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Selumetinib

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
Brands: Koselugo

Medically reviewed by Drugs.com. Last updated on April 27, 2020.

Introduction

Selumetinib sulfate is an antineoplastic agent.

Uses for Selumetinib

Selumetinib sulfate has the following uses:

Selumetinib sulfate is a kinase inhibitor indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).1

Selumetinib Dosage and Administration

General

Selumetinib sulfate is available in the following dosage form(s) and strength(s):

Capsules: 10 mg and 25 mg (of selumetinib).1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration
  • 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.1

  • Do not consume food 2 hours before each dose or 1 hour after each dose.1

  • The recommended dosage is 25 mg/m2 taken orally twice daily on an empty stomach.1 The recommended dosage of selumetinib based on body surface area (BSA) is shown in Table 1.

  • Reduce the recommended dosage to 20 mg/m2 orally twice daily for patients with moderate hepatic impairment (Child-Pugh B). The recommended dosage for use in patients with severe hepatic impairment (Child-Pugh C) has not been established.1

Table 1 Recommended Dosage of 25 mg/m2 Based on Body Surface Area

Body Surface Area

Recommended Dosage

<0.55 m2

Dosage not established

0.55 – 0.69 m2

20 mg in the morning and 10 mg in the evening

0.70 – 0.89 m2

20 mg twice daily

0.90 – 1.09 m2

25 mg twice daily

1.10 – 1.29 m2

30 mg twice daily

1.30 – 1.49 m2

35 mg twice daily

1.50 – 1.69 m2

40 mg twice daily

1.70 – 1.89 m2

45 mg twice daily

≥1.90 m2

50 mg twice daily

Cautions for Selumetinib

Contraindications

None.1

Warnings/Precautions

Cardiomyopathy

Cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥ 10% below baseline, occurred in 23% of 74 pediatric patients who received selumetinib sulfate in the principal efficacy study (SPRINT). Four percent of patients experienced decreased LVEF below the institutional lower limit of normal (LLN). Grade 3 decreased LVEF occurred in one patient and resulted in dose reduction. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. Decreased LVEF resolved in 71% of these patients.1

Left ventricular dysfunction or decreased LVEF resulting in permanent discontinuation of selumetinib sulfate occurred in an unapproved population of adult patients with multiple tumor types who received selumetinib sulfate. Decreased LVEF resulting in permanent discontinuation of selumetinib sulfate occurred in a pediatric population with NF1 in an expanded access program.1

The safety of selumetinib sulfate has not been established in patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutional LLN.1

Assess ejection fraction by echocardiogram prior to initiating treatment, every 3 months during the first year of treatment, every 6 months thereafter, and as clinically indicated. Withhold, reduce dose, or permanently discontinue selumetinib sulfate based on severity of adverse reaction. In patients who interrupt selumetinib sulfate for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks. Upon resolution of decreased LVEF to greater than or equal to the institutional LLN, obtain an echocardiogram or a cardiac MRI every 2 to 3 months or as directed by the cardiologist.1

Ocular Toxicity

Blurred vision, photophobia, cataracts, and ocular hypertension occurred in 15% of 74 pediatric patients receiving selumetinib sulfate in SPRINT. Blurred vision resulted in dose interruption in 2.7% of patients. Ocular toxicity resolved in 82% of 11 patients.1

Serious ocular toxicities including retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED), occurred in an unapproved population of adult patients with multiple tumor types who received selumetinib sulfate as a single agent or in combination with other anti-cancer agents. RPED occurred in the pediatric population during treatment with single agent selumetinib sulfate and resulted in permanent discontinuation.1

Conduct comprehensive ophthalmic assessments prior to initiating selumetinib sulfate, at regular intervals during treatment, and for new or worsening visual changes. Permanently discontinue selumetinib sulfate in patients with RVO. Withhold selumetinib sulfate in patients with RPED, follow up with optical coherence tomography assessments every 3 weeks until resolution, and resume selumetinib sulfate at a reduced dose. For other ocular toxicities, withhold, reduce dose, or permanently discontinue selumetinib sulfate based on severity of the adverse reaction.1

