Selumetinib sulfate, an inhibitor of mitogen-activated extracellular signal-regulated kinases 1 and 2 (MEK1/2), is an antineoplastic agent.1, 3
Selumetinib is used for the treatment of adult and pediatric patients ≥1 year of age with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas.1 Selumetinib is designated an orphan drug by the FDA for use in the treatment of NF1.2
The current indication for selumetinib in pediatric patients is based principally on the results of a multicenter, open-label, noncomparative phase 2 study (SPRINT Stratum 1) involving 50 patients ≥2 years of age with NF1 and inoperable plexiform neurofibromas.1 Inoperable plexiform neurofibroma was defined as plexiform neurofibromas that could not be completely removed without risk of substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the plexiform neurofibroma.1 Eligible patients were required to have significant morbidity related to the target plexiform neurofibromas and have the ability to swallow intact capsules.1, 5 Morbidities that were present in ≥20% of patients included disfigurement, pain, visual impairment, or motor, airway, bladder, or bowel dysfunction.1 Patients with current or history of retinal vein occlusion and retinal pigment epithelial detachment (RPED), intraocular pressure >21 mm Hg, uncontrolled hypertension, uncontrolled glaucoma, or abnormal left ventricular ejection fraction (LVEF) were excluded.1 In this study, patients received selumetinib 25 mg/m2 orally twice daily in 28-day continuous cycles.1, 5 Treatment was continued until disease progression or unacceptable toxicity occurred.1, 5 The primary efficacy endpoint was overall response rate; an additional endpoint was duration of response.1 Response was measured by assessing the target plexiform neurofibroma (defined as the plexiform neurofibroma that caused relevant clinical symptoms or complications [plexiform neurofibroma-related morbidities]) by volumetric MRI analysis according to Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria.1, 5 The median age of patients enrolled in the study was 10.2 (range 3.5-17.4) years of a 60% were male, 84% were white, 8% were Black and 2% were Asian.1 The median volume of the target plexiform neurofibroma at baseline was 487 mL (range 5-3820 mL).3 Approximately one-half (42%) of patients were characterized as having progressive plexiform neurofibroma with significant complications.5 The most common neurofibroma-related symptoms were disfigurement (88%), motor dysfunction (66%), pain (52%), airway impairment (32%), vision changes (20%), bowel dysfunction (20%), and bladder dysfunction (20%).5
The overall response rate was 66%; all of these patients had a partial response (defined as ≥20% reduction in plexiform neurofibroma volume).1 The median time to onset of response was 7.2 months (range: 3.3 months to 1.6 years).1 A duration of response of ≥12 months occurred in 82% of patients.1 Selumetinib also was associated with improvements in pain, quality of life, motor function, and airway impairment.5
Selumetinib also was evaluated in the SPRINT Stratum 2 study in 25 patients without significant plexiform neurofibroma-related morbidity† but whose tumors impose risk for development of morbidity.5, 6 At the time of data cut-off, the results of SPRINT Stratum 2 were consistent with the primary Stratum 1 results and similarly durable in patients with non-clinically significant plexiform neurofibroma-related morbidity.6
The current indication for selumetinib in adults is based principally on the results of a multicenter, randomized, placebo-controlled, parallel, double-blind, phase 3 study (KOMET) involving 145 patients ≥18 years of age with NF1 and symptomatic inoperable plexiform neurofibromas.1, 13 Inoperable plexiform neurofibroma was defined as a plexiform neurofibroma that could not be completely removed without risk of substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the plexiform neurofibroma.1 Eligible patients were required to have at least 1 measurable plexiform neurofibroma and at least 1 other diagnostic criterion for NF1.13 In KOMET, eligible patients were randomly assigned to receive selumetinib 25 mg/m2 (capped at 50 mg) or placebo orally twice daily for 12 cycles (28-day cycles).1, 13 After cycle 12, or earlier if disease progression was confirmed, patients randomly assigned to placebo crossed over to selumetinib in an open-label phase1, 13 The primary efficacy endpoint was overall response rate by the end of cycle 16; an additional endpoint was duration of response.1, 13
The median age of patients enrolled in the study was 29 (range 18-60) years of a 52% were male, 56% were White, 6% were Black or African American, 31% were Asian, and 10% Hispanic or Latino ethnicity.1 The most common plexiform neurofibroma-related morbidities (>20%) were pain, motor dysfunction, and disfigurement.1
The overall response rate was significantly improved in the selumetinib group (14 [20%] of 71 patients) as compared to placebo (4 [5%] of 74 patients).1, 13 Selumetinib therapy was associated with a rapid response (median 3.7 months).13 The duration of response was not reached in the selumetinib group and was not determined for the placebo group.1 Among patients with a confirmed objective response to selumetinib, 86% maintained a response for at least 6 months.1, 13
NF1 plexiform neurofibroma is a rare, benign tumor that can cause substantial morbidity for patients starting at a young age.6 Surgical intervention is common and typically based on progressive plexiform neurofibroma-related symptoms or functional impairment.6 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.6
Selumetinib is available in two oral dosage forms: capsules and granules.1 The granules should be prescribed to patients who have difficulty swallowing the capsules.1
Selumetinib capsules may be administered without regard to meals.1 Do not administer selumetinib to patients who are unable to swallow an intact capsule.1 Capsules must be swallowed whole; do not open, chew, or crush capsules.1
Selumetinib granules should be sprinkled on or mixed with a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry.1 The patient should consume the preparation within 30 minutes; if not consumed within 30 minutes, discard and prepare a new dose.1 If a dose was partially consumed within 30 minutes of preparation, discard the remainder of the dose.1 The patient should not prepare a new dose in this situation but rather should aim to complete dosing within 30 minutes with the next preparation.1
Selumetinib granules should be free-flowing.1 The granules should not be used if clumped or stuck inside the capsule shell.1 The capsule shells of the selumetinib granules should be discarded after use.1 The capsule shells should not be swallowed, chewed, or dissolved.1 Selumetinib oral granules should not be chewed or crushed and should not be added to liquids.1 The granules should also not be mixed in grapefruit or any juice, fruit puree, or jam containing Seville orange.1
If a dose of capsules or granules is missed by ≤6 hours, the missed dose should be taken as soon as the patient or caregiver remembers.1 If a dose is missed by >6 hours, the missed dose should be skipped.1
If vomiting occurs following administration of selumetinib capsules or granules, a replacement dose should not be administered, and the next dose should be taken at the regularly scheduled time.1
Selumetinib capsules should be stored at 20-25°C (excursions permitted to 15-30°C).1 The capsules should be dispensed and stored in the original container to protect from light and moisture.1
Selumetinib oral granules should be stored and transported under refrigeration (2-8°C).1 After dispensing, patients can store the granules at room temperature 20-25°C not exceeding 30°C.1 The oral granules may clump together or stick to the capsule shell if exposed to high temperatures; this may lead to an underdose of selumetinib.1
The dessicant should not be removed from the capsule or granule bottle and the bottle should be tightly closed after initial opening.1
Dosage of selumetinib sulfate is expressed in terms of selumetinib.1
For the management of NF1 with inoperable plexiform neurofibromas in adult and pediatric patients ≥1 year of age, the recommended selumetinib dosage is 25 mg/m2 twice daily.1 The calculated dosage based on body surface area (BSA) for selumetinib capsules and selumetinib granules is shown in Table 1 and Table 2, respectively.1
Continue treatment until disease progression or unacceptable toxicity occurs.1
BSA (m2) | 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 |
BSA (m2) | Recommended Dosage |
|---|---|
<0.40 m2 | Dosage not established |
0.40-0.59 m2 | 12.5 mg twice daily |
0.60-0.69 m2 | 15 mg twice daily |
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 |
Dosage Modification for Toxicity
If adverse reactions occur during selumetinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1 If dosage reduction is required, the dosage of selumetinib should be reduced based on BSA as described in Table 3 for selumetinib capsules and Table 4 for selumetinib granules.1 If more than 2 dosage reductions are required, permanently discontinue selumetinib.1
BSA (m2) | First Dosage Reduction | Second Dosage Reduction |
|---|---|---|
0.55-0.69 m2 | Reduce selumetinib dosage to 10 mg twice daily | Reduce selumetinib dosage to 10 mg once daily |
0.70-0.89 m2 | Reduce selumetinib dosage to 20 mg in the morning and 10 mg in the evening | Reduce selumetinib dosage to 10 mg twice daily |
0.90-1.09 m2 | Reduce selumetinib dosage to 25 mg in the morning and 10 mg in the evening | Reduce selumetinib dosage to 10 mg twice daily |
1.10-1.29 m2 | Reduce selumetinib dosage to 25 mg in the morning and 20 mg in the evening | Reduce selumetinib dosage to 20 mg in the morning and 10 mg in the evening |
1.30-1.49 m2 | Reduce selumetinib dosage to 25 mg twice daily | Reduce selumetinib dosage to 25 mg in the morning and 10 mg in the evening |
1.50-1.69 m2 | Reduce selumetinib dosage to 30 mg twice daily | Reduce selumetinib dosage to 25 mg in the morning and 20 mg in the evening |
1.70-1.89 m2 | Reduce selumetinib dosage to 35 mg in the morning and 30 mg in the evening | Reduce selumetinib dosage to 25 mg in the morning and 20 mg in the evening |
≥1.90 m2 | Reduce selumetinib dosage to 35 mg twice daily | Reduce selumetinib dosage to 25 mg twice daily |
BSA (m2) | First Dosage Reduction | Second Dosage Reduction |
|---|---|---|
0.40-0.59 m2 | Reduce selumetinib dosage to 10 mg twice daily | Reduce selumetinib dosage to 7.5 mg twice daily |
0.60-0.69 m2 | Reduce selumetinib dosage to 12.5 mg twice daily | Reduce selumetinib dosage to 10 mg twice daily |
0.70-0.89 m2 | Reduce selumetinib dosