Selumetinib (Monograph)

Brand name: Koselugo
Drug class: Antineoplastic Agents
Chemical name: 6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide
Molecular formula: C₁₇H₁₅BrClFN₄O₃
CAS number: 606143-52-6

Medically reviewed by Drugs.com on May 23, 2022. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2.

Uses for Selumetinib

Neurofibromatosis Type 1

Treatment of pediatric patients ≥2 years of age with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (designated an orphan drug by FDA).

Surgical intervention is common and typically based on progressive plexiform neurofibroma-related symptoms or functional impairment. Because of the absence of functional neurofibromin and upregulation of RAS signaling of the RAF/MEK/ERK pathway in patients with NF1, the MEK inhibitor selumetinib is a treatment option for NF1-related tumors, including plexiform neurofibromas.

Other Uses

Has been used as a single agent and in combination with chemotherapy^{† [off-label]} in adults with unresectable malignant melanoma^{† [off-label]}, metastatic uveal melanoma^{† [off-label]}, colorectal cancer^{† [off-label]}, advanced pancreatic cancer^{† [off-label]}, metastatic differentiated thyroid cancer^†, and non-small cell lung cancer^†.

Has also been investigated for use in pediatric patients with NF1 and non-NF1 glioma (optic pathway hypothalamic glioma, pediatric low-grade glioma)^†.

Related/similar drugs

Koselugo

Selumetinib Dosage and Administration

General

Pretreatment Screening

• Assess ejection fraction by echocardiogram prior to initiating therapy.

• Perform comprehensive ophthalmologic examinations prior to initiating therapy.

• Obtain serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations prior to initiating therapy.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Assess ejection fraction by echocardiogram every 3 months during the first year of therapy, then every 6 months thereafter, and as clinically indicated.

• Perform comprehensive ophthalmologic examinations at regular intervals during therapy.

• Monitor for severe dermatologic rashes.

• Obtain serum CK concentrations periodically during treatment and as clinically indicated.

• In patients receiving a vitamin K antagonist or antiplatelet agent, monitor INR or prothrombin time more frequently, and adjust dosage of the vitamin K antagonist or anti-platelet agent, as clinically indicated.

Other General Considerations

• Selumetinib 10 mg and 25 mg capsules contain 32 mg and 36 mg of vitamin E, respectively, as an excipient. Because vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors, supplemental vitamin E during selumetinib therapy is not recommended if the total daily vitamin E intake, including the amount of vitamin E in selumetinib capsules, will exceed the recommended or safe limits of daily vitamin E intake.

Administration

Oral Administration

Administer orally twice daily (approximately 12 hours apart) without food (i.e., at least 1 hour before or 2 hours after a meal).

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

If a dose is missed by ≤6 hours, take the missed dose as soon as the patient or caregiver remembers. If a dose is missed by >6 hours, skip the missed dose.

If vomiting occurs following administration of selumetinib, do not administer a replacement dose; take the next dose at the regularly scheduled time.

Dosage

Dosage of selumetinib sulfate is expressed in terms of selumetinib.

Pediatric Patients

Neurofibromatosis Type 1

Oral

≥2 years of age: 25 mg/m² twice daily. Continue treatment until disease progression or unacceptable toxicity occurs.

See Table 1 for calculated dosage based on body surface area (BSA).

Dosage Modification for Toxicity

Oral

If adverse reactions occur during selumetinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary. If dosage reduction is required, reduce dosage of selumetinib based on BSA as described in Table 2. If more than 2 dosage reductions are required, permanently discontinue selumetinib.

If an adverse reaction occurs, modify dosage accordingly (see Table 3).

Dosage Modification for Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes

Avoid concomitant use of selumetinib with moderate or potent inhibitors of CYP3A4 or fluconazole.

If concomitant use cannot be avoided, reduce the dosage of selumetinib from 25 mg/m² twice daily to 20 mg/m² twice daily; in those currently receiving selumetinib 20 mg/m² twice daily, reduce the dosage to 15 mg/m² twice daily. The calculated dosage based on BSA is shown in Table 4. If concomitant use of the moderate or potent inhibitor of CYP3A4 or fluconazole is discontinued, return selumetinib dosage (after 3 terminal half-lives of the moderate or potent CYP3A4 inhibitor or fluconazole) to the dosage used prior to initiation of the moderate or potent CYP3A4 inhibitor or fluconazole.

Special Populations

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C): Appropriate dosage not established.

Moderate hepatic impairment (Child-Pugh class B): Reduce dosage of selumetinib to 20 mg/m² twice daily. See Table 5 for the calculated dosage based on BSA in patients with moderate hepatic impairment.

Renal Impairment

No dosage adjustment necessary in patients with renal impairment or in those with end-stage renal disease.

Geriatric Patients

No specific dosage recommendations for geriatric patients.

Cautions for Selumetinib

Contraindications

• None.

Warnings/Precautions

Cardiac Effects

Cardiomyopathy (defined as a decrease in LVEF from baseline of ≥10%), reported in pediatric patients. In the SPRINT study, all patients with decreased LVEF were identified during routine echocardiogram and were asymptomatic. Decreased LVEF resolved in 71% of patients receiving selumetinib.

Safety of selumetinib not established in patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutional LLN.

Assess LVEF using echocardiogram prior to initiating therapy, every 3 months during the first year of therapy, then every 6 months thereafter and as clinically indicated. If left ventricular dysfunction occurs, temporary interruption of therapy, dosage reduction, or discontinuance of selumetinib may be necessary.

In patients who interrupt selumetinib because of decreased LVEF, obtain an echocardiogram or cardiac MRI every 3–6 weeks. When decreased LVEF resolves to the institutional lower limit of normal (LLN) or greater, obtain an echocardiogram or cardiac MRI every 2–3 months or as directed by the cardiologist.

Ocular Effects

Adverse ocular effects (e.g., blurred vision, photophobia, cataracts, ocular hypertension) reported. In the SPRINT study, ocular adverse effects resolved in 82% of 11 patients.

Serious ocular toxicities (i.e., retinal vein occlusion, retinal pigment epithelial detachment [RPED]) also reported in adults with various tumor types who received selumetinib as a single agent or in combination with other anti-cancer agents. RPED has resulted in permanent discontinuation of selumetinib in pediatric patients.

Perform comprehensive ophthalmologic examinations prior to initiating selumetinib, regularly during therapy, and as clinically indicated (i.e., if new or worsening visual disturbances occur). If retinal vein occlusion occurs, permanently discontinue selumetinib. If RPED occurs, temporarily interrupt therapy and perform optical coherence tomography every 3 weeks until RPED resolves; may then resume selumetinib at a reduced dosage. Temporary interruption, dosage reduction, or discontinuance of selumetinib may be necessary if other ocular toxicities occur during therapy with the drug.

GI Effects

Risk of diarrhea. Median time to first onset of diarrhea is 17 days and the median duration of diarrhea is 2 days. Serious GI toxicities, including GI perforation, colitis, ileus, and intestinal obstruction, reported in adults with various tumor types who received selumetinib as a single agent or in combination with other anti-cancer agents. Colitis also has been reported in pediatric patients with various tumor types who received selumetinib as a single agent.

Increase fluid intake and initiate an antidiarrheal agent (e.g., loperamide) immediately following the first episode of unformed, loose stool. Temporary interruption, dosage reduction, or discontinuance of selumetinib may be necessary if diarrhea recurs or persists.

Dermatologic Effects

Dermatologic effects (e.g., rash, dermatitis acneiform, maculopapular rash, eczema) reported. Rash resulted in dosage interruption in 11% of patients and dosage reduction in 4% of patients in the SPRINT study. Early treatment with topical clindamycin or corticosteroids and oral tetracycline has been used for acneiform rash. Other dermatologic effects, including severe palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), reported in adults with various tumor types who received selumetinib as a single agent or in combination with other anti-cancer agents.

Monitor for severe skin rash. Temporary interruption, dosage reduction, or discontinuance of selumetinib may be necessary if other dermatologic effects occur during therapy with the drug.

Musculoskeletal Effects

Increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, myalgia, and rhabdomyolysis reported. Increased serum CK concentrations resulting in dosage reduction occurred in 7% of patients. Rhabdomyolysis reported in adults receiving selumetinib as a single agent.

Assess serum CK concentrations at baseline, periodically during selumetinib therapy, and as clinically indicated. If elevated CK concentrations occur, evaluate patient for rhabdomyolysis or other etiology. Temporary interruption, dosage reduction, or discontinuance of selumetinib may be necessary if other musculoskeletal effects occur during therapy with the drug.

Vitamin E Intake and Risk of Bleeding

Selumetinib sulfate capsules contain vitamin E (10 and 25 mg selumetinib sulfate capsules contain 32 and 36 mg, respectively, of vitamin E as the excipient D-alpha-tocopheryl polyethylene glycol 1000 succinate [TPGS]). Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors; therefore, risk of bleeding may be increased if daily vitamin E intake exceeds the daily recommended or safe limits.

Supplemental vitamin E during selumetinib therapy is not recommended if the total daily vitamin E intake, including the amount of vitamin E in selumetinib capsules, will exceed the recommended or safe limits of daily vitamin E intake.

Increased risk of bleeding in patients receiving concomitant warfarin or anti-platelet antagonists; monitor such patients for bleeding and assess international normalized ratio (INR) or prothrombin time more frequently. Adjust dosage of warfarin or anti-platelet agents as appropriate.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on animal findings and its mechanism of action,.

Verify pregnancy status in females of reproductive potential prior to initiation of selumetinib therapy. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with selumetinib and for 1 week after the last dose.

Advise pregnant females of the potential risk to the fetus.

Specific Populations

Pregnancy

May cause fetal harm.

Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Lactation

Selumetinib and its active metabolites distribute into milk in rats; not known whether selumetinib or its active metabolites distribute into human milk. Women should be advised not to breast-feed while receiving the drug and for 1 week after the last dose. The effects of the drug on breast-fed infants or on the production of milk are unknown.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with selumetinib and for 1 week after the last dose.

Advise pregnant females of the potential risk to the fetus.

Pediatric Use

Safety and efficacy established in pediatric patients ≥2 years of age with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas.

Safety and efficacy not established in pediatric patients <2 years of age.

Growth plate dysplasia has been reported in animal studies. Because of the intended chronic use of the drug for pediatric patients with NF-1 plexiform neurofibromas, monitor growth and development long-term.

Geriatric Use

Clinical studies did not include in patients ≥65 years of age.

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Total and unbound systemic exposure of selumetinib is decreased by 14% and 31%, respectively.

Moderate (Child-Pugh class B) hepatic impairment: Total and unbound systemic exposure of selumetinib is increased by 59 and 41%, respectively. Reduce dosage of selumetinib to 20 mg/m² twice daily.

Severe (Child-Pugh class C) hepatic impairment: Total and unbound systemic exposure of selumetinib is increased by 57% and 3.2-fold, respectively. An appropriate dosage for patients with severe hepatic impairment (Child-Pugh class C) not established.

Renal Impairment

Systemic exposure not affected by end-stage renal disease (Cl_cr <15 mL/minute) in patients requiring dialysis compared with individuals with normal renal function (Cl_cr ≥90 mL/minute).

No dosage adjustment necessary in patients with renal impairment or in those with end-stage renal disease.

Common Adverse Effects

Adverse effects reported in ≥40% of pediatric patients in the SPRINT phase 2 stratum 1 study: Vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, pruritus.

Drug Interactions

Selumetinib is primarily metabolized by cytochrome P-450 (CYP) 3A4 and, to a lesser extent, by CYP isoenzymes 2C19, 1A2, 2C9, 2E1, and 3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. Metabolism of selumetinib to the active metabolite N-Desmethyl selumetinib is mediated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6. N-desmethyl selumetinib is metabolized via the same routes as selumetinib.

In vitro, does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, or 2E1. Does not induce CYP isoenzymes 3A4, 1A2, or 2B6.

Does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K transporters. Substrate of BCRP and P-gp transporters.

Drugs Affecting Hepatic Microsomal Enzymes

Moderate or potent CYP3A4 inhibitors: Concomitant use may result in increased systemic exposure (area under the concentration-time curve [AUC]) of selumetinib, and increased risk of adverse effects to selumetinib. Avoid concomitant use. If concomitant use cannot be avoided, reduce the dosage of selumetinib from 25 mg/m² twice daily to 20 mg/m² twice daily; in those currently receiving selumetinib 20 mg/m² twice daily, reduce the dosage to 15 mg/m² twice daily. The calculated dosage based on BSA is shown in Table 6. If concomitant use of the moderate or potent inhibitor of CYP3A4 or fluconazole is discontinued, the selumetinib dosage should be returned (after 3 terminal half-lives of the moderate or potent CYP3A4 inhibitor or fluconazole) to the dosage used prior to initiation of the moderate or potent CYP3A4 inhibitor or fluconazole.

