selumetinib (Rx)

Brand and Other Names:Koselugo
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Dosing & Uses

AdultPediatric

See Pediatric Dosing

Dosage Forms & Strengths

capsule

  • 10mg
  • 25mg

Type 1 Neurofibromatosis

Indicated for neurofibromatosis type 1 (NF1) in patients aged ≥2 years who have symptomatic, inoperable plexiform neurofibromas (PN)

<2 years or body surface area (BSA) <0.55 m2: Safety and efficacy not established

≥2 years

BSA ≥0.55 m2: 25 mg/m2 PO BID (~q12hr)

Recommended dosage based on BSA
  • 0.55-0.69 m2: 20 mg PO qAM and 10 mg PO qPM
  • 0.7-0.89 m2: 20 mg PO BID
  • 0.9-1.09 m2: 25 mg PO BID
  • 1.1-1.29 m2: 30 mg PO BID
  • 1.3-1.49 m2: 35 mg PO BID
  • 1.5-1.69 m2: 40 mg PO BID
  • 1.7-1.89 m2: 45 mg PO BID
  • ≥1.9 m2: 50 mg PO BID

Dosage Modifications

Dose reductions for adverse reactions based on BSA

  • First dose reduction
    • 0.55-0.69 m2: 10 mg BID
    • 0.7-0.89 m2: 20 mg qAM and 10 mg qPM
    • 0.9-1.09 m2: 25 mg qAM and 10 mg qPM
    • 1.1-1.29 m2: 25 mg qAM and 20 mg qPM
    • 1.3-1.49 m2: 25 mg BID
    • 1.5-1.69 m2: 30 mg BID
    • 1.7-1.89 m2: 35 mg qAM and 30 mg qPM
    • ≥1.9 m2: 35 mg BID
  • Second dose reduction
    • 0.55-0.69 m2: 10 mg qDay
    • 0.7-1.09 m2: 10 mg BID
    • 1.1-1.29 m2: 20 mg qAM and 10 mg qPM
    • 1.3-1.49 m2: 25 mg qAM and 10 mg qPM
    • 1.5-1.89 m2: 25 mg qAM and 20 mg qPM
    • ≥1.9 m2: 25 mg BID
  • Subsequent dose reductions
    • Permanently discontinue in patients unable to tolerate selumetinib after 2 dose reductions

Cardiomyopathy

  • Asymptomatic decrease in left ventricular ejection fraction (LVEF) ≥10% from baseline and lower level of normal (LLN): Withhold until resolution; resume at reduced dose
  • Symptomatic decreased LVEF OR Grade 3 or 4 decreased LVEF: Permanently discontinue

Ocular toxicity

  • Retinal pigment epithelial detachment (RPED): Withhold until resolution; resume at reduced dose
  • Retinal vein occlusion (RVO): Permanently discontinue

Gastrointestinal toxicity

  • Grade 3 diarrhea: Withhold until improved to Grade <1; resume at same dose; permanently discontinue if no improvement within 3 days
  • Grade 4 diarrhea OR Grade 3 or 4 colitis: Permanently discontinue

Skin toxicity

  • Grade 3 or 4: Withhold until improvement; resume at reduced dose

Increased creatine phosphokinase (CPK)

  • Grade 4 increased CPK OR any increased CPK and myalgia: Withhold until improved to Grade <1; resume at reduced dose; permanently discontinue if no improvement within 3 weeks

Other adverse reactions

  • Intolerable Grade 2 OR Grade 3: Withhold until improved to Grade <1; resume at reduced dose
  • Grade 4: Withhold until improved to Grade <1; resume at reduced dose; consider discontinuation

