Selumetinib is a mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. In a noncomparative, phase 2 trial, the overall response rate after treatment with selumetinib was 66% with a duration of at least 24 months in 79% of patients and at least 36 months in 64% of patients. Selumetinib can cause asymptomatic cardiomyopathy; regularly monitor echocardiograms during treatment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Pediatrics: Doses 20 to 30mg/m2: Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
-Can be taken with or without food.
-Administer approximately every 12 hours.
-Do not take a missed dose unless it is more than 6 hours until the next scheduled dose.
-If vomiting occurs after administration, do not take an additional dose; continue with the next scheduled dose.
Oral Solid Formulations
-Swallow capsules whole with water; do not chew, dissolve, or open the capsule.
-Do not administer to patients who are unable to swallow a whole capsule.
Cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) of at least 10% below baseline, occurred in 23% of pediatric patients with neurofibromatosis type 1 who received selumetinib in a phase 2 clinical trial (n = 50); four percent of patients experienced LVEF decreased below the institutional lower limit of normal. One patient experienced a grade 3 decrease in LVEF. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography; resolution occurred in 71% of patients. Monitor ejection fraction prior to and during therapy; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if decreased LVEF occurs.
Sinus tachycardia occurred in 20% of pediatric patients with neurofibromatosis type 1 who received selumetinib in a phase 2 clinical trial (n = 50).
Hypertension occurred in less than 20% of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Visual impairment was reported in less than 20% of pediatric patients with neurofibromatosis type 1 who received selumetinib in a phase 2 clinical trial (n = 50). Blurred vision, photophobia, cataracts, and ocular hypertension occurred in 15% of patients; ocular toxicity resolved in 82% of patients. Serious ocular toxicities including retinal vein occlusion (RVO) and retinal pigment epithelial detachment (retinal detachment) (RPED) have also occurred. Conduct comprehensive ophthalmic assessments prior to and during therapy with selumetinib. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for ocular toxicities based on severity. Permanently discontinue treatment for if RVO occurs.
Diarrhea occurred in 70% to 77% of pediatric patients with neurofibromatosis type 1 in a phase 2 clinical trial (grade 3, 15% to 16%) for a median duration of 2 days; the median time to first onset of diarrhea was 17 days. Serious gastrointestinal toxicities including colitis occurred in unapproved adult and pediatric populations with multiple tumor types. Patients should begin antidiarrheal treatment (e.g., loperamide) immediately after the first episode of unformed, loose stool. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of diarrhea.
Constipation occurred in 34% and abdominal pain in 76% of pediatric patients with neurofibromatosis type 1 who received selumetinib in a phase 2 clinical trial. Serious gastrointestinal toxicities including GI perforation, ileus, and GI obstruction have also occurred in an unapproved adult population with multiple tumor types; colitis also occurred in an unapproved pediatric population with multiple tumor types.
Nausea (66%; grade 3 or 4, 2%) and vomiting (82%; grade 3 or 4, 6%) have been reported in pediatric patients with neurofibromatosis type 1 in a phase 2 clinical trial.
Stomatitis including oral ulceration occurred in 50% of pediatric patients with neurofibromatosis type 1 in a phase 2 clinical trial. Xerostomia was additionally reported in less than 20% of patients.
Weight gain occurred in less than 20% of pediatric patients with neurofibromatosis type 1 in a phase 2 clinical trial.
Decreased appetite/anorexia was reported in 22% of pediatric patients with neurofibromatosis type 1 in a phase 2 clinical trial.
Rash occurred in 91% (grade 3, 8%) of pediatric patients with neurofibromatosis type 1 treated with selumetinib at doses ranging from 20 mg/m2 to 30 mg/m2 in a phase 2 clinical trial; the incidence was slightly lower but still common (80%; grade 3 or 4, 6%) in pediatric NF1 patients treated with the FDA-approved dose of 25 mg/m2. The most frequent rashes included acneiform rash (50% to 54%; grade 3 or 4, 4%), maculopapular rash (39%), and eczema (28%). Dermatitis including atopic dermatitis, diaper dermatitis, eczema, seborrhea, and skin irritation was separately reported in 36%; erythema, urticaria, and exfoliative dermatitis have also been reported. Other skin toxicities including severe palmar-plantar erythrodysesthesia (hand and foot syndrome) occurred in an unapproved population of adult patients with multiple tumor types. Monitor for severe skin rashes; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity.
Xerosis was reported in 60% and pruritus in 46% of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Hair changes including alopecia and hair discoloration occurred in 32% of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Skin infections including abscess, cellulitis, impetigo, and staphylococcal skin infection occurred in 20% (grade 3 or 4, 2%) of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial. Paronychia was additionally reported in 48% (grade 3 or 4, 6%) of patients.