Moderate or potent CYP3A4 inducers: May result in decreased systemic exposure (AUC) of selumetinib and reduced selumetinib efficacy. Avoid concomitant use.

Specific Drugs

Selumetinib Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailability in adults: 62%.

Median time to peak plasma concentration at steady state is 1-1.5 hours in pediatric patients.

Food

Administration with a high- or low-fat meal, delayed absorption of the drug by approximately 1.5 or 0.9 hours, respectively; peak plasma concentration and systemic exposure decreased by 50% and 16%, respectively, following a high-fat meal, and by 60% and 38%, respectively, following a low-fat meal.

Special Populations

Mild hepatic impairment (Child-Pugh class A): Total and unbound systemic exposure of selumetinib is decreased by 14% and 31%, respectively.

Moderate (Child-Pugh class B) hepatic impairment: Total and unbound systemic exposure of selumetinib is increased by 59 and 41%, respectively.

Severe (Child-Pugh class C) hepatic impairment: Total and unbound systemic exposure of selumetinib is increased by 57% and 3.2-fold, respectively.

Systemic exposure not affected by end-stage renal disease (Cl_cr <15 mL/minute) in patients requiring dialysis compared with individuals with normal renal function (Cl_cr ≥90 mL/minute).

No clinically meaningful effect on pharmacokinetics of selumetinib or N-desmethyl selumetinib based on race (white, Asian, Black).

Distribution

Extent

Not known whether selumetinib is distributed into human milk.

Plasma Protein Binding

Approximately 98.4% (96% albumin and <35% alpha-1 acid glycoprotein).

Elimination

Metabolism

Primarily metabolized by CYP3A4 and, to a lesser extent, by CYP isoenzymes 2C19, 1A2, 2C9, 2E1, and 3A5. Undergoes glucuronidation by UGT1A1 and UGT1A3.

Metabolism to the active metabolite N-desmethyl selumetinib is mediated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6. N-Desmethyl selumetinib is metabolized via the same routes as selumetinib.

Elimination Route

Urine 33% (<1% unchanged drug); feces 59% (19% unchanged drug).

Half-life

Pediatric patients: Mean elimination half-life is approximately 6.2 hours.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30ºC).

Dispense in original bottle. Keep the bottle tightly closed and protect from moisture.

Actions

• Inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2.

• In genetically modified mouse models of NF1 associated with neurofibromas that recapitulate the genotype and phenotype of human NF1, oral administration of selumetinib inhibited phosphorylation of ERK and reduced the quantity, volume, and proliferation of neurofibromas.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Advise patients and caregivers that selumetinib sulfate can cause a reduction in LVEF and to immediately report any signs or symptoms of cardiomyopathy to their healthcare provider.

• Advise patients and caregivers that selumetinib sulfate can cause ocular toxicity that can lead to blindness and to contact their healthcare provider if the patient experiences any changes in their vision.

• Advise patients and caregivers that selumetinib sulfate can cause diarrhea and to contact their healthcare provider at the onset of diarrhea.

• Advise patients and caregivers that selumetinib sulfate can cause serious skin toxicities and to contact their healthcare provider for severe skin changes.

• Advise patients and caregivers that selumetinib sulfate can cause increased CK and to report any signs and symptoms of muscle pain or weakness to their healthcare provider.

• Advise patients and caregivers to notify their healthcare provider if they are taking a supplement containing vitamin E, a vitamin-K antagonist, or an anti-platelet agent.

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

• Advise females of reproductive potential to use effective contraception during treatment with selumetinib sulfate and for 1 week after the last dose.

• Advise males with female partners of reproductive potential to use effective contraception during treatment with selumetinib sulfate and for at least 1 week after the last dose.

• Advise women not to breastfeed during treatment with selumetinib sulfate and for 1 week after the last dose.

• Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John’s wort, grapefruit or grapefruit juice while taking selumetinib sulfate.

• Inform patients and caregivers on how to take selumetinib sulfate with food and what to do for missed or vomited doses.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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