Gastrointestinal Toxicity

Diarrhea occurred in 77% of 74 pediatric patients who received selumetinib sulfate in SPRINT, including Grade 3 in 15% of patients. Diarrhea resulting in permanent discontinuation occurred in 1.4% of patients. Diarrhea resulting in dose interruption or dose reduction occurred in 15% and 1.4% of patients, respectively. The median time to first onset of diarrhea was 17 days and the median duration was 2 days.1

Serious gastrointestinal toxicities, including perforation, colitis, ileus, and intestinal obstruction, occurred in an unapproved population of adult patients with multiple tumor types who received selumetinib sulfate as a single agent or in combination with other anti-cancer agents. Colitis occurred in an unapproved population of pediatric patients with multiple tumor types who received selumetinib sulfate as a single agent.1

Advise patients to start an anti-diarrheal agent (e.g., loperamide) immediately after the first episode of unformed, loose stool and to increase fluid intake during diarrhea episodes. Withhold, reduce dose, or permanently discontinue selumetinib sulfate based on severity of adverse reaction.1

Skin Toxicity

Rash occurred in 91% of 74 pediatric patients who received selumetinib sulfate in SPRINT. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred in 8% of patients. Rash resulted in dose interruption in 11% of patients and dose reduction in 4% of patients.1

Other skin toxicities, including severe palmar-plantar erythrodysesthesia syndrome (PPES), occurred in an unapproved population of adult patients with multiple tumor types who received selumetinib sulfate as a single agent or in combination with other anti-cancer agents. 1

Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue selumetinib sulfate based on severity of adverse reaction.1

Increased Creatinine Phosphokinase

Increased creatinine phosphokinase (CPK) occurred in 76% of 74 pediatric patients who received selumetinib sulfate in SPRINT, including Grade 3 or 4 in 9% of patients. Increased CPK resulted in dose reduction in 7% of patients. Increased CPK concurrent with myalgia occurred in 8% of patients, including one patient who permanently discontinued selumetinib sulfate for myalgia. 1

Rhabdomyolysis occurred in an unapproved adult population who received selumetinib sulfate as a single agent. 1

Obtain serum CPK prior to initiating selumetinib sulfate, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue selumetinib sulfate based on severity of adverse reaction.1

Increased Levels of Vitamin E and Risk of Bleeding

Selumetinib sulfate capsules contain vitamin E (10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS); while selumetinib sulfate 25 mg capsules contain 36 mg vitamin E as TPGS). Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. Daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in selumetinib sulfate and supplement) will exceed the recommended or safe limits.1

An increased risk of bleeding in patients may occur in patients who are coadministered vitamin-K antagonists or anti-platelet antagonists with selumetinib sulfate. Monitor for bleeding in these patients. Increase international normalized ratio (INR) monitoring, as appropriate, in patients taking a vitamin-K antagonist. Perform anticoagulant assessments, including INR or prothrombin time, more frequently and adjust the dose of vitamin K antagonists or anti-platelet agents as appropriate.1

Embryo-fetal Toxicity

Based on findings from animal studies and its mechanism of action, selumetinib sulfate can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryo-fetal survival at approximate exposures > 5 times the human exposure at the clinical dose of 25 mg/m2 twice daily. Advise pregnant women of the potential risk to a fetus. 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 1 week after the last dose.1

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies and its mechanism of action, selumetinib sulfate can cause fetal harm when administered to a pregnant woman. There are no available data on the use of selumetinib sulfate in pregnant women to evaluate drug-associated risk. In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryofetal survival at exposures approximately > 5 times the human exposure at the clinical dose of 25 mg/m2 twice daily). Advise pregnant women of the potential risk to the fetus.1

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Animal Data: In embryo-fetal development studies in mice at doses > 2.5 mg/kg twice daily (~5 times the human exposure based on area under the curve [AUC] at the clinical dose of 25 mg/m2 twice daily), selumetinib caused increases in post-implantation loss, a reduction in mean fetal and litter weights, and an increased occurrence of open eye and cleft palate, but did not induce significant maternal toxicity. 1