Dosage modifications for drug interactions

Strong or moderate CYP3A4 inhibitors or fluconazole
  • Avoid coadministration
  • If coadministration cannot be avoided, reduce selumetinib dosage based on the recommendations below
  • Resume selumetinib after discontinuation of the strong or moderate CYP3A4 inhibitor or fluconazole for 3 elimination half-lives
  • Reduce current dose by 5 mg/m2 (eg, 25 mg/m2 to 20 mg/m2 OR 20 mg/m2 to 15 mg/m2)
  • Dosage reduction to 20 mg/m2 based on BSA
    • 0.55-0.69 m2: 10 mg BID
    • 0.7-0.89 m2: 20 mg qAM and 10 mg qPM
    • 0.9-1.09 m2: 20 mg BID
    • 1.1-1.29 m2: 25 mg BID
    • 1.3-1.49 m2: 30 mg qAM and 25 mg qPM
    • 1.5-1.69 m2: 35 mg qAM and 30 mg qPM
    • 1.7-1.89 m2: 35 mg BID
    • ≥1.9 m2: 40 mg BID
  • Dosage reduction to 15 mg/m2 based on BSA
    • 0.55-0.69 m2: 10 mg qDay
    • 0.7-0.89 m2: 10 mg BID
    • 0.9-1.09 m2: 20 mg qAM and 10 mg qPM
    • 1.1-1.29 m2: 25 mg qAM and 10 mg qPM
    • 1.3-1.49 m2: 25 mg qAM and 20 mg qPM
    • 1.5-1.69 m2: 25 mg BID
    • 1.7-1.89 m2: 30 mg qAM and 25 mg qPM
    • ≥1.9 m2: 30 mg BID

Renal impairment

  • No dosage adjustment necessary

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment necessary
  • Moderate (Child-Pugh B): Reduce recommended dose to 20 mg/m2 BID

    • 0.55-0.69 m2: 10 mg BID
    • 0.7-0.89 m2: 20 mg qAM and 10 mg qPM
    • 0.9-1.09 m2: 20 mg BID
    • 1.1-1.29 m2: 25 mg BID
    • 1.3-1.49 m2: 30 mg qAM and 25 mg qPM
    • 1.5-1.69 m2: 35 mg qAM and 30 mg qPM
    • 1.7-1.89 m2: 35 mg BID
    • ≥1.9 m2: 40 mg BID
  • Severe (Child-Pugh C): Selumetinib unbound AUC increased 3.2-fold in subjects with severe hepatic impairment compared with normal hepatic function; no dosage recommended
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Interactions

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              • abametapir

                abametapir will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

              • amiodarone

                amiodarone will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • amobarbital

                amobarbital will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • apalutamide

                apalutamide will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • aprepitant

                aprepitant will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • armodafinil

                armodafinil will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • atazanavir

                atazanavir will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • bexarotene

                bexarotene will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • bicalutamide

                bicalutamide will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • bosentan

                bosentan will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • brigatinib

                brigatinib will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • butabarbital

                butabarbital will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • butalbital

                butalbital will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • carbamazepine

                carbamazepine will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • ceritinib

                ceritinib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • chloramphenicol

                chloramphenicol will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • clarithromycin

                clarithromycin will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • clobazam

                clobazam will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • clozapine

                clozapine will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • cobicistat

                cobicistat will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • conivaptan

                conivaptan will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • crizotinib

                crizotinib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • cyclosporine

                cyclosporine will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • dabrafenib

                dabrafenib will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • darunavir

                darunavir will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • desipramine

                desipramine will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • diltiazem

                diltiazem will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • doxycycline

                doxycycline will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • dronedarone

                dronedarone will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of a strong CYP2C9 inhibitors is unavoidable, closely monitor adverse reactions and modify dose of erdafitinib accordingly. If strong CYP2C9 inhibitor is discontinued, consider increasing erdafitinib dose in the absence of any drug-related toxicities.

              • efavirenz

                efavirenz will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • elagolix

                elagolix will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • encorafenib

                encorafenib will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • enzalutamide

                enzalutamide will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • erythromycin base

                erythromycin base will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • erythromycin ethylsuccinate

                erythromycin ethylsuccinate will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • erythromycin lactobionate

                erythromycin lactobionate will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • erythromycin stearate

                erythromycin stearate will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • eslicarbazepine acetate

                eslicarbazepine acetate will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • etravirine

                etravirine will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • fedratinib

                fedratinib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • fluconazole

                fluconazole will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • fosamprenavir

                fosamprenavir will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • fosphenytoin

                fosphenytoin will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • fostamatinib

                fostamatinib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • grapefruit

                grapefruit will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • haloperidol

                haloperidol will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • idelalisib

                idelalisib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • iloperidone

                iloperidone will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • imatinib

                imatinib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • indinavir

                indinavir will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • isoniazid

                isoniazid will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • itraconazole

                itraconazole will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • ivacaftor

                ivacaftor will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • ivosidenib

                ivosidenib will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • ketoconazole

                ketoconazole will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • lapatinib

                lapatinib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • larotrectinib

                larotrectinib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • letermovir

                letermovir will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • lonafarnib

                lonafarnib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with sensitive CYP3A substrates. If coadministration unavoidable, monitor for adverse reactions and reduce CYP3A substrate dose in accordance with product labeling.