Increased creatinine phosphokinase (CPK) commonly occurred in pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial (76%; grade 3 or 4, 9%); increased CPK with concurrent myalgia occurred in 8% of patients. Musculoskeletal pain including back pain, extremity pain, and neck pain was reported in 58% of patients in this trial. Rhabdomyolysis occurred in an unapproved adult population who received selumetinib in clinical trials. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of the reaction.
Fatigue, including malaise, was reported in 56% of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Edema, including peripheral edema, occurred in 20% of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial. Additionally, facial edema and periorbital edema were reported in less than 20% of patients.
Fever occurred in 56% (grade 3 or 4, 8%) of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Headache occurred in 48% (grade 3 or 4, 2%) of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Proteinuria occurred in 22% of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial. Additionally, acute kidney injury / renal failure (unspecified) occurred in less than 20% of patients.
Treatment with selumetinib can increase the risk of bleeding due to the vitamin E content in the capsules (10 mg capsules contain 32 mg vitamin E; 25 mg capsules contain 36 mg vitamin E). Epistaxis was reported in 28% and hematuria in 22% (grade 3 or 4, 2%) of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Dyspnea, including both exertional dyspnea and dyspnea at rest, occurred in less than 20% of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Malignant peripheral nerve sheath tumor (new primary malignancy) occurred in pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Anemia (41%; grade 3 or 4, 4%), neutropenia (33%; grade 3 or 4, 4%), and lymphopenia (20%; grade 3 or 4, 2%) were reported in pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Hypoalbuminemia occurred in 51% of pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Elevated hepatic enzymes were reported in pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial, including increased AST (41%; grade 3 or 4, 2%), increased ALT (35%; grade 3 or 4, 4%), and increased alkaline phosphatase (18%).
Hyperamylasemia (18%) and elevated lipase (32%; grade 3 or 4, 5%) were reported in pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial.
Electrolyte abnormalities reported in pediatric patients with neurofibromatosis type 1 (NF1) in a phase 2 clinical trial included hyperkalemia (27%; grade 3 or 4, 4%), hypokalemia (18%; grade 3 or 4, 2%), hypernatremia (18%), and hyponatremia (16%).
Use selumetinib with caution in patients with a history of heart failure; the safety of selumetinib in patients with a history of impaired LVEF or a baseline ejection fraction below the institutional lower limit of normal (LLN) has not been established. Assess the left ventricular ejection fraction (LVEF) by echocardiogram prior to initiating treatment, every 3 months during the first year of treatment, and every 6 months thereafter and as clinically indicated; an interruption of therapy or discontinuation of therapy may be necessary if decreased EF occurs. In patients who interrupt therapy for decreased LVEF, obtain an echocardiogram or cardiac MRI every 3 to 6 weeks; upon resolution of LVEF to greater than or equal to the institutional LLN, obtain an echocardiogram or cardiac MRI every 2 to 3 months or as directed by the cardiologist. Cardiomyopathy has occurred in patients with neurofibromatosis type 1 (NF1) who were treated with selumetinib; all patients with decreased LVEF were asymptomatic and were identified during routine echocardiography.
Use selumatinib with caution in patients with a history of visual impairment or cataracts; blurred vision, photophobia, cataracts, and ocular hypertension have occurred in pediatric patients treated with selumetanib. Serious ocular toxicities including retinal vein occlusion (RVO) and retinal pigment epithelial detachment (retinal detachment) have also occurred. Conduct comprehensive ophthalmic assessments prior to initiating selumetinib therapy, at regular intervals during treatment, and for new or worsening visual changes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for ocular toxicities, depending on the severity.
Increased creatine phosphokinase (CPK) commonly occurred in pediatric patients treated with selumetinib in a phase 2 clinical trial; rhabdomyolysis has also occurred. Obtain serum CPK prior to initiation of therapy, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.
An increased risk of bleeding may occur in patients who are concurrently taking vitamin K antagonists or antiplatelet agents with selumetinib; monitor for signs of bleeding in these patients. Increase INR monitoring, as appropriate, in patients taking vitamin K antagonists. Selumetinib capsules contain vitamin E (10 mg capsules contain 32 mg vitamin E; 25 mg capsules contain 36 mg vitamin E) which can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. Daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount in selumetinib and the supplement) will exceed the recommended or safe limits.
Pregnancy should be avoided by females of reproductive potential during selumetinib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, selumetinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving selumetinib should be apprised of the potential hazard to the fetus. In embryo-fetal development studies in mice at doses approximately 5 times human exposure based on AUC at the recommended dose, selumetinib caused increases in post-implantation lose, a reduction in mean fetal and litter weights, and an increased occurrence of open eye and cleft palate. Administration to pregnant mice from gestation day 6 through lactation day 20 resulted in reduced pup body weights; fewer pups also met the pupil constriction on day 21 post-partum. The incidence of malformations (e.g., prematurely open eye(s) and cleft palate) was increased even at the lowest dose that resulted in maximum concentrations of approximately 0.6 times those achieved at the recommended dose.