Administration of selumetinib to pregnant mice from gestation Day 6 through lactation Day 20 resulted in reduced pup body weights and fewer pups met the pupil constriction criterion on day 21 post-partum. The incidence of malformations (e.g. prematurely open eye[s], cleft palate) was increased even at the lowest dose of 0.5 mg/kg twice daily (maternal maximal concentration [Cmax] of ~0.6 times the human Cmax at the clinical dose of 25 mg/m2 twice daily).1

Lactation

Risk Summary: There are no data on the presence of selumetinib or its active metabolite in human milk or their effects on the breastfed child or milk production. Selumetinib and its active metabolite were present in the milk of lactating mice Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with selumetinib sulfate and for 1 week after the last dose. 1

Animal Data: Selumetinib and its active metabolite were present in milk from mice dosed with selumetinib throughout gestation and lactation, with a mean plasma/milk ratio of 1.5 in lactating dams dosed at 5 mg/kg twice daily. Administration of selumetinib to dams during gestation and early lactation was associated with adverse events in pups, including reduced growth rates and incidence of malformations. 1

Females and Males of Reproductive Potential

Selumetinib sulfate can cause fetal harm when administered to a pregnant woman.1

Verify the pregnancy status of females of reproductive potential prior to initiating selumetinib sulfate.1

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

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

Pediatric Use

The safety and effectiveness have been established in pediatric patients 2 years of age and older with NF1 who have inoperable PN and the information on this use is discussed throughout the labeling. The safety and effectiveness of selumetinib sulfate have not been established in pediatric patients younger than 2 years of age.1

In 3-month general toxicology studies, male rats receiving selumetinib at doses ≥ 10 mg/kg daily (~60 times the human exposure based on AUC at the clinical dose of 25 mg/m2 twice daily) showed growth plate dysplasia. 1

Geriatric Use

Clinical studies did not include patients 65 years of age and older.1

Renal Impairment

No dose adjustment is recommended in patients with renal impairment or those with end stage renal disease. 1

Hepatic Impairment

Selumetinib exposures increased in patients with moderate or severe hepatic impairment . Reduce the dose of selumetinib sulfate for patients with moderate hepatic impairment (Child-Pugh B). A recommended dosage of selumetinib sulfate for use in patients with severe hepatic impairment (Child-Pugh C) has not been established.1

Common Adverse Effects

Most common adverse reactions (≥ 40%) are: vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Strong or Moderate CYP3A4 Inhibitors or Fluconazole: Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with selumetinib sulfate. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the dose of selumetinib sulfate.1

  • Strong or Moderate CYP3A4 Inducers: Avoid concomitant use of strong and moderate CYP3A4 inducers.1

Actions

Mechanism of Action

Selumetinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers. 1

In genetically modified mouse models of NF1 that generate neurofibromas that recapitulate the genotype and phenotype of human NF1, oral dosing of selumetinib inhibited ERK phosphorylation, and reduced neurofibroma numbers, volume, and proliferation.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

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.1

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.1

Advise patients and caregivers that selumetinib sulfate can cause diarrhea and to contact their healthcare provider at the onset of diarrhea. 1

Advise patients and caregivers that selumetinib sulfate can cause serious skin toxicities and to contact their healthcare provider for severe skin changes.1

Advise patients and caregivers that selumetinib sulfate can cause increased CPK and to report any signs and symptoms of muscle pain or weakness to their healthcare provider.1

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.1

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. 1

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

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.1

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

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.1

Inform patients and caregivers on how to take selumetinib sulfate with food and what to do for missed or vomited doses.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

Selumetinib Sulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsule

10 mg (of selumetinib)

Koselugo

AstraZeneca Pharmaceuticals LP

25 mg (of selumetinib)

Koselugo

AstraZeneca Pharmaceuticals LP

AHFS Drug Information. © Copyright 2021, Selected Revisions April 27, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. AstraZeneca Pharmaceuticals LP. KOSELUGO (SELUMETINIB) ORAL prescribing information. 2020 Apr. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7d042c61-f28f-4ab5-ab10-d7558c0d49ff