              • lorlatinib

                lorlatinib will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • lumacaftor/ivacaftor

                lumacaftor/ivacaftor will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • metronidazole

                metronidazole will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • mifepristone

                mifepristone will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • mitotane

                mitotane will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • modafinil

                modafinil will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • nafcillin

                nafcillin will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • nefazodone

                nefazodone will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • nelfinavir

                nelfinavir will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • netupitant/palonosetron

                netupitant/palonosetron will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • pentobarbital

                pentobarbital will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • phenobarbital

                phenobarbital will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • phenytoin

                phenytoin will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • posaconazole

                posaconazole will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • primidone

                primidone will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • quinupristin/dalfopristin

                quinupristin/dalfopristin will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • ribociclib

                ribociclib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • rifabutin

                rifabutin will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • rifampin

                rifampin will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • rifapentine

                rifapentine will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • ritonavir

                ritonavir will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • saquinavir

                saquinavir will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • schisandra

                schisandra will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • secobarbital

                secobarbital will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • sertraline

                sertraline will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • St John's Wort

                St John's Wort will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • stiripentol

                stiripentol will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • telotristat ethyl

                telotristat ethyl will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • tetracycline

                tetracycline will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • tipranavir

                tipranavir will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • tucatinib

                tucatinib will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.

              • verapamil

                verapamil will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • voriconazole

                voriconazole will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              • voxelotor

                voxelotor will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

              Monitor Closely (18)

              • abciximab

                abciximab and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • anagrelide

                anagrelide and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • aspirin

                aspirin and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • berotralstat

                selumetinib increases levels of berotralstat by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Reduced berotralstat dose to 110 mg/day when coadministered with P-gp inhibitors.

              • cangrelor

                cangrelor and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • cilostazol

                cilostazol and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • clopidogrel

                clopidogrel and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • dipyridamole

                dipyridamole and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • eptifibatide

                eptifibatide and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • fostemsavir

                fostemsavir will increase the level or effect of selumetinib by Other (see comment). Modify Therapy/Monitor Closely. Fostemsavir inhibits BCRP transporters. If possible, avoid coadministration or modify dose of BCRP substrate coadministered with fostemsavir.

              • ponesimod

                ponesimod and selumetinib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

              • prasugrel

                prasugrel and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • ticagrelor

                ticagrelor and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • ticlopidine

                ticlopidine and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • tirofiban

                tirofiban and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • vitamin E

                vitamin E and selumetinib both increase Other (see comment). Modify Therapy/Monitor Closely. Selumetinib contains vitamin E. Daily vitamin E intake (ie, amount in selumetinib, supplement, dietary) that exceeds recommendations may increase bleeding risk.

              • vorapaxar

                vorapaxar and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              • warfarin

                warfarin and selumetinib both increase anticoagulation. Modify Therapy/Monitor Closely. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an antiplatelet agent with selumetinib. Monitor for bleeding and INR or PT in patients coadministered a vitamin-K antagonist or an antiplatelet agent with selumetinib.

              Minor (0)

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                Adverse Effects

                >10%

                All grades

                • Vomiting (82%)
                • Rash (80%)
                • Increased CPK (79%)
                • Abdominal pain (76%)
                • Diarrhea (70%)
                • Nausea (66%)
                • Dry skin (60%)
                • Musculoskeletal pain (58%)
                • Fatigue (56%)
                • Pyrexia (56%)
                • Decreased albumin (51%)
                • Acneiform rash (50%)
                • Stomatitis (50%)
                • Paronychia (48%)
                • Headache (48%)
                • Pruritus (46%)
                • Increased AST (41%)
                • Decreased hemoglobin (41%)
                • Dermatitis (36%)
                • Increased ALT (35%)
                • Constipation (34%)
                • Decreased neutrophils (33%)
                • Increased lipase (32%)
                • Hair changes (32%)
                • Epistaxis (28%)
                • Hematuria (22%)
                • Proteinuria (22%)
                • Decreased appetite (22%)
                • Decreased ejection fraction (EF) (22%)
                • Sinus tachycardia (20%)
                • Skin infection (20%)
                • Edema (20%)
                • Decreased lymphocytes (20%)
                • Visual impairment (<20%)
                • Dry mouth (<20%)
                • Facial edema, including periorbital and face edema (<20%)
                • Increased weight (<20%)
                • Acute kidney injury (<20%)
                • Dyspnea, including exertional dyspnea and dyspnea at rest (<20%)
                • Hypertension (<20%)
                • Increased alkaline phosphatase (18%)
                • Increased amylase (18%)
                • Decreased potassium (18%)
                • Increased sodium (18%)
                • Decreased sodium (18%)

                Grade 3 or 4

                • Diarrhea (16%)

                1-10%

                Grade 3 or 4

                • Pyrexia (8%)
                • Increased CPK (7%)
                • Rash (6%)
                • Vomiting (6%)
                • Paronychia (6%)
                • Increased lipase (5%)
                • Increased ALT (4%)
                • Rash acneiform (4%)
                • Dermatitis (4%)
                • Increased potassium (4%)
                • Decreased hemoglobin (4%)
                • Decreased neutrophils (4%)
                • Decreased lymphocytes (2%)
                • Increased ALT (2%)
                • Headache (2%)
                • Hematuria (2%)
                • Skin infection (2%)
                • Nausea (2%)
                • Decreased potassium (2%)
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                Warnings

                Contraindications

                None

                Cautions

                Rash occurred; other skin toxicities, including severe palmoplantar erythrodysesthesia syndrome, occurred; monitor for severe rashes

                Increased CPK occurred; rhabdomyolysis occurred in an unapproved adult population who received selumetinib; obtain serum CPK before initiating, periodically during treatment, and as clinically indicated

                May cause fetal harm when administered to a pregnant woman based on animal studies and mechanism of action

                Gastrointestinal toxicity

                • Diarrhea occurred
                • Serious gastrointestinal toxicities (eg, perforation, colitis, ileus, intestinal obstruction) occurred in an unapproved population of adult patients
                • Colitis occurred in an unapproved population of pediatric patients
                • Advise to start an antidiarrheal agent (eg, loperamide) immediately after first episode of unformed, loose stool and to increase fluid intake during diarrhea episodes

                Ocular toxicity

                • Blurred vision, photophobia, cataracts, and ocular hypertension occurred
                • Serious ocular toxicities, including RVO and RPED, occurred in an unapproved population of adult patients with multiple tumor types
                • RPED occurred in the pediatric population during treatment and resulted in permanent discontinuation
                • Conduct comprehensive ophthalmic assessments before initiating treatment, at regular intervals during treatment, and for new or worsening visual changes

                Cardiomyopathy

                • Cardiomyopathy (decreased in LVEF ≥10% below baseline) occurred; all patients with decreased LVEF were asymptomatic and identified during routine echocardiography
                • Safety has not been established in patients with a history of impaired LVEF or a baseline ejection fraction below the institutional LLN
                • Assess ejection fraction by echocardiogram before initiating treatment, q3months during the first year of treatment, q6months thereafter, and as clinically indicated.
                • If dose is withheld, obtain an echocardiogram or a cardiac MRI every 3-6 weeks, then every 2-3 months or as directed by the cardiologist once resolved

