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

Interaction Checker

and selumetinib

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    Contraindicated

      Serious - Use Alternative

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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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            Formulary

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            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.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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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.