 inhibitor is coadministered with sonidegib for 4 months.(4) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, schisandra, rilzabrutinib, stiripentol, tofisopam, treosulfan, and verapamil.(5)

Selected Sensitive Cyp3a4 Substrates/Nirogacestat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Nirogacestat is a moderate inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.(1)

CLINICAL EFFECTS: Concurrent use of nirogacestat may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant nirogacestat use with CYP3A4 substrates where minimal concentration changes may lead to serious adverse reactions.(1) Concurrent use of nirogacestat with alfentanil should be avoided. If concurrent use is warranted, limit the dosages and duration of alfentanil to the minimum possible while achieving the desired clinical effect. If starting a CYP3A4 inhibitor with an opioid, consider a dosage reduction of the opioid. If an opioid is indicated in a patient already taking a CYP3A4 inhibitor, prescribe a lower dose of the opioid and titrate based upon clinical response.(2) Concurrent use of nirogacestat with cobimetinib should be avoided. For patients taking cobimetinib 60 mg daily, if concurrent short-term use (14 days or less) of a moderate CYP3A4 inhibitor cannot be avoided, reduce cobimetinib dose to 20 mg daily. After discontinuation of the moderate CYP3A4 inhibitor, resume the previous 60 mg dose. Patients who are taking cobimetinib 40 mg or 20 mg daily should not receive a moderate or strong CYP3A4 inhibitor.(3)

DISCUSSION: Midazolam (CYP3A4 substrate) maximum concentration (Cmax) is predicted to increase by 1.77-fold and area-under-curve (AUC) by 2.07-fold following concomitant use with multiple doses of nirogacestat (150 mg twice daily).(1) CYP3A4 sensitive substrates linked to this monograph include: cobimetinib, fentanyl, lovastatin, and simvastatin.(4,5)

Selected Sensitive Cyp3a4 Substrates/Oral Lefamulin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,3)

CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2)

DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, ticagrelor, triazolam, and ulipristal.(1,3,5)

There are no moderate interactions for this drug.

*None.

• Lactation

• Chronic heart failure
• Diabetic retinopathy
• Hemorrhage
• Hypertensive retinopathy
• Myopathy with CK elevation
• Pregnancy
• Retinal detachment

There are no moderate contraindications for this drug.

Adverse effects reported in 20% or more of patients receiving cobimetinib in combination with vemurafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation include diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting. Laboratory abnormalities of grade 3 or 4 severity reported in 5% or more of patients receiving cobimetinib in combination with vemurafenib include elevated concentrations of CPK, elevated concentrations of aminotransferases (i.e., AST, ALT), lymphopenia, elevated concentrations of alkaline phosphatase, hypophosphatemia, elevated concentrations of gamma-glutamyltransferase (gamma-glutamyltranspeptidase, GGT, GGTP), and hyponatremia.

Adverse effects reported in 20% or more of patients receiving cobimetinib monotherapy for histiocytic neoplasms include acneiform dermatitis, diarrhea, infection, fatigue, nausea, edema, dry skin, maculopapular rash, pruritis, dyspepsia, vomiting, dyspnea, and urinary tract infections. Laboratory abnormalities of grade 3 or 4 severity reported in 5% or more of patients receiving cobimetinib monotherapy for histiocytic neoplasms include hyponatremia, elevated concentrations of CPK, hypokalemia, increased serum creatinine, elevated concentrations of AST, hypocalcemia, lymphopenia, leukopenia, and anemia.

More Frequent

• Abnormal hepatic function tests
• Hemorrhage
• Increased alanine transaminase
• Increased aspartate transaminase

Less Frequent

• Acute respiratory failure
• Anemia
• Basal cell carcinoma of skin
• Cardiomyopathy
• Hepatitis
• Hyperbilirubinemia
• Hyperkalemia
• Hypertension
• Hypocalcemia
• Hypokalemia
• Hypoxia
• Infection
• Keratoacanthoma
• Leukopenia
• Pneumonia
• Pulmonary edema
• Retinal detachment
• Retinal disorder
• Squamous cell carcinoma
• Vision impairment

Rare or Very Rare

• Interstitial pneumonitis
• Pulmonary hemorrhage
• Retinal vascular occlusion
• Rhabdomyolysis
• Second primary melanoma
• Stevens-johnson syndrome

More Frequent

• Acneiform eruption
• Diarrhea
• Dry skin
• Dyspnea
• Edema
• Fatigue
• Fever
• Hyponatremia
• Hypophosphatemia
• Increased creatine kinase level
• Lymphopenia
• Maculopapular rash
• Nausea
• Pruritus of skin
• Skin photosensitivity
• Stomatitis
• Urinary tract infection
• Vomiting

Less Frequent

• Blurred vision
• Chills
• Headache disorder
• Oral hypoesthesia
• Pain
• Pain in oropharynx
• Skin rash
• Xerostomia

Rare or Very Rare

• Sarcoidosis

No enhanced messaging available.

Safety and efficacy of cobimetinib have not been established in pediatric patients.

Safety and efficacy were assessed, but were not established, in a clinical study of 55 pediatric patients 2--17 years of age with solid tumors; no new safety events were observed. Cobimetinib exposure at the maximally tolerated dosage in pediatric patients was lower than that observed in adult patients receiving the recommended dosage.

Mortality from unknown cause has been observed in immature rats receiving cobimetinib (exposure level on postnatal days 10-17 of approximately 0.13-0.5 times the AUC at the recommended human adult dosage).

Cobimetinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.

It is not known whether cobimetinib is distributed into human milk. The effects of the drug on nursing infants or on the production of milk are unknown. Because of the potential for serious adverse reactions to cobimetinib in nursing infants, advise women not to breast-feed during cobimetinib therapy and for 2 weeks following the final dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Clinical studies of cobimetinib did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.