Counsel patients about the reproductive risk and contraception requirements during selumetinib treatment. Selumetinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with selumetinib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during and for at least 1 week after treatment with selumetinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of selumetinib. Women who become pregnant while receiving selumetinib should be apprised of the potential hazard to the fetus.
Due to the potential for serious adverse reactions in nursing infants from selumetinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether selumetinib is present in human milk.
For the treatment of neurofibromatosis type 1 in patients with symptomatic, inoperable plexiform neurofibromas:
NOTE: Selumetinib is designated by the FDA as an orphan drug for this indication.
Oral dosage:
Children and Adolescents 2 to 17 years with a BSA of 0.55 to 0.69 m2: 20 mg PO every morning and 10 mg PO every evening (for a target dose of 25 mg/m2 twice daily) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, noncomparative clinical trial (n = 50), treatment with selumetinib resulted in a partial response rate of 66% in patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas; there were no complete responses. An independent centralized review of tumor response per REiNS criteria resulted in an overall response rate of 44% (95% CI, 30% to 59%). The median time to onset of response was 7.2 months. The duration of response was at least 24 months in 79% of patients and at least 36 months in 64% of patients.
Children and Adolescents 2 to 17 years with a BSA of 0.7 m2 or higher: 25 mg/m2 PO twice daily (maximum dose, 50 mg PO twice daily) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, noncomparative clinical trial (n = 50), treatment with selumetinib resulted in a partial response rate of 66% in patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas; there were no complete responses. An independent centralized review of tumor response per REiNS criteria resulted in an overall response rate of 44% (95% CI, 30% to 59%). The median time to onset of response was 7.2 months. The duration of response was at least 24 months in 79% of patients and at least 36 months in 64% of patients.
Therapeutic Drug Monitoring:
Dose Adjustments for Treatment-Related Toxicities:
Interrupt selumetinib therapy per specific instructions below. Restart selumetinib as appropriate at the following reduced doses; permanently discontinue selumetinib in patients unable to tolerate treatment after 2 dose reductions.
-BSA 0.55 to 0.69 m2: First dose reduction, 10 mg PO twice daily. Second dose reduction, 10 mg PO once daily.
-BSA 0.7 to 0.89 m2: First dose reduction, 20 mg PO every morning and 10 mg PO every evening. Second dose reduction, 10 mg PO twice daily.
-BSA 0.9 to 1.09 m2: First dose reduction, 25 mg PO every morning and 10 mg PO every evening. Second dose reduction, 10 mg PO twice daily.
-BSA 1.1 to 1.29 m2: First dose reduction, 25 mg PO every morning and 20 mg PO every evening. Second dose reduction, 20 mg PO every morning and 10 mg PO every evening.
-BSA 1.3 to 1.49 m2: First dose reduction, 25 mg PO twice daily. Second dose reduction, 25 mg PO every morning and 10 mg PO every evening.
-BSA 1.5 to 1.69 m2: First dose reduction, 30 mg PO twice daily. Second dose reduction, 25 mg PO every morning and 20 mg PO every evening.
-BSA 1.7 to 1.89 m2: First dose reduction, 35 mg PO every morning and 30 mg PO every evening. Second dose reduction, 25 mg PO every morning and 20 mg PO every evening.
-BSA 1.9 m2 or more: First dose reduction, 35 mg PO twice daily. Second dose reduction, 25 mg PO twice daily.
Cardiomyopathy
-Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or more from baseline and less than the lower limit of normal: Hold selumetinib therapy and obtain an echocardiogram or cardiac MRI every 3 to 6 weeks. Upon resolution, resume treatment at a reduced dose and monitor echocardiograms or cardiac MRIs every 2 to 3 months or as directed by the cardiologist.
-Symptomatic decrease in LVEF: Permanently discontinue selumetinib therapy.
-Grade 3 or 4 decrease in LVEF: Permanently discontinue selumetinib therapy.
Gastrointestinal Toxicity
-Grade 1 or 2 diarrhea: Begin an anti-diarrheal agent (e.g., loperamide) immediately after the first episode of unformed, loose stool. Increase fluid intake.
-Grade 3 diarrhea: Hold selumetinib therapy and begin an anti-diarrheal agent (e.g., loperamide) immediately after the first episode of unformed, loose stool; increase fluid intake. When diarrhea improves to grade 1 or less, resume treatment at the same dose. Permanently discontinue selumetinib if there is no improvement within 3 days.
-Grade 4 diarrhea: Begin an anti-diarrheal agent (e.g., loperamide) immediately after the first episode of unformed, loose stool. Increase fluid intake. Permanently discontinue selumetinib therapy.