                Drug interaction overview

                Selumetinib is a substrate of CYP3A4, BCRP, and P-gp transporters

                • Antiplatelet antagonists or vitamin K antagonists
                  • Capsules contain vitamin E and daily intake of vitamin E that exceeds the recommended or safe limits may increase the risk of bleeding
                  • An increased risk of bleeding in patients may occur when coadministered with vitamin K antagonists or antiplatelet antagonists
                  • Supplemental vitamin E is not recommended if daily vitamin E intake will exceed the recommended or safe limits
                  • Monitor for bleeding and international normalized ratio
                • Strong and moderate CYP3A4 inhibitors
                  • Coadministration with a strong or moderate CYP3A4 inhibitor or fluconazole may increase selumetinib plasma concentration
                  • Avoid coadministration
                • Strong or moderate CYP3A4 inducers
                  • Coadministration with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations
                  • Avoid coadministration
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                Pregnancy & Lactation

                Pregnancy

                Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman

                No data available on use in pregnant women to evaluate drug-associated risk

                Verify pregnancy status before initiating treatment

                Animal data

                • Administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryofetal survival at exposures approximately >5x the human exposure at the clinical dose of 25 mg/m2 BID
                • Advise pregnant women of the potential risk to the fetus

                Contraception

                • Females of reproductive potential or males with females of reproductive potential: Use effective contraception during treatment and for 1 week after the last dose

                Lactation

                There are no data on the presence of selumetinib or its active metabolite in human milk or their effects on breastfed child or milk production

                Selumetinib and its active metabolite were present in the milk of lactating mice

                Advise femalesnot to breastfeed during treatment and for 1 week after the last dose

                Pregnancy Categories

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

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

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

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

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

                NA: Information not available.

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                Pharmacology

                Mechanism of Action

                Inhibitor of mitogen-activated protein kinases 1 and 2 (MEK1/2)

                MEK 1/2 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

                In genetically modified mouse models, oral dosing of selumetinib inhibited ERK phosphorylation and reduced neurofibroma numbers, volume, and proliferation

                Absorption

                • Oral bioavailability (adults): 62%
                • Peak plasma distribution (pediatric patients): 731 ng/mL (first dose); 783 ng/mL (steady-state)
                • Peak plasma time (pediatric patients): 1-1.5 hr (steady-state)
                • AUC (pediatric patients): 2000 ng⋅hr/mL (first dose); 1958 ng⋅hr/mL (steady-state)
                • Effect of food

                  • High-fat meal (1000 calories, 50% fat): Mean peak plasma concentration and AUC of selumetinib decreased by 50% and 16%, respectively, in healthy adults administered a single dose of 75 mg; peak plasma time was delayed by ~1.5 hr
                  • Low-fat meal (400 calories, 25% fat): Peak plasma concentration and AUC decreased by 60% and 38%, respectively, in healthy adults administered a single dose of 50 mg; peak plasma time was delayed by ~0.9 hr

                Distribution

                Vd (steady-state in pediatric patients): 78 L (20 mg/m2); 171 L (30 mg/m2)

                Protein bound: 98%; binds to serum albumin (96%) and alpha-1 acid glycitein (<35%)

                Metabolism

                Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5

                Undergoes glucuronidation by UGT1A1 and UGT1A3

                N-desmethyl selumetinib (active metabolite of selumetinib) is generated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6, and metabolized through the same routes as selumetinib

                Elimination

                Oral clearance: 8.8 L/hr (pediatric patients)

                Half-life (pediatric patients): 6.2 hr (25 mg/m2)

                Excretion: 59% (feces [19% unchanged]); 33% (urine [<1% unchanged])

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                Administration

                Oral Administration

                Take on an empty stomach; do not consume food 2 hr before or within 1 hr after each dose

                Swallow capsules whole with water; do not chew, dissolve, or open capsule

                Do not administer to patients who are unable to swallow a whole capsule

                Missed dose

                • Do not take a missed dose unless it is >6 hr until the next scheduled dose
                • If vomiting occurs after administration, do not take an additional dose, but continue with the next scheduled dose

                Storage

                Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

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                Images

                No images available for this drug.
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                Patient Handout

                A Patient Handout is not currently available for this monograph.
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                Formulary

                FormularyPatient Discounts

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                • View the formulary and any restrictions for each plan.
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                • Access your plan list on any device – mobile or desktop.

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

                Tier Description
                1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                NC NOT COVERED – Drugs that are not covered by the plan.
                Code Definition
                PA Prior Authorization
                Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                QL Quantity Limits
                Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
                ST Step Therapy
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                Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.