Cobimetinib is a selective mitogen-activated protein kinase (MEK) inhibitor. It is indicated in combination with vemurafenib for the treatment of unresectable or metastatic melanoma in adult patients with a BRAF V600E or V600K mutation. Cobimetinib is also indicated for the treatment of adult patients with histiocytic neoplasms. Major hemorrhage events, cardiomyopathy, and severe dermatologic, ocular, and liver toxicities have been reported with cobimetinib therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH (Draft) 2020 List: Table 2
-Approved by FDA after NIOSH 2016 list published. The manufacturer recommends this drug be handled as a hazardous drug.
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Emetic Risk
-Minimal/Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer cobimetinib orally, with or without food.
-If a dose is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose.
Pain was reported in 15% of patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Fall was reported in 14% (grade 3 or 4, 4%) of patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Bleeding, including major bleeding that is symptomatic in a critical area or organ, has been reported with cobimetinib therapy. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop severe bleeding. Bleeding (13%; grade 3 or 4, 1.2%) including intracranial bleeding/cerebral hemorrhage (0.8%), GI bleeding (3.6%), reproductive system hemorrhage (2%), and hematuria (2.4%) occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 247) in a randomized trial. The term bleeding included conjunctival hemorrhage, contusion, ecchymosis, epistaxis, GI bleeding, gingival bleeding, hematemesis, hematochezia, hematuria, hemoptysis, hemorrhagic ovarian cyst, hemorrhoidal hemorrhage, melena, menometrorrhagia, menorrhagia, metrorrhagia, nailbed bleeding, ocular hemorrhage, pulmonary hemorrhage, cerebral/subarachnoid hemorrhage, purpura, rectal hemorrhage, retinal hemorrhage, hematoma, uterine bleeding, and vaginal bleeding. Bleeding (e.g., epistaxis, contusion, purpura, hematoma, and rectal hemorrhage) was reported in 19% of patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Cardiomyopathy has been reported with cobimetinib therapy. Evaluate left ventricular ejection fraction (LVEF) prior to starting therapy, at 1 month, and then every 3 months thereafter. Interruption, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop left ventricular dysfunction. Evaluate LVEF at approximately 2, 4, 10, and 16 weeks, and then as clinically indicated in patients who restart cobimetinib after a dose reduction or interruption of therapy. Decreased LVEF/heart failure (grade 2 or 3, 26%) and hypertension (15%; grade 3 or 4, 4%) occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 247) in a randomized trial. The median time to first onset of LVEF decrease was 4 months (range, 23 days to 13 months). The median time to resolution was 3 months (range, 4 days to 12 months) in the 62% of patients with decreased LVEF that resolved to above the lower limit of normal (LLN) or within 10% of baseline. Decreased LVEF (19%; grade 3 or 4, 12%) and hypertension (15%; grade 3 or 4, 4%) were reported in patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26). The median time to first onset of LVEF decrease was 29 (range, 22 to 114) days. The median time to resolution was 31 (range, 13 to 126) days in the 60% of patients with decreased LVEF that resolved to above the LLN or within 10% of baseline.
Skin reactions have been reported with cobimetinib therapy. Interruption, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop severe skin reactions or photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF 30 or higher) when outdoors. Rash (grade 3 or 4, 16%), acneiform rash/dermatitis (16%; grade 3 or 4, 2%), and photosensitivity reaction including solar dermatitis and sunburn (46%; grade 3 or 4, 4%) occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 247) in a randomized trial; 3.2% of patients required hospitalization due to rash. The median time to onset of grade 3 or 4 rash was 11 days (range, 3 days to 2.8 months); 95% of these patients experienced complete resolution at a median time of 21 days (range, 4 days to 17 months). The median time to onset of photosensitivity was 2 months (range, 1 day to 14 months); the median duration was 3 months (range, 2 days to 14 months). Resolution of photosensitivity was reported in 63% of patients who experienced a reaction. Rash (81%) including acneiform rash/dermatitis (65%) and maculopapular rash (31%), xerosis/dry skin (31%), and pruritus (31%; grade 3 or 4, 4%) were reported in patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Ocular toxicity has been reported with cobimetinib therapy. Perform ophthalmological evaluations at regular intervals and following patient reports of new or worsening visual disturbances. Interruption, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop ocular toxicity. Visual impairment including blurred vision and reduced visual acuity (15%; grade 3 or 4, less than 1%) and symptomatic and asymptomatic retinopathy (26%) including chorioretinopathy (13%; grade 3 or 4, less than 1%) or retinal detachment (12%; grade 3 or 4, 2%) occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 247) in a randomized trial. Retinal vein occlusion (RVO) was reported in 1 patient; RVO may result in macular edema, visual impairment, neovascularization, and glaucoma. Blurred vision (12%), retinopathy (4%), and retinal vascular disorder (grade 3, 4%) were reported in patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Hepatotoxicity has been reported with cobimetinib therapy. Monitor liver function tests prior to starting therapy and then once monthly or more frequently as clinically indicated. Interruption, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop hepatotoxicity. Elevated hepatic enzymes including increased AST (73%; grade 3 or 4, 8%), ALT (68%; grade 3 or 4, 11%), alkaline phosphatase (71%; grade 3 or 4, 7%), and GGT (65%; grade 3 or 4, 21%) levels and grade 3 or 4 hyperbilirubinemia (1.6%) occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 247) in a randomized trial. One patient (0.4%) treated with cobimetinib plus vemurafenib experienced a concurrent increase in ALT level (more than 3 times the ULN) and bilirubin level (more than 2 times the ULN) without an elevated alkaline phosphatase level of more than 2 times the ULN. Grade 3 or 4 increased AST (9%) and ALT (5%) levels were reported in patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Rhabdomyolysis and nephrotoxicity have been reported with cobimetinib therapy. Monitor serum creatine phosphokinase (CPK) and serum creatinine (SCr) levels prior to and periodically during therapy and as clinically indicated. Evaluate for signs and symptoms of rhabdomyolysis or other causes if the CPK level is elevated. Interruption, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop an elevated CPK level. Increased CPK (79%; grade 3 or 4, 14%) and SCr (100%; grade 3 or 4, 3.3%) levels occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 213) in a randomized trial. Additionally, 3.6% of patients treated with cobimetinib plus vemurafenib experienced a concurrent increase in CPK level (more than 10 times from baseline) and SCr level (1.5 times or more from baseline). The median time to elevated CPK level onset was 16 days (range, 12 days to 11 months); the median time to resolution was 15 days (range, 9 days to 11 months). Increased CPK (54%; grade 3 or 4, 27%) and SCr (grade 3 or 4, 9%) levels and acute kidney injury (15%; grade 3 or 4, 12%) were reported in patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Diarrhea (60%; grade 3 or 4, 6%), nausea (41%; grade 3 or 4, 1%), vomiting (24%; grade 3 or 4, 1%), and stomatitis including oral ulceration/inflammation (14%; grade 3 or 4, 1%) occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 213) in a randomized trial. Diarrhea (62%; grade 3 or 4, 8%), nausea (46%), dyspepsia including gastritis and gastroesophageal reflux disease (27%), vomiting (27%), xerostomia/dry mouth (15%), oral dysesthesia or oropharyngeal pain (15%), and stomatitis (12%) were reported in patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Pneumonitis occurred in less than 10% of patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 247) in a randomized trial. Dyspnea (27%; grade 3 or 4, 15%), cough (15%), hypoxia (12%), pulmonary edema (4%), and respiratory failure (8%) were reported in patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Fever (28%; grade 3 or 4, 2%) and chills (10%) occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 247) in a randomized trial.
Anemia (69%; grade 3 or 4, 2.5%), lymphopenia (73%; grade 3 or 4, 10%), and thrombocytopenia (18%) occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 247) in a randomized trial. Grade 3 or 4 lymphopenia (27%), leukopenia (9%), anemia (8%), and neutropenia (5%) were reported in patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Hypophosphatemia (68%; grade 3 or 4, 12%), hypoalbuminemia (42%; grade 3 or 4, 0.8%), hyponatremia (38%; grade 3 or 4, 6%), hypokalemia (25%; grade 3 or 4, 4.5%), hyperkalemia (26%; grade 3 or 4, 2.9%), and hypocalcemia (24%; grade 3 or 4, 0.4%) occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib (n = 247) in a randomized trial. Grade 3 or 4 hyponatremia (18%), hypokalemia (12%), and hypocalcemia (9%) were reported in patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
New primary malignancy including skin cancer such as cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA) (6%), basal cell carcinoma (4.5%), and new primary melanoma (0.8%) and non-cutaneous malignancy (0.8%) occurred in patients with advanced melanoma who received cobimetinib plus vemurafenib therapy (n = 247) in a randomized trial. Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and for 6 months after the last dose. Suspicious skin lesions should be managed with excision and dermatopathologic evaluation; dose modifications are not necessary. Additionally, monitor patients for signs or symptoms of non-cutaneous malignancies when cobimetinib is administered with vemurafenib. The median time to first detection of cuSCC/KA was 4 (range, 2 to 11) months; the median time to detection of basal cell carcinoma was also 4 months (range, 27 days to 13 months). The time to onset in the 2 patients with new primary melanoma was 9 months and 12 months.
Fatigue including malaise was reported in 42% of patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Headache was reported in 12% of patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26).
Edema was reported in 42% (grade 3 or 4, 4%) of patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26). The term edema included facial edema, periorbital edema, genital edema, peripheral edema, and lymphoedema.
Infection (62%; grade 3 or 4, 23%) including urinary tract infection (23%; grade 3 or 4, 8%) and pneumonia or bronchitis (19%; grade 3 or 4, 12%) occurred in patients with histiocytic neoplasms who received cobimetinib in a single-arm trial (n = 26). The term infection included influenza-like illness, mucosal infection, paronychia, pharyngitis, sepsis, sinusitis, skin infection, tooth infection, and upper respiratory tract infection.
New primary malignancy, both cutaneous and non-cutaneous, has occurred with cobimetinib administration. Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and for 6 months after the last dose. Suspicious skin lesions should be managed with excision and dermatopathologic evaluation; dose modifications are not necessary. Additionally, monitor patients for signs or symptoms of non-cutaneous malignancies. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA) and basal cell carcinoma (skin cancer) occurred more often in patients who received combination therapy with cobimetinib plus vemurafenib (n = 247) compared with vemurafenib plus placebo (n = 248); second primary melanoma occurred more often in patients who received vemurafenib plus placebo. In the cobimetinib arm, the median time to detection of first cuSCC/KA was 4 months (range, 2 to 11 months); the median time to detection of basal cell carcinoma was also 4 months (range, 27 days to 13 months). The time to onset in the two patients with second primary melanoma was 9 months and 12 months. Based on its mechanism of action, vemurafenib may promote the growth and development of malignancies; in this clinical trial, non-cutaneous malignancies occurred more often when vemurafenib was administered with placebo than with cobimetinib.
Serious bleeding (e.g., GI bleeding, intracranial bleeding) has been reported with cobimetinib therapy. Treatment interruptions and transfusions may be necessary if severe bleeding occurs. Thrombocytopenia or concomitant antiplatelet/anticoagulant therapy may increase the risk of bleeding. Use cobimetinib in patients with a known risk of bleeding only if the benefits of therapy outweigh the risks.
Monitor left ventricular ejection fraction (LVEF) prior to initiation of therapy, 1 month after initiation, and every 3 months thereafter until treatment discontinuation. If the LVEF decreases or symptomatic cardiomyopathy occurs, an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary; in patients restarting cobimetinib after an interruption of therapy or dose reduction, evaluate the LVEF at 2, 4, 10, and 16 weeks, and then as clinically indicated. Serum electrolytes and ECG should also be monitored before initiating therapy and routinely during treatment when cobimetinib is administered with vemurafenib. The safety of cobimetinib has not been established in patients with a baseline LVEF that is either below the institutional lower limit of normal (LLN) or less than 50%; patients with a history of acute coronary syndrome within 6 months or evidence of NYHA Class II or greater congestive heart failure (CHF) were excluded from the clinical trial. Cautious use of cobimetinib may be warranted in patients with cardiac disease, especially heart failure, cardiomyopathy, or ventricular dysfunction, as it can result in the development of left ventricular dysfunction and CHF. Patients with advanced age (geriatric patients) or pre-existing cardiac disease may also be at increased risk. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the median time to first onset of LVEF decrease was 4 months (range, 23 days to 13 months); resolution to above LLN or within 10% of baseline occurred in 62% of cobimetinib-treated patients with a median time to resolution of 3 months (range, 4 days to 12 months). Clinically relevant QT prolongation has been reported with vemurafenib, but was not exacerbated by coadministration with cobimetinib.
Serious rash has been reported in patients treated with cobimetinib plus vemurafenib in a multicenter, randomized, double-blind, placebo-controlled clinical trial; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Although the overall incidence of grade 3 or 4 rash was similar in patients receiving cobimetinib plus vemurafenib to patients treated with vemurafenib plus placebo, patients who received combination therapy had a higher incidence of grade 4 rash and rash resulting in hospitalization. The median time to onset of grade 3 or 4 rash in cobimetinib-treated patients was 11 days (range, 3 days to 2.8 months); complete resolution occurred in 95% of patients with a median time to resolution of 21 days (range, 4 days to 17 months).
Photosensitivity can occur with cobimetinib treatment; an interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary for grade 2 or higher photosensitivity. Patients should avoid or limit sunlight (UV) exposure, including sunlamps and tanning booths, and be advised to wear protective clothing and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF >= 30) when outdoors. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the median time to first onset of photosensitivity of any grade in patients treated with cobimetinib was 2 months (range, 1 day to 14 months), with a median duration of 3 months (range, 2 days to 14 months). Resolution of the photosensitivity reaction was reported in 63% of patients.
Serious ophthalmic adverse events including serous retinopathy (fluid accumulation under layers of the retina) and retinal detachment have been reported with cobimetinib therapy. Perform an ophthalmological evaluation at regular intervals and any time a patient reports a new or worsening visual disturbance; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the time to first onset of serous retinopathy ranged from 2 days to 9 months, and the duration ranged from 1 day to 15 months. Cautious use of cobimetinib may be warranted in patients with pre-existing ocular disease; patients with evidence of retinal pathology were excluded from the clinical trial.
Hepatotoxicity has been reported with cobimetinib therapy. Monitor liver function tests before initiation of cobimetinib and monthly during treatment, or more frequently as clinically indicated; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Cautious use of cobimetinib may be warranted in patients with pre-existing hepatic disease; patients with abnormal liver function tests were excluded from the clinical trial.
Musculoskeletal adverse reactions, elevated serum creatine phosphokinase (CPK) levels, and rhabdomyolysis, in some cases leading to renal failure, have been reported with cobimetinib therapy. Obtain baseline CPK and serum creatinine levels prior starting therapy with cobimetinib, periodically during treatment, and as clinically indicated; if CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the median time to onset of grade 3 or higher CPK elevations in patients receiving cobimetinib plus vemurafenib (n = 246) was 16 days (range, 12 days to 11 months) and the median time to complete resolution was 15 days (range, 9 days to 11 months).
Although there are no adequate and well-controlled studies in pregnant women, cobimetinib may cause fetal harm when administered during pregnancy due to its mechanism of action. Administration of cobimetinib to pregnant rats during organogenesis resulted in increased post-implantation loss due to early resorptions, including total litter loss, at exposures of 0.9 to 1.4 times the AUC in humans at the recommended dose. Fetal malformations of the great vessels and skull (eye sockets) occurred at the same exposures.
Counsel patients about the reproductive risk and contraception requirements during cobimetinib treatment. Cobimetinib can be teratogenic and embryotoxic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 2 weeks after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of cobimetinib. Women who become pregnant while receiving cobimetinib should be apprised of the potential hazard to the fetus. In addition, based on animal data, cobimetinib may cause impaired fertility or infertility.
It is not known whether cobimetinib is present in human milk; many drugs are excreted in human milk. Due to the potential for serious adverse reactions in nursing infants from cobimetinib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose.
For the treatment of malignant melanoma:
NOTE: Cobimetinib was designated by the FDA as an orphan drug for the treatment of stage IIb, IIc, III, and IV melanoma in patients with a BRAFV600 mutation.
NOTE: 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 V600E mutations is available at http://www.fda.gov/CompanionDiagnostics.
-for the treatment of unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib:
Oral dosage:
Adults: 60 mg orally once daily for 21 days in combination with vemurafenib 960 mg orally twice daily for 28 days; repeat cycle every 28 days until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. At a median follow-up of 14.2 months, the median investigator-assessed progression-free survival (PFS) time was significantly improved with cobimetinib plus vemurafenib compared with placebo plus vemurafenib (12.3 months vs. 7.2 months; hazard ratio (HR) = 0.58; 95% CI, 0.46 to 0.72) in patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma in a multinational, randomized, double-blind, phase 3 trial (n = 495; the CoBRIM trial). Additionally, the median PFS (12.6 months vs. 7.2 months) and median overall survival (OS) (22.5 months vs. 17.4 months; HR = 0.8; 95% CI, 0.64 to 0.99) times were significantly improved with cobimetinib plus vemurafenib compared with placebo plus vemurafenib at a median follow-up of 21.2 months. The 5-year PFS rates were 14% and 10% in the cobimetinib plus vemurafenib and placebo plus vemurafenib arms, respectively; the 5-year OS rates were 31% and 26%, respectively.
-for the treatment of unresectable or metastatic melanoma in patients with a BRAF V600E mutation, in combination with vemurafenib and atezolizumab*:
NOTE: Atezolizumab in combination with cobimetinib and vemurafenib is FDA-approved for this indication.
Oral dosage:
Adults: 60 mg orally once daily for 21 days (on days 1 to 21); give in combination with atezolizumab (840 mg IV repeated every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks starting on cycle 2) and vemurafenib (cycle 1: 960 mg orally twice daily on days 1 to 21 then 720 mg orally twice daily on days 22 to 28; cycle 2 and beyond: 720 mg orally twice daily). Cycle 1 consists of cobimetinib and vemurafenib only. Treatment cycles are repeated every 28 days. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. At a median follow-up time of 18.9 months, the investigator-assessed median progression-free survival (PFS) time was significantly longer in patients who received atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib (15.1 months vs. 10.6 months; hazard ratio (HR) = 0.78; 95% CI, 0.63 to 0.97) in an international, randomized, double-blind, placebo-controlled, phase 3 trial (n = 514; IMspire150 trial). When PFS was assessed by an independent review committee, the median PFS time was not significantly improved in the atezolizumab arm (16.1 months vs. 12.3 months; HR = 0.85; 95% CI, 0.67 to 1.07). Additionally, the median overall survival (OS) time was not significantly improved in patients who received atezolizumab compared with placebo (39 months vs. 25.8 months; HR = 0.84; 95% CI, 0.66 to 1.06) in an interim OS analysis of the IMspire150 trial performed at median follow-up times of 29.1 and 22.8 months, respectively. Patients (median age 54 years; range, 43 to 64 years) in this trial had BRAF V600 mutation-positive unresectable stage IIIc or stage IV melanoma and had not received previous systemic therapy for metastatic disease.
For the treatment of histiocytic neoplasm:
Cobimetinib has been designated by the FDA as an orphan drug for the treatment histiocytic neoplasms.
Oral dosage:
Adults: 60 mg orally once daily for 21 days; repeat cycle every 28 days until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Using PET response criteria, the best overall response rate (documented twice at least 4 weeks apart) was 76.9% (complete response (CR) rate, 61.5%) in 26 patients (median age, 50.5 years; range, 18 to 79 years) with histiocytic neoplasms who received treatment with single-agent cobimetinib in a nonrandomized trial. At a median follow-up time of 11.4 (range, 0.2 to 36.8) months, the median duration of response was 31 (range, 2 to 31) months. Using RECIST response criteria, the overall response rate was 46.2% (CR rate, 11.5%). Histiocytic neoplasms included Langerhans cell histiocytosis (n = 4), Rosai-Dorfman disease (n = 4), Erdheim-Chester disease (n = 13), xanthogranuloma (n = 2), and mixed histiocytosis (n = 3). In this trial, 81% of patients had received prior systemic therapies and 77% of patients had BRAF V600 wild-type mutational status.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
New primary malignancy: No dose modification required.
Hemorrhage
-Grade 3: Hold cobimetinib therapy. If improved to grade 0 or 1 within 4 weeks, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). Permanently discontinue therapy if not improved within 4 weeks, or if unable to tolerate 20 mg once daily.
-Grade 4: Permanently discontinue cobimetinib therapy.
Cardiomyopathy
-Asymptomatic, absolute decrease in LVEF from baseline of greater than 10% and LVEF is below the institutional lower limit of normal (LLN): Hold cobimetinib therapy for 2 weeks and repeat LVEF. If the LVEF is at or above LLN and the absolute decrease from baseline is 10% or less, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). After a dose reduction or interruption of therapy, evaluate LVEF at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then clinically as indicated. Permanently discontinue therapy if the LVEF is less than LLN or the absolute decrease from baseline is greater than 10% after 2 weeks; additionally, if the patient is unable to tolerate 20 mg once daily, permanently discontinue therapy.
-Symptomatic LVEF decrease from baseline (any percentage): Hold cobimetinib for up to 4 weeks and repeat LVEF. If symptoms resolve, the LVEF is at or above LLN, and the absolute decrease from baseline is 10% or less, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). After a dose reduction or interruption of therapy, evaluate LVEF at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then clinically as indicated. Permanently discontinue therapy if symptoms persist, the LVEF is less than LLN, or the absolute decrease from baseline is greater than 10% after 4 weeks; additionally, if the patient is unable to tolerate 20 mg once daily, permanently discontinue therapy.
Dermatologic Reactions
-Intolerable grade 2, or grade 3 or 4: Hold cobimetinib or reduce the dose (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). Permanently discontinue therapy if the patient is unable to tolerate 20 mg once daily.
Ocular Reactions
-Serous Retinopathy: Hold cobimetinib therapy. If visual signs and symptoms improve within 4 weeks, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). Permanently discontinue therapy if not improved within 4 weeks, if symptoms recur at the lower dose within 4 weeks, or if the patient is unable to tolerate 20 mg once daily.
-Retinal vein occlusion: Permanently discontinue cobimetinib therapy.
Rhabdomyolysis and Creatine Phosphokinase (CPK) elevations
-Grade 4 CPK elevation, or any CPK elevation with myalgia: Hold cobimetinib therapy. If improved to grade 3 or lower within 4 weeks, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). Permanently discontinue therapy if not improved within 4 weeks, or if the patient is unable to tolerate 20 mg once daily.
Photosensitivity
-Intolerable grade 2, or grade 3 or 4: Hold cobimetinib therapy. If improved to grade 0 or 1 within 4 weeks, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). Permanently discontinue therapy if not improved within 4 weeks, or if the patient is unable to tolerate 20 mg once daily.
Other Toxicity
-Intolerable grade 2, or any grade 3: Hold cobimetinib therapy. If improved to grade 0 or 1 within 4 weeks, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). Permanently discontinue therapy if not improved within 4 weeks, or if the patient is unable to tolerate 20 mg once daily.
-Grade 4, first occurrence: Hold cobimetinib therapy. When it has improved to grade 0 or 1, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). Alternatively, permanently discontinue cobimetinib therapy. If the patient is unable to tolerate 20 mg once daily, permanently discontinue therapy.
-Grade 4, recurrent: Permanently discontinue cobimetinib therapy.
Maximum Dosage Limits:
-Adults
60 mg by mouth once daily for 21 days, repeated every 28 days.
-Geriatric
60 mg by mouth once daily for 21 days, repeated every 28 days.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
No adjustment to the starting dose is necessary in patients with mild, moderate, or severe hepatic impairment.
Treatment-Related Hepatotoxicity
-Grade 4, first occurrence: Hold cobimetinib therapy. If improved to grade 0 or 1 within 4 weeks, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). If not improved within 4 weeks, or if the patient is unable to tolerate 20 mg once daily, permanently discontinue therapy.
-Grade 4, recurrent: Permanently discontinue cobimetinib therapy.
Patients with Renal Impairment Dosing
Baseline Renal Impairment
-Mild to moderate renal impairment (CrCL 30 to 89 mL/min): Dose adjustment not recommended.
-Severe renal impairment: A dedicated trial in patients with renal impairment has not been conducted; a recommended dose of cobimetinib has not been established for patients with severe renal impairment.
Treatment-Related Nephrotoxicity
-Intolerable grade 2, or any grade 3: Hold cobimetinib therapy. If improved to grade 0 or 1 within 4 weeks, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). If not improved within 4 weeks, or if the patient is unable to tolerate 20 mg once daily, permanently discontinue therapy.
-Grade 4, first occurrence: Hold cobimetinib therapy. When it has improved to grade 0 or 1, resume treatment at the next lower dose level (1st dose reduction, 40 mg PO once daily; 2nd dose reduction, 20 mg PO once daily). Alternatively, permanently discontinue cobimetinib therapy. If the patient is unable to tolerate 20 mg once daily, permanently discontinue therapy.
-Grade 4, recurrent: Permanently discontinue cobimetinib therapy.
*non-FDA-approved indication
Abrocitinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with abrocitinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein substrate; abrocitinib is a P-gp inhibitor.
Adagrasib: (Major) Avoid coadministration of adagrasib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A inhibitor increased cobimetinib exposure by 6.7-fold.
Alogliptin; Pioglitazone: (Moderate) If concurrent use of cobimetinib and pioglitazone is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and pioglitazone is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
Amiodarone: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with amiodarone is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; amiodarone is a P-gp inhibitor.
Amobarbital: (Major) Avoid the concurrent use of cobimetinib with barbiturates due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and barbiturates are moderate inducers of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concurrent use of cobimetinib with clarithromycin due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; clarithromycin is a P-gp inhibitor and a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Apalutamide: (Major) Avoid the concurrent use of cobimetinib with apalutamide due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Aprepitant, Fosaprepitant: (Major) Avoid the concurrent use of cobimetinib with a multi-day aprepitant, fosaprepitant regimen due to the risk of cobimetinib toxicity. For patients taking cobimetinib 60 mg daily, reduce the dose to 20 mg once daily if concurrent short-term (14 days or less) use of aprepitant is unavoidable; after discontinuation of aprepitant, resume cobimetinib at the previous dose. Use an alternative to aprepitant in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of cobimetinib. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold on day 1 and by 3.3-fold on day 5 when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8 and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, IV fosaprepitant (single dose) is rapidly converted to aprepitant and shares some of the same drug interactions but it only weakly inhibits CYP3A4 for a duration of 2 days, increasing the midazolam AUC by approximately 1.8-fold on day 1 with no effect by day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Guidance is not provided regarding concomitant use of cobimetinib with weak CYP3A inhibitors. There is no evidence of CYP3A4 induction with fosaprepitant.
Armodafinil: (Moderate) If concurrent use of cobimetinib and armodafinil is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and armodafinil is a weak in vitro inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid the concurrent use of cobimetinib with butalbital due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and butalbital is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Atazanavir: (Major) Avoid the concurrent use of cobimetinib with atazanavir due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro, and atazanavir is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Atazanavir; Cobicistat: (Major) Avoid the concurrent use of cobimetinib with atazanavir due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro, and atazanavir is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). (Major) Avoid the concurrent use of cobimetinib with chronic cobicistat due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cobicistat is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cobicistat, resume cobimetinib at the previous dose. Use an alternative to cobicistat in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cobicistat is a moderate inhibitor of both P-gp and CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Berotralstat: (Major) Avoid using cobimetinib and berotralstat together for more than 14 days due to the risk for cobimetinib toxicity. For short-term coadministration, defined as 14 days or less of combination therapy, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg per day; consider alternative therapy for patients already taking a reduced dose of cobimetinib (40 or 20 mg per day). After discontinuation of berotralstat, resume cobimetinib 60 mg per day. Cobimetinib is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Simulations have demonstrated that a short course of cobimetinib 20 mg once daily taken with a moderate CYP3A inhibitor produces similar concentrations to cobimetinib 60 mg per day alone.
Bexarotene: (Major) Avoid the concurrent use of cobimetinib with bexarotene due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and bexarotene is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Bosentan: (Major) Avoid the concurrent use of cobimetinib with bosentan due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and bosentan is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Brigatinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with brigatinib is necessary. In vitro, cobimetinib is a P-glycoprotein (P-gp) substrate; drugs that inhibit P-gp may increase cobimetinib concentrations. Brigatinib is a P-gp inhibitor.
Butalbital; Acetaminophen: (Major) Avoid the concurrent use of cobimetinib with butalbital due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and butalbital is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid the concurrent use of cobimetinib with butalbital due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and butalbital is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid the concurrent use of cobimetinib with butalbital due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and butalbital is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid the concurrent use of cobimetinib with butalbital due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and butalbital is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Cabozantinib: (Minor) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with cabozantinib is necessary. Cobimetinib is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
Cannabidiol: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with cannabidiol is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; cannabidiol is a P-gp inhibitor.
Capmatinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with capmatinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; capmatinib is a P-gp inhibitor.
Carvedilol: (Minor) If concurrent use of cobimetinib and carvedilol is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and carvedilol is a weak P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Cenobamate: (Major) Avoid the concurrent use of cobimetinib with cenobamate due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A4 substrate, and cenobamate is a moderate inducer of CYP3A4. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A4 inducer.
Ceritinib: (Major) Avoid coadministration of ceritinib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
Chloramphenicol: (Major) Avoid the concurrent use of cobimetinib with chloramphenicol due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro, and chloramphenicol is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Chloroquine: (Moderate) Concurrent use of chloroquine and cobimetinib is not recommended as there is an increased risk of retinal toxicity.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cimetidine: (Moderate) If concurrent use of cobimetinib and cimetidine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and cimetidine is a weak inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Ciprofloxacin: (Major) Avoid the concurrent use of cobimetinib with chronic ciprofloxacin therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of ciprofloxacin is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of ciprofloxacin, resume cobimetinib at the previous dose. Use an alternative to ciprofloxacin in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and ciprofloxacin is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with a strong CYP3A4 inhibitor increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Clarithromycin: (Major) Avoid the concurrent use of cobimetinib with clarithromycin due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; clarithromycin is a P-gp inhibitor and a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Cobicistat: (Major) Avoid the concurrent use of cobimetinib with chronic cobicistat due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cobicistat is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cobicistat, resume cobimetinib at the previous dose. Use an alternative to cobicistat in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cobicistat is a moderate inhibitor of both P-gp and CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Cocaine: (Major) If concurrent use of cobimetinib and cocaine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and cocaine is a weak inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Conivaptan: (Major) Avoid using cobimetinib and conivaptan together for more than 14 days due to the risk of cobimetinib toxicity. If short-term use of conivaptan is necessary, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking cobimetinib 60 mg per day. After discontinuation of conivaptan, resume cobimetinib 60 mg per day. Use alternative therapy in patients who are already taking a reduced dose of cobimetinib (20 or 40 mg daily). Cobimetinib is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor. Simulations suggest that a short course of cobimetinib 20 mg once daily taken with a moderate CYP3A inhibitor produces similar concentrations to cobimetinib 60 mg per day alone.
Crizotinib: (Major) Avoid the concurrent use of cobimetinib with cobimetinib due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate and cobimetinib is a moderate inhibitor of CYP3A. Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone.
Cyclosporine: (Major) Avoid the concurrent use of cobimetinib with chronic cyclosporine therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cyclosporine is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cyclosporine, resume cobimetinib at the previous dose. Use an alternative to cyclosporine in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cyclosporine is a moderate inhibitor of CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Dabrafenib: (Major) Avoid the concomitant use of dabrafenib and cobimetinib; decreased cobimetinib concentrations and loss of efficacy may occur. Use of an alternative agent is recommended. Dabrafenib is a moderate CYP3A4 inducer and cobimetinib is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
Daclatasvir: (Minor) If concurrent use of cobimetinib and daclatasvir is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and daclatasvir is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Danazol: (Major) Avoid the concurrent use of cobimetinib with chronic danazol therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of danazol is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of danazol, resume cobimetinib at the previous dose. Use an alternative to danazol in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and danazol is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Daridorexant: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with daridorexant is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; daridorexant is a P-gp inhibitor.
Darunavir: (Major) Avoid coadministration of darunavir with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
Darunavir; Cobicistat: (Major) Avoid coadministration of darunavir with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold. (Major) Avoid the concurrent use of cobimetinib with chronic cobicistat due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cobicistat is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cobicistat, resume cobimetinib at the previous dose. Use an alternative to cobicistat in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cobicistat is a moderate inhibitor of both P-gp and CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of darunavir with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold. (Major) Avoid the concurrent use of cobimetinib with chronic cobicistat due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cobicistat is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cobicistat, resume cobimetinib at the previous dose. Use an alternative to cobicistat in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cobicistat is a moderate inhibitor of both P-gp and CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Deferasirox: (Major) Avoid the concurrent use of cobimetinib with deferasirox due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and deferasirox is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Delavirdine: (Major) Avoid the concurrent use of cobimetinib with delavirdine due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro, and delavirdine is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desogestrel; Ethinyl Estradiol: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Dextromethorphan; Quinidine: (Minor) If concurrent use of cobimetinib and quinidine is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and quinidine is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Diltiazem: (Major) Avoid the concurrent use of cobimetinib with diltiazem therapy due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate; diltiazem is a moderate inhibitor of CYP3A.
Dronedarone: (Major) Avoid the concurrent use of cobimetinib with chronic dronedarone therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of dronedarone is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of dronedarone, resume cobimetinib at the previous dose. Use an alternative to dronedarone in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; dronedarone is a moderate inhibitor of CYP3A and a weak P-gp inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Drospirenone; Ethinyl Estradiol: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Duvelisib: (Major) Avoid the concurrent use of cobimetinib with duvelisib due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate and duvelisib is a moderate inhibitor of CYP3A. Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone.
Efavirenz: (Major) Avoid the concurrent use of cobimetinib with efavirenz due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and efavirenz is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concurrent use of cobimetinib with efavirenz due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and efavirenz is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concurrent use of cobimetinib with efavirenz due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and efavirenz is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Elacestrant: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with elacestrant is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; elacestrant is a P-gp inhibitor.
Elagolix: (Major) Avoid the concurrent use of cobimetinib with elagolix due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and elagolix is a weak to moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid the concurrent use of cobimetinib with elagolix due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and elagolix is a weak to moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Elbasvir; Grazoprevir: (Moderate) Administering cobimetinib with elbasvir; grazoprevir may result in elevated cobimetinib plasma concentrations. Cobimetinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eliglustat: (Minor) If concurrent use of cobimetinib and eliglustat is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and eliglustat is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid the concurrent use of cobimetinib with chronic cobicistat due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cobicistat is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cobicistat, resume cobimetinib at the previous dose. Use an alternative to cobicistat in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cobicistat is a moderate inhibitor of both P-gp and CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concurrent use of cobimetinib with chronic cobicistat due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cobicistat is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cobicistat, resume cobimetinib at the previous dose. Use an alternative to cobicistat in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cobicistat is a moderate inhibitor of both P-gp and CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Enasidenib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with enasidenib is necessary. In vitro, cobimetinib is a P-gp substrate; enasidenib is a P-gp inhibitor.
Encorafenib: (Major) Avoid coadministration of cobimetinib with encorafenib as concurrent use may decrease cobimetinib exposure, which may reduce its efficacy. Cobimetinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Based on simulations, cobimetinib exposure may decrease by 83% when coadministered with a strong CYP3A inducer.
Enzalutamide: (Major) Avoid the concurrent use of cobimetinib with enzalutamide due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; enzalutamide is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Erdafitinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with erdafitinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; erdafitinib is a P-gp inhibitor.
Erythromycin: (Major) Avoid the concurrent use of cobimetinib with chronic erythromycin therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of erythromycin is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of erythromycin, resume cobimetinib at the previous dose. Use an alternative to erythromycin in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; erythromycin is a moderate inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Eslicarbazepine: (Major) Avoid the concurrent use of cobimetinib with eslicarbazepine due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and eslicarbazepine is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Ethinyl Estradiol; Norelgestromin: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Ethinyl Estradiol; Norethindrone Acetate: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Ethinyl Estradiol; Norgestrel: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Etonogestrel; Ethinyl Estradiol: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Etravirine: (Major) Avoid the concurrent use of cobimetinib with etravirine due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and etravirine is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Fedratinib: (Major) Avoid the concurrent use of cobimetinib with fedratinib due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate and fedratinib is a moderate inhibitor of CYP3A.
Felodipine: (Minor) If concurrent use of cobimetinib and felodipine is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and felodipine is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Flibanserin: (Minor) If concurrent use of cobimetinib and flibanserin is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and flibanserin is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Fluconazole: (Major) Avoid the concurrent use of cobimetinib with chronic fluconazole therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of fluconazole is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of fluconazole, resume cobimetinib at the previous dose. Use an alternative to fluconazole in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and fluconazole is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Fluoxetine: (Major) If concurrent use of cobimetinib and fluoxetine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and fluoxetine is a weak inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Flutamide: (Major) Avoid the concurrent use of cobimetinib with flutamide due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and flutamide is a moderate in vitro inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Fluvoxamine: (Major) When a patient taking full dose cobimetinib receives a moderate inhibitor of CYP3A4 for 14 days or less, reduce cobimetinib to 20 mg; resume 60 mg when the inhibitor is discontinued. Do not use a moderate CYP3A4 inhibitor, such as fluvoxamine, in patients receiving a reduced dose of cobimetinib.
Fosamprenavir: (Major) Avoid using cobimetinib and fosamprenavir together for more than 14 days due to the risk for cobimetinib toxicity. For short-term coadministration, defined as 14 days or less of combination therapy, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg per day; consider alternative therapy for patients already taking a reduced dose of cobimetinib (40 or 20 mg per day). After discontinuation of fosamprenavir, resume cobimetinib 60 mg per day. Cobimetinib is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Simulations have demonstrated that a short course of cobimetinib 20 mg once daily taken with a moderate CYP3A inhibitor produces similar concentrations to cobimetinib 60 mg per day alone.
Fosphenytoin: (Major) Avoid the concurrent use of cobimetinib with fosphenytoin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; fosphenytoin is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Fostamatinib: (Moderate) Monitor for cobimetinib toxicities that may require cobimetinib dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a sensitive CYP3A4 or P-gp substrate may increase the concentration of the CYP3A4 or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; cobimetinib is a sensitive substrate for CYP3A4 and a P-gp substrate. Coadministration of fostamatinib with another sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%.
Futibatinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with futibatinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein substrate; futibatinib is a P-gp inhibitor.
Gilteritinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with gilteritinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein substrate; gilteritinib is a P-gp inhibitor.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and cobimetinib as coadministration may increase serum concentrations of cobimetinib and increase the risk of adverse effects. Cobimetinib is a substrate of P-glycoprotein (P-gp); glecaprevir is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and cobimetinib as coadministration may increase serum concentrations of cobimetinib and increase the risk of adverse effects. Cobimetinib is a substrate of P-glycoprotein (P-gp); pibrentasvir is a P-gp inhibitor.
Grapefruit juice: (Major) Avoid the concurrent use of cobimetinib with grapefruit juice due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro, and grapefruit juice is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Idelalisib: (Major) Avoid the concurrent use of cobimetinib with idelalisib due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro, and idelalisib is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Iloperidone: (Minor) If concurrent use of cobimetinib and iloperidone is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and iloperidone is a weak P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Imatinib: (Major) Avoid the concurrent use of cobimetinib with chronic imatinib, STI-571 therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of imatinib is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of imatinib, resume cobimetinib at the previous dose. Use an alternative to imatinib in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and imatinib is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Indinavir: (Major) Avoid the concurrent use of cobimetinib with indinavir due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro, and indinavir is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Isavuconazonium: (Major) Avoid the concurrent use of cobimetinib with chronic isavuconazonium therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of isavuconazonium is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of isavuconazonium, resume cobimetinib at the previous dose. Use an alternative to isavuconazonium in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; isavuconazonium is a moderate inhibitor of CYP3A and a weak P-gp inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concurrent use of cobimetinib with rifampin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; rifampin is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Isoniazid, INH; Rifampin: (Major) Avoid the concurrent use of cobimetinib with rifampin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; rifampin is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Istradefylline: (Moderate) Monitor for cobimetinib-related adverse reactions if coadministration of istradefylline is necessary as concurrent use may increase cobimetinib exposure. Cobimetinib is a P-gp substrate and istradefylline is a P-gp inhibitor.
Itraconazole: (Major) Avoid cobimetinib use during and for 2 weeks after discontinuation of itraconazole due to increased cobimetinib exposure. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate; itraconazole is a P-gp inhibitor and a strong CYP3A inhibitor. In healthy subjects, coadministration of itraconazole increased the mean cobimetinib AUC by 6.7-fold and the mean Cmax by 3.2-fold.
Ivosidenib: (Moderate) Monitor for loss of efficacy of cobimetinib during coadministration of ivosidenib; a cobimetinib dose adjustment may be necessary. Cobimetinib is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased cobimetinib concentrations.
Ketoconazole: (Major) Avoid coadministration of ketoconazole with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid the concurrent use of cobimetinib with clarithromycin due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; clarithromycin is a P-gp inhibitor and a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Lapatinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with lapatinib is necessary. Cobimetinib is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of cobimetinib.
Lasmiditan: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with lasmiditan is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein substrate; lasmiditan is a P-gp inhibitor.
Ledipasvir; Sofosbuvir: (Minor) If concurrent use of cobimetinib and ledipasvir; sofosbuvir is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and ledipasvir is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Lefamulin: (Major) Reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily if concurrent use of oral lefamulin is necessary; after discontinuation of oral lefamulin, resume cobimetinib at the previous dose. Use an alternative to oral lefamulin in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Lenacapavir: (Major) Avoid concurrent use of cobimetinib and lenacapavir due to the risk for cobimetinib toxicity. Cobimetinib is a CYP3A and P-gp substrate and lenacapavir is a moderate CYP3A and P-gp inhibitor.
Letermovir: (Moderate) Avoid coadministration of letermovir with cobimetinib, as concurrent use may increase cobimetinib concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Cobimetinib is a sensitive substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Levoketoconazole: (Major) Avoid coadministration of ketoconazole with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
Levonorgestrel; Ethinyl Estradiol: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Lonafarnib: (Major) Avoid coadministration of lonafarnib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 and P-gp substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
Lopinavir; Ritonavir: (Major) Avoid the concurrent use of cobimetinib with ritonavir due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; ritonavir is a P-gp inhibitor as well as a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Lorlatinib: (Major) Avoid the concurrent use of cobimetinib with lorlatinib due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate, and lorlatinib is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Maribavir: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with maribavir is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein substrate; maribavir is a P-gp inhibitor.
Mavacamten: (Major) Avoid coadministration of cobimetinib with mavacamten as concurrent use may decrease cobimetinib exposure, which may reduce its efficacy. Cobimetinib is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Mefloquine: (Minor) If concurrent use of cobimetinib and mefloquine is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and mefloquine is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Mifepristone: (Major) Avoid the concurrent use of cobimetinib with chronic mifepristone therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of mifepristone is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of mifepristone, resume cobimetinib at the previous dose. Use an alternative to mifepristone in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; mifepristone is a strong inhibitor of CYP3A as well as a P-gp inhibitor.
Mitapivat: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with mitapivat is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein substrate; mitapivat is a P-gp inhibitor.
Mitotane: (Major) Avoid the concomitant use of mitotane with cobimetinib due to decreased cobimetinib exposure leading to decreased efficacy. Mitotane is a strong CYP3A4 inducer and cobimetinib is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of cobimetinib. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Modafinil: (Major) Avoid the concurrent use of cobimetinib with modafinil due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and modafinil is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Nafcillin: (Major) Avoid the concurrent use of cobimetinib with nafcillin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and nafcillin is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Nefazodone: (Major) Avoid the concurrent use of cobimetinib with nefazodone due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro, and nefazodone is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Nelfinavir: (Major) Avoid the concurrent use of cobimetinib with nelfinavir due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; nelfinavir is a P-gp inhibitor as well as a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Neratinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with neratinib is necessary. In vitro, cobimetinib is a P-glycoprotein (P-gp) substrate; drugs that inhibit P-gp may increase cobimetinib concentrations. Neratinib is a P-gp inhibitor.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid the concurrent use of cobimetinib with chronic netupitant; palonosetron therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of netupitant; palonosetron is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of netupitant; palonosetron, resume cobimetinib at the previous dose. Use an alternative to netupitant; palonosetron in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and netupitant is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Nilotinib: (Major) Avoid the concurrent use of cobimetinib with nilotinib due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate and nilotinib is a moderate inhibitor of CYP3A. Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone.
Nirmatrelvir; Ritonavir: (Major) Avoid the concurrent use of cobimetinib with ritonavir due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; ritonavir is a P-gp inhibitor as well as a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Nirogacestat: (Major) Avoid using cobimetinib and nirogacestat together for more than 14 days due to the risk for cobimetinib toxicity. For short-term coadministration, defined as 14 days or less of combination therapy, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg per day; consider alternative therapy for patients already taking a reduced dose of cobimetinib (40 or 20 mg per day). After discontinuation of nirogacestat, resume cobimetinib 60 mg per day. Cobimetinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Simulations have demonstrated that a short course of cobimetinib 20 mg once daily taken with a moderate CYP3A inhibitor produces similar concentrations to cobimetinib 60 mg per day alone.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Norethindrone; Ethinyl Estradiol: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Norgestimate; Ethinyl Estradiol: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Olanzapine; Fluoxetine: (Major) If concurrent use of cobimetinib and fluoxetine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and fluoxetine is a weak inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid the concurrent use of cobimetinib with rifabutin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and rifabutin is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Oritavancin: (Moderate) If concurrent use of cobimetinib and oritavancin is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and oritavancin is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
Osimertinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with osimertinib is necessary. Cobimetinib is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of cobimetinib.
Pacritinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with pacritinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; pacritinib is a P-gp inhibitor.
Pazopanib: (Moderate) If concurrent use of cobimetinib and pazopanib is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; pazopanib is a weak inhibitor of CYP3A and a moderate P-gp inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Pentobarbital: (Major) Avoid the concurrent use of cobimetinib with barbiturates due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and barbiturates are moderate inducers of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Perampanel: (Moderate) If concurrent use of cobimetinib and perampanel is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and perampanel is a weak in vitro inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
Pexidartinib: (Major) Avoid coadministration of cobimetinib with pexidartinib as concurrent use may decrease cobimetinib exposure, which may reduce its efficacy. Cobimetinib is a CYP3A4 substrate and pexidartinib is a moderate inducer of CYP3A4. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A4 inducer.
Phenobarbital: (Major) Avoid the concurrent use of cobimetinib with phenobarbital due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; phenobarbital is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concurrent use of cobimetinib with phenobarbital due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; phenobarbital is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Phentermine; Topiramate: (Moderate) If concurrent use of cobimetinib and topiramate is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and topiramate is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
Phenytoin: (Major) Avoid the concurrent use of cobimetinib with phenytoin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; phenytoin is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Pioglitazone: (Moderate) If concurrent use of cobimetinib and pioglitazone is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and pioglitazone is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
Pioglitazone; Glimepiride: (Moderate) If concurrent use of cobimetinib and pioglitazone is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and pioglitazone is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
Pioglitazone; Metformin: (Moderate) If concurrent use of cobimetinib and pioglitazone is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and pioglitazone is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
Pirfenidone: (Moderate) If concurrent use of cobimetinib and pirfenidone is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; pirfenidone is a weak in vitro inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Pirtobrutinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with pirtobrutinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Porfimer: (Major) Avoid coadministration of porfimer with cobimetinib due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like cobimetinib may increase the risk of a photosensitivity reaction.
Posaconazole: (Major) Avoid the concurrent use of cobimetinib with posaconazole due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; posaconazole is a P-gp inhibitor as well as a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Pretomanid: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with pretomanid is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein substrate; pretomanid is a P-gp inhibitor.
Primidone: (Major) Avoid the concurrent use of cobimetinib with primidone due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; primidone is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Propafenone: (Minor) If concurrent use of cobimetinib and propafenone is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and propafenone is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Quinidine: (Minor) If concurrent use of cobimetinib and quinidine is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and quinidine is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Quinine: (Major) Avoid the concurrent use of cobimetinib with quinine due to altered cobimetinib exposure. Cobimetinib is a CYP3A substrate in vitro, and quinine is both a moderate inhibitor and a moderate in vitro inducer of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Additionally, based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer. Exposure to cobimetinib may be affected unpredictably if coadministered with quinine.
Ranolazine: (Moderate) If concurrent use of cobimetinib and ranolazine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; in vitro, ranolazine is a weak inhibitor of CYP3A and a moderate P-gp inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Repotrectinib: (Major) Avoid coadministration of cobimetinib with repotrectinib as concurrent use may decrease cobimetinib exposure, which may reduce its efficacy. Cobimetinib is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Ribociclib: (Major) Avoid coadministration of ribociclib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
Rifabutin: (Major) Avoid the concurrent use of cobimetinib with rifabutin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and rifabutin is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Rifampin: (Major) Avoid the concurrent use of cobimetinib with rifampin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; rifampin is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Rifapentine: (Major) Avoid coadministration of cobimetinib with rifapentine as concurrent use may decrease cobimetinib exposure, which may reduce its efficacy. Cobimetinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Based on simulations, cobimetinib exposure may decrease by 83% when coadministered with a strong CYP3A4 inducer.
Ritonavir: (Major) Avoid the concurrent use of cobimetinib with ritonavir due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; ritonavir is a P-gp inhibitor as well as a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Rivaroxaban: (Minor) If concurrent use of cobimetinib and rivaroxaban is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and rivaroxaban is a weak, in vitro, P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Rolapitant: (Minor) If concurrent use of cobimetinib and rolapitant is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and rolapitant is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Saquinavir: (Major) Avoid the concurrent use of cobimetinib with saquinavir due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; saquinavir is a P-gp inhibitor as well as a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Avoid the concurrent use of cobimetinib with barbiturates due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and barbiturates are moderate inducers of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Segesterone Acetate; Ethinyl Estradiol: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Selpercatinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with selpercatinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein substrate; selpercatinib is a P-gp inhibitor.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with taurursodiol is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; taurursodiol is a P-gp inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of cobimetinib, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
Sorafenib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with sorafenib is necessary. Cobimetinib is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
Sotorasib: (Major) Avoid coadministration of cobimetinib with sotorasib as concurrent use may alter cobimetinib exposure, which may lead to decreased efficacy or increased toxicity. Cobimetinib is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Sparsentan: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with sparsentan is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; sparsentan is a P-gp inhibitor.
St. John's Wort, Hypericum perforatum: (Major) Avoid the concurrent use of cobimetinib with St. John's Wort, Hypericum perforatum due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; St. John's Wort is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Stiripentol: (Moderate) Consider a dose adjustment of cobimetinib when coadministered with stiripentol. Coadministration may alter plasma concentrations of cobimetinib resulting in an increased risk of adverse reactions and/or decreased efficacy. Cobimetinib is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Tacrolimus: (Minor) If concurrent use of cobimetinib and tacrolimus is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and tacrolimus is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Temsirolimus: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with temsirolimus is necessary. Cobimetinib is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of cobimetinib.
Tepotinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with tepotinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein; tepotinib is a P-gp inhibitor.
Ticagrelor: (Moderate) If concurrent use of cobimetinib and ticagrelor is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) inhibitor; ticagrelor is a weak inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Tipranavir: (Major) Avoid the concurrent use of cobimetinib with tipranavir due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro; tipranavir is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Topiramate: (Moderate) If concurrent use of cobimetinib and topiramate is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and topiramate is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
Trandolapril; Verapamil: (Major) Avoid the concurrent use of cobimetinib with chronic verapamil therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of verapamil is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of verapamil, resume cobimetinib at the previous dose. Use an alternative to verapamil in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; verapamil is a moderate inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Tucatinib: (Major) Avoid coadministration of tucatinib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
Valproic Acid, Divalproex Sodium: (Moderate) If concurrent use of cobimetinib and valproic acid, divalproex sodium is necessary, use caution and monitor for decreased efficacy of cobimetinib as well as increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and valproic acid is a both a weak in vitro inhibitor and inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Additionally, in healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers or inhibitors; exposure to cobimetinib may be affected unpredictably if coadministered with valproic acid.
Vemurafenib: (Minor) Cobimetinib is indicated for the treatment of unresectable or metastatic melanoma in combination with vemurafenib. Cobimetinib is a P-glycoprotein (P-gp) substrate, and vemurafenib is a P-gp inhibitor; theoretically, coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions when studied.
Verapamil: (Major) Avoid the concurrent use of cobimetinib with chronic verapamil therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of verapamil is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of verapamil, resume cobimetinib at the previous dose. Use an alternative to verapamil in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; verapamil is a moderate inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with cobimetinib is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like cobimetinib may increase the risk of a photosensitivity reaction.
Voclosporin: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with voclosporin is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein; voclosporin is a P-gp inhibitor. Drugs that inhibit P-gp may increase cobimetinib concentrations.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid the concurrent use of cobimetinib with clarithromycin due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; clarithromycin is a P-gp inhibitor and a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Voriconazole: (Major) Avoid the concurrent use of cobimetinib with chronic voriconazole therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of voriconazole is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of voriconazole, resume cobimetinib at the previous dose. Use an alternative to voriconazole in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and voriconazole is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Voxelotor: (Major) Avoid using cobimetinib and voxelotor together for more than 14 days due to the risk for cobimetinib toxicity. For short-term coadministration, defined as 14 days or less of combination therapy, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg per day; consider alternative therapy for patients already taking a reduced dose of cobimetinib (40 or 20 mg per day). After discontinuation of voxelotor, resume cobimetinib 60 mg per day. Cobimetinib is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Simulations have demonstrated that a short course of cobimetinib 20 mg once daily taken with a moderate CYP3A inhibitor produces similar concentrations to cobimetinib 60 mg per day alone.
Zafirlukast: (Moderate) If concurrent use of cobimetinib and zafirlukast is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and zafirlukast is a weak inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Zonisamide: (Minor) If concurrent use of cobimetinib and zonisamide is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and zonisamide is a weak, in vitro, P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Cobimetinib reversibly inhibits mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-regulated 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 is FDA-approved in combination with vemurafenib, which targets a different kinase in the RAS/RAF/MEK/ERK pathway. Coadministration results 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.
Cobimetinib is administered orally. Over the dose range of 3.5 to 100 mg (0.06 to 1.7 times the recommended dosage), cobimetinib exhibits linear pharmacokinetics; at the recommended dose, steady-state was reached by 9 days, with a mean accumulation ratio of 2.4-fold (CV, 44%). In vitro, cobimetinib is 95% bound to plasma proteins, independent of drug concentrations; preferential binding to human red blood cells was not observed (blood to plasma ratio, 0.93). Based on a population pharmacokinetic analysis, the estimated apparent volume of distribution (Vd) in cancer patients was 806 liters. The mean elimination half-life was 44 hours (range, 23 to 70 hours) and the mean apparent clearance (CL/F) was 13.8 L/h (CV, 61%). After a single 20 mg radiolabeled dose of cobimetinib, 76% was recovered in the feces (unchanged drug, 6.6%), and 17.8% was recovered in the urine (unchanged drug, 1.6%).
Affected cytochrome P450 (CYP) isoenzymes and drug transporters: CYP3A, P-glycoprotein (P-gp)
CYP3A oxidation and UGT2B7 glucuronidation were the major pathways of metabolism for cobimetinib; additionally, it is a substrate of efflux transporter P-gp. While in vitro data indicated that cobimetinib may inhibit CYP2D6 and 3A4, dextromethorphan (2D6 substrate) and midazolam (3A4 substrate) exposures were not affected by coadministration with cobimetinib (60 mg once daily for 15 days) in patients with solid tumors (n = 20). At clinically relevant concentrations, cobimetinib also does not inhibit CYP1A2, 2B6, 2C8, 2C9, and 2C19, P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, or OAT3; it does not induce CYP1A2, 2B6, or 3A4. After oral administration of a single 20 mg radiolabeled dose, oxidative metabolites constituted < 10% of the total circulating radioactivity.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration, the median time to peak plasma levels (Tmax) was 2.4 hours (range, 1 to 24 hours), the Cmax was 273 ng/mL (CV, 60%), and the geometric mean steady-state AUC was 4,340 ng*h/mL (CV, 61%). The absolute bioavailability (F) was 46% (90% CI, 40% to 53%) in healthy subjects. A high fat meal had no effect on cobimetinib AUC and Cmax in healthy subjects after a single dose of cobimetinib 20 mg.
-Special Populations
Hepatic Impairment
The geometric mean of total cobimetinib exposure (AUCinf) after administration of a single 10 mg dose was similar in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function; the cobimetinib AUC was decreased by 31% in patients with severe hepatic impairment.
Renal Impairment
A dedicated pharmacokinetic trial has not been conducted in patients with renal impairment; however, cobimetinib undergoes minimal renal elimination. In a population pharmacokinetic analysis, patients with mild to moderate renal impairment (CrCL 30 to 89 mL/min) (n = 199) had similar exposure to patients with normal renal function (CrCL >= 90 mL/min) (n = 286).
Pediatrics
In a multicenter, open-label, phase 1/2 (iMATRIX-cobi) trial, peak concentration and exposure values were about 50% lower in pediatric patients treated with the recommended phase 2 dose of cobimetinib compared with adult patients who received the approved cobimetinib dosage of 60 mg/day. The steady-state mean Cmax and AUC(0-24 h) values were 142 nanograms (ng)/mL and 1,862 ng X hour/mL, respectively, in 12 patients (median age, 5 years; range, 3 to 29 years) with low-grade glioma who received the recommended phase 2 dose of cobimetinib oral suspension 1 mg/kg (maximum of 60 mg) daily on days 1 to 21 repeated every 28 days.
Geriatric
Based on a population pharmacokinetic analysis, age (19 to 88 years) does not have a clinically important effect on the systemic exposure of cobimetinib.
Gender Differences
Based on a population pharmacokinetic analysis, gender does not have a clinically important effect on the systemic exposure of cobimetinib.
Ethnic Differences
Based on a population pharmacokinetic analysis, ethnicity does not have a clinically important effect on the systemic exposure of cobimetinib.