-Grade 3 or 4 colitis: Begin an anti-diarrheal agent (e.g., loperamide) immediately after the first episode of unformed, loose stool. Increase fluid intake. Permanently discontinue selumetinib therapy.
Musculoskeletal
-Grade 4 increase in creatine phosphokinase (CPK): Hold selumetinib therapy and evaluate patients for rhabdomyolysis or other causes. If CPK improves to grade 1 or less within 3 weeks, resume treatment at a reduced dose. Permanently discontinue selumetinib therapy if no improvement in CPK within 3 weeks.
-Any increase in CPK with myalgia: Hold selumetinib therapy and evaluate patients for rhabdomyolysis or other causes. If CPK improves to grade 1 or less within 3 weeks, resume treatment at a reduced dose. Permanently discontinue selumetinib therapy if no improvement in CPK within 3 weeks.
-Rhabdomyolysis: Permanently discontinue selumetinib therapy.
Ocular Toxicity
-Retinal Pigment Epithelial Detachment (RPED): Hold selumetinib therapy and conduct optical coherence tomography assessments every 3 weeks until resolution. Upon resolution, resume treatment at a reduced dose.
-Retinal vein occlusion: Permanently discontinue selumetinib therapy.
Skin Toxicity
-Grade 3 or 4: Hold selumetinib therapy. Upon resolution, resume treatment at a reduced dose.
Other Adverse Reactions
-Intolerable grade 2: Hold selumetinib therapy. Upon improvement to grade 1 or less, resume treatment at a reduced dose.
-Grade 3: Hold selumetinib therapy. Upon improvement to grade 1 or less, resume treatment at a reduced dose.
-Grade 4: Hold selumetinib therapy. Upon improvement to grade 1 or less, resume treatment at a reduced dose. Consider discontinuation of therapy.
Maximum Dosage Limits:
-Adolescents
25 mg/m2 PO twice daily, not to exceed 50 mg PO twice daily.
-Children
25 mg/m2 PO twice daily, not to exceed 50 mg PO twice daily.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
-Child-Pugh A hepatic impairment: No dosage adjustment is necessary.
-Child-Pugh B hepatic impairment: Reduce the dose of selumetinib to 20 mg/m2 PO twice daily.
-Child-Pugh C hepatic impairment: The recommended dose of selumetinib has not been established.
Patients with Renal Impairment Dosing
No dosage adjustment is recommended in patients with renal impairment or end-stage renal disease.
*non-FDA-approved indication
Abciximab: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Adagrasib: (Major) Avoid coadministration of selumetinib and adagrasib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If adagrasib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of adagrasib. Selumetinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased selumetinib exposure by 49%.
Amobarbital: (Major) Avoid coadministration of selumetinib and amobarbital due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and amobarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of selumetinib and clarithromycin due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If clarithromycin is discontinued, resume the original selumetinib dose after 3 elimination half-lives of clarithromycin. Selumetinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Anagrelide: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Apalutamide: (Major) Avoid coadministration of selumetinib and apalutamide due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Aprepitant, Fosaprepitant: (Major) Avoid coadministration of selumetinib and aprepitant, fosaprepitant due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If aprepitant, fosaprepitant is discontinued, resume the original selumetinib dose after 3 elimination half-lives of aprepitant, fosaprepitant. Selumetinib is a CYP3A4 substrate; when administered as a 3 day oral regimen, aprepitant is a moderate inhibitor of CYP3A4. Single oral and IV doses have not been shown to alter concentrations of CYP3A4 substrates. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of selumetinib and butalbital due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Aspirin, ASA; Dipyridamole: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Atazanavir: (Major) Avoid coadministration of selumetinib and atazanavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If atazanavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of atazanavir. Selumetinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Atazanavir; Cobicistat: (Major) Avoid coadministration of selumetinib and atazanavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If atazanavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of atazanavir. Selumetinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%. (Major) Avoid coadministration of selumetinib and cobicistat due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If cobicistat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of cobicistat. Selumetinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Berotralstat: (Major) Avoid coadministration of selumetinib and berotralstat due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If berotralstat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of berotralstat. Selumetinib is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Bexarotene: (Major) Avoid coadministration of selumetinib and bexarotene due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Bosentan: (Major) Avoid coadministration of selumetinib and bosentan due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Butalbital; Acetaminophen: (Major) Avoid coadministration of selumetinib and butalbital due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of selumetinib and butalbital due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of selumetinib and butalbital due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid coadministration of selumetinib and butalbital due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Carbamazepine: (Major) Avoid coadministration of selumetinib and carbamazepine due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Cenobamate: (Major) Avoid coadministration of selumetinib and cenobamate due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Ceritinib: (Major) Avoid coadministration of selumetinib and ceritinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ceritinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ceritinib. Selumetinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Chloramphenicol: (Major) Avoid coadministration of selumetinib and chloramphenicol due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If chloramphenicol is discontinued, resume the original selumetinib dose after 3 elimination half-lives of chloramphenicol. Selumetinib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
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.
Cilostazol: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Ciprofloxacin: (Major) Avoid coadministration of selumetinib and ciprofloxacin due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ciprofloxacin is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ciprofloxacin. Selumetinib is a CYP3A4 substrate and ciprofloxacin is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Clarithromycin: (Major) Avoid coadministration of selumetinib and clarithromycin due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If clarithromycin is discontinued, resume the original selumetinib dose after 3 elimination half-lives of clarithromycin. Selumetinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Clopidogrel: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Cobicistat: (Major) Avoid coadministration of selumetinib and cobicistat due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If cobicistat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of cobicistat. Selumetinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Conivaptan: (Major) Avoid coadministration of selumetinib and conivaptan due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If conivaptan is discontinued, resume the original selumetinib dose after 3 elimination half-lives of conivaptan. Selumetinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase selumetinib exposure by 41%.
Cranberry, Vaccinium macrocarpon Ait.: (Moderate) Coadministration of selumetinib with supplemental vitamin E is not recommended if the total daily dose of vitamin E (amount in selumetinib plus the supplement) exceeds the recommended or safe daily limit; high dose vitamin E may increase the bleeding risk by antagonizing vitamin K dependent clotting factors and inhibiting platelet aggregation. Selumetinib contains 32 mg of vitamin E in the 10 mg capsules and 36 mg of vitamin E in the 25 mg capsules.
Crizotinib: (Major) Avoid coadministration of selumetinib and crizotinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If crizotinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of crizotinib. Selumetinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Cyclosporine: (Major) Avoid coadministration of selumetinib and cyclosporine due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If cyclosporine is discontinued, resume the original selumetinib dose after 3 elimination half-lives of cyclosporine. Selumetinib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Dabrafenib: (Major) Avoid coadministration of selumetinib and dabrafenib due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Danazol: (Major) Avoid coadministration of selumetinib and danazol due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If danazol is discontinued, resume the original selumetinib dose after 3 elimination half-lives of danazol. Selumetinib is a CYP3A4 substrate and danazol is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Darunavir: (Major) Avoid coadministration of selumetinib and darunavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If darunavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of darunavir. Selumetinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Darunavir; Cobicistat: (Major) Avoid coadministration of selumetinib and cobicistat due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If cobicistat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of cobicistat. Selumetinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%. (Major) Avoid coadministration of selumetinib and darunavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If darunavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of darunavir. Selumetinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of selumetinib and cobicistat due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If cobicistat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of cobicistat. Selumetinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%. (Major) Avoid coadministration of selumetinib and darunavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If darunavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of darunavir. Selumetinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Delavirdine: (Major) Avoid coadministration of selumetinib and delavirdine due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If delavirdine is discontinued, resume the original selumetinib dose after 3 elimination half-lives of delavirdine. Selumetinib is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
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.
Diltiazem: (Major) Avoid coadministration of selumetinib and diltiazem due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If diltiazem is discontinued, resume the original selumetinib dose after 3 elimination half-lives of diltiazem. Selumetinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Dipyridamole: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Dronedarone: (Major) Avoid coadministration of selumetinib and dronedarone due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If dronedarone is discontinued, resume the original selumetinib dose after 3 elimination half-lives of dronedarone. Selumetinib is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Duvelisib: (Major) Avoid coadministration of selumetinib and duvelisib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If duvelisib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of duvelisib. Selumetinib is a CYP3A4 substrate and duvelisib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Efavirenz: (Major) Avoid coadministration of selumetinib and efavirenz due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease selumetinib exposure by 38%.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of selumetinib and efavirenz due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease selumetinib exposure by 38%.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of selumetinib and efavirenz due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease selumetinib exposure by 38%.
Elagolix: (Major) Avoid coadministration of selumetinib and elagolix due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and elagolix is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of selumetinib and elagolix due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and elagolix is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of selumetinib and cobicistat due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If cobicistat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of cobicistat. Selumetinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of selumetinib and cobicistat due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If cobicistat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of cobicistat. Selumetinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Encorafenib: (Major) Avoid coadministration of selumetinib and encorafenib due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased selumetinib exposure by 51%.
Enzalutamide: (Major) Avoid coadministration of selumetinib and enzalutamide due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Eptifibatide: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Erythromycin: (Major) Avoid coadministration of selumetinib and erythromycin due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If erythromycin is discontinued, resume the original selumetinib dose after 3 elimination half-lives of erythromycin. Selumetinib is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor. Coadministration with erythromycin is predicted to increase selumetinib exposure by 41%.
Eslicarbazepine: (Major) Avoid coadministration of selumetinib and eslicarbazepine due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Etravirine: (Major) Avoid coadministration of selumetinib and etravirine due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and etravirine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Fedratinib: (Major) Avoid coadministration of selumetinib and fedratinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If fedratinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of fedratinib. Selumetinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Coadministration of selumetinib with supplemental vitamin E is not recommended if the total daily dose of vitamin E (amount in selumetinib plus the supplement) exceeds the recommended or safe daily limit; high dose vitamin E may increase the bleeding risk by antagonizing vitamin K dependent clotting factors and inhibiting platelet aggregation. Selumetinib contains 32 mg of vitamin E in the 10 mg capsules and 36 mg of vitamin E in the 25 mg capsules.
Fluconazole: (Major) Avoid coadministration of selumetinib and fluconazole due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If fluconazole is discontinued, resume the original selumetinib dose after 3 elimination half-lives of fluconazole. Selumetinib is a CYP3A4 and CYP2C19 substrate and fluconazole is a moderate CYP3A4 and strong CYP2C19 inhibitor. Coadministration with fluconazole increased selumetinib exposure by 53%.
Fluvoxamine: (Major) Avoid coadministration of selumetinib and fluvoxamine due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If fluvoxamine is discontinued, resume the original selumetinib dose after 3 elimination half-lives of fluvoxamine. Selumetinib is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Fosamprenavir: (Major) Avoid coadministration of selumetinib and fosamprenavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If fosamprenavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of fosamprenavir. Selumetinib is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase selumetinib exposure by 41%.
Fosphenytoin: (Major) Avoid coadministration of selumetinib and fosphenytoin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Grapefruit juice: (Major) Advise patients to avoid grapefruit juice or grapefruit-containing foods during use of selumetinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. Selumetinib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Idelalisib: (Major) Avoid coadministration of selumetinib and idelalisib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If idelalisib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of idelalisib. Selumetinib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Imatinib: (Major) Avoid coadministration of selumetinib and imatinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If imatinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of imatinib. Selumetinib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Indinavir: (Major) Avoid coadministration of selumetinib and indinavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If indinavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of indinavir. Selumetinib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Isavuconazonium: (Major) Avoid coadministration of selumetinib and isavuconazonium due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If isavuconazonium is discontinued, resume the original selumetinib dose after 3 elimination half-lives of isavuconazonium. Selumetinib is a CYP3A4 substrate and isavuconazonium is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of selumetinib and rifampin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased selumetinib exposure by 51%.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of selumetinib and rifampin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased selumetinib exposure by 51%.
Itraconazole: (Major) Avoid coadministration of selumetinib and itraconazole due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If itraconazole is discontinued, resume the original selumetinib dose after 3 elimination half-lives of itraconazole. Selumetinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased selumetinib exposure by 49%.
Ketoconazole: (Major) Avoid coadministration of selumetinib and ketoconazole due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ketoconazole is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ketoconazole. Selumetinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of selumetinib and clarithromycin due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If clarithromycin is discontinued, resume the original selumetinib dose after 3 elimination half-lives of clarithromycin. Selumetinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Lefamulin: (Major) Avoid coadministration of selumetinib and oral lefamulin due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If oral lefamulin is discontinued, resume the original selumetinib dose after 3 elimination half-lives of oral lefamulin. Selumetinib is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor. An interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Lenacapavir: (Major) Avoid coadministration of selumetinib and lenacapavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If lenacapavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of lenacapavir. Selumetinib is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase selumetinib exposure by 41%.
Letermovir: (Major) Avoid coadministration of selumetinib and letermovir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If letermovir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of letermovir. Selumetinib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Levoketoconazole: (Major) Avoid coadministration of selumetinib and ketoconazole due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ketoconazole is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ketoconazole. Selumetinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Lonafarnib: (Major) Avoid coadministration of selumetinib and lonafarnib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If lonafarnib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of lonafarnib. Selumetinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Lopinavir; Ritonavir: (Major) Avoid coadministration of selumetinib and ritonavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ritonavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ritonavir. Selumetinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Lorlatinib: (Major) Avoid coadministration of selumetinib and lorlatinib due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of selumetinib and lumacaftor; ivacaftor due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of selumetinib and lumacaftor; ivacaftor due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Mavacamten: (Major) Avoid coadministration of selumetinib and mavacamten due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease selumetinib exposure by 38%.
Methohexital: (Major) Avoid coadministration of selumetinib and methohexital due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and methohexital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Mifepristone: (Major) Avoid coadministration of selumetinib and mifepristone due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If mifepristone is discontinued, resume the original selumetinib dose after 3 elimination half-lives of mifepristone. Selumetinib is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Mitotane: (Major) Avoid coadministration of selumetinib and mitotane due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Modafinil: (Major) Avoid coadministration of selumetinib and modafinil due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Nafcillin: (Major) Avoid coadministration of selumetinib and nafcillin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Nefazodone: (Major) Avoid coadministration of selumetinib and nefazodone due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If nefazodone is discontinued, resume the original selumetinib dose after 3 elimination half-lives of nefazodone. Selumetinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Nelfinavir: (Major) Avoid coadministration of selumetinib and nelfinavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If nelfinavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of nelfinavir. Selumetinib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of selumetinib and netupitant due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If netupitant is discontinued, resume the original selumetinib dose after 3 elimination half-lives of netupitant. Selumetinib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Nilotinib: (Major) Avoid coadministration of selumetinib and nilotinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If nilotinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of nilotinib. Selumetinib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of selumetinib and ritonavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ritonavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ritonavir. Selumetinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Nirogacestat: (Major) Avoid coadministration of selumetinib and nirogacestat due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If nirogacestat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of nirogacestat. Selumetinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase selumetinib exposure by 41%.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of selumetinib and rifabutin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Pexidartinib: (Major) Avoid coadministration of selumetinib and pexidartinib due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Phenobarbital: (Major) Avoid coadministration of selumetinib and phenobarbital due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of selumetinib and phenobarbital due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Phenytoin: (Major) Avoid coadministration of selumetinib and phenytoin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Platelet Inhibitors: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Posaconazole: (Major) Avoid coadministration of selumetinib and posaconazole due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If posaconazole is discontinued, resume the original selumetinib dose after 3 elimination half-lives of posaconazole. Selumetinib is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Prasugrel: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Primidone: (Major) Avoid coadministration of selumetinib and primidone due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Repotrectinib: (Major) Avoid coadministration of selumetinib and repotrectinib due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease selumetinib exposure by 38%.
Ribociclib: (Major) Avoid coadministration of selumetinib and ribociclib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ribociclib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ribociclib. Selumetinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Ribociclib; Letrozole: (Major) Avoid coadministration of selumetinib and ribociclib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ribociclib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ribociclib. Selumetinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Rifabutin: (Major) Avoid coadministration of selumetinib and rifabutin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Rifampin: (Major) Avoid coadministration of selumetinib and rifampin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased selumetinib exposure by 51%.
Rifapentine: (Major) Avoid coadministration of selumetinib and rifapentine due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Ritlecitinib: (Major) Avoid coadministration of selumetinib and ritlecitinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ritlecitinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ritlecitinib. Selumetinib is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase selumetinib exposure by 41%.
Ritonavir: (Major) Avoid coadministration of selumetinib and ritonavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ritonavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ritonavir. Selumetinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
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 coadministration of selumetinib and secobarbital due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and secobarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Sotorasib: (Major) Avoid coadministration of selumetinib and sotorasib due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by approximately 38%.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of selumetinib and St. John's Wort due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Ticagrelor: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Tirofiban: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Trandolapril; Verapamil: (Major) Avoid coadministration of selumetinib and verapamil due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If verapamil is discontinued, resume the original selumetinib dose after 3 elimination half-lives of verapamil. Selumetinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Tucatinib: (Major) Avoid coadministration of selumetinib and tucatinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If tucatinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of tucatinib. Selumetinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Verapamil: (Major) Avoid coadministration of selumetinib and verapamil due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If verapamil is discontinued, resume the original selumetinib dose after 3 elimination half-lives of verapamil. Selumetinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Vitamin D: (Moderate) Coadministration of selumetinib with supplemental vitamin E is not recommended if the total daily dose of vitamin E (amount in selumetinib plus the supplement) exceeds the recommended or safe daily limit; high dose vitamin E may increase the bleeding risk by antagonizing vitamin K dependent clotting factors and inhibiting platelet aggregation. Selumetinib contains 32 mg of vitamin E in the 10 mg capsules and 36 mg of vitamin E in the 25 mg capsules.
Vitamin E: (Moderate) Coadministration of selumetinib with supplemental vitamin E is not recommended if the total daily dose of vitamin E (amount in selumetinib plus the supplement) exceeds the recommended or safe daily limit; high dose vitamin E may increase the bleeding risk by antagonizing vitamin K dependent clotting factors and inhibiting platelet aggregation. Selumetinib contains 32 mg of vitamin E in the 10 mg capsules and 36 mg of vitamin E in the 25 mg capsules.
Vitamin E: (Moderate) Coadministration of selumetinib with supplemental vitamin E is not recommended if the total daily dose of vitamin E (amount in selumetinib plus the supplement) exceeds the recommended or safe daily limit; high dose vitamin E may increase the bleeding risk by antagonizing vitamin K dependent clotting factors and inhibiting platelet aggregation. Selumetinib contains 32 mg of vitamin E in the 10 mg capsules and 36 mg of vitamin E in the 25 mg capsules.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of selumetinib and clarithromycin due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If clarithromycin is discontinued, resume the original selumetinib dose after 3 elimination half-lives of clarithromycin. Selumetinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Vorapaxar: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Voriconazole: (Major) Avoid coadministration of selumetinib and voriconazole due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If voriconazole is discontinued, resume the original selumetinib dose after 3 elimination half-lives of voriconazole. Selumetinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Voxelotor: (Major) Avoid coadministration of selumetinib and voxelotor due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If voxelotor is discontinued, resume the original selumetinib dose after 3 elimination half-lives of voxelotor. Selumetinib is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase selumetinib exposure by 41%.
Warfarin: (Moderate) Closely monitor the INR and for bleeding if coadministration of warfarin and selumetinib is necessary as concurrent use may increase the bleeding risk; adjust the warfarin dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors.
Selumetinib is a kinase inhibitor targeting mitogen-activated protein kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers. Oral administration of selumetinib inhibited ERK phosphorylation and reduced neurofibroma numbers, volume, and proliferation in genetically modified mouse models of neurofibromatosis type 1 (NF1) that generate neurofibromas that recapitulate the genotype and phenotype of human NF1.
Selumetinib is administered orally. It is 98.4% bound to plasma proteins in vitro; selumetinib binds to albumin (96%) and alpha-1 acid glycoprotein (less than 35%). The mean apparent volume of distribution at steady state of selumetinib across a dose range of 20 mg/m2 to 30 mg/m2 ranged from 78 liters to 171 liters in pediatric patients. The apparent oral clearance was 8.8 liters/hour and the mean elimination half-life was 6.2 hours after an oral dose of 25 mg/m2. After a single radiolabeled dose of selumetinib to healthy adults, 59% of the dose was recovered in feces (19% unchanged) and 33% in urine (less than 1% unchanged).
Affected cytochrome P450 isoenzymes: CYP3A4, CYP2C19, CYP2C9, CYP2E1, CYP3A5, UGT1A1, UGT1A3
Selumetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5. It also undergoes glucuronidation by UGT1A1 and UGT1A3. Approximately 56% of the intrinsic clearance of selumetinib can be attributed to CYP metabolism and about 29% to direct glucuronidation by UGT enzymes in vitro. Metabolism by CYP2C19 and CYP1A2 (with additional contribution by CYP2C9 and CYP2A6) generate an active metabolite (N-desmethyl selumetinib) that represents less than 10% of selumetinib levels in human plasma, but is 3 to 5 times more potent than the parent compound and contributes to about 21% to 35% of the overall pharmacologic activity. N-desemethyl selumetinib is metabolized through the same routes as the parent drug.
-Route-Specific Pharmacokinetics
Oral Route
At the recommended dose of 25 mg/m2 twice daily in pediatric patients (age 2 to 17 years), the mean Cmax after the first dose was 731 ng/mL (CV, 62%) and at steady-state was 798 ng/mL (CV, 52%). The median time to peak plasma concentrations (Tmax) at steady-state was 1 to 1.5 hours. The mean AUC after the first dose was 2,009 ng x hour/mL (CV, 35%) and at steady-state was 1,958 ng x hour/mL (CV, 41%). The AUC and Cmax of selumetinib increase proportionally over a dose range from 20 mg/m2 to 30 mg/m2; the accumulation was 1.1-fold after administration at the recommended dose. The mean oral bioavailability of selumetinib is 62% in healthy adults.
Following a low-fat meal (400 calories, 25% fat), the Cmax and AUC of selumetinib decreased by 24% and 8%, respectively; Tmax was delayed by approximately 0.6 hours. A population pharmacokinetic analysis showed that a low or high fat meal had no clinically relevant effect on the AUC of selumetinib.
-Special Populations
Hepatic Impairment
The dose-normalized total AUC decreased by 14% in subjects with mild hepatic impairment (Child-Pugh A) following a single dose of selumetinib. In subjects with moderate hepatic impairment (Child-Pugh B) and severe hepatic impairment, the dose-normalized total AUC increased by 59% and 57%, respectively, compared to subjects with normal hepatic function. The unbound AUC of selumetinib decreased by 31% in subjects with mild hepatic impairment, increased by 41% in subjects with moderate hepatic impairment, and increased by 3.2-fold in subjects with severe hepatic impairment compared to those with normal hepatic function.
Renal Impairment
Selumetinib exposures were similar in subjects with end-stage renal disease (CrCl less than 15 mL/min) who required dialysis compared to subjects with normal renal function (CrCl 90 mL/min or more) after administration of a single 50-mg dose.
Ethnic Differences
No clinically meaningful effect on the pharmacokinetics of selumetinib or N-desmethyl selumetinib was observed based on race (White, Asian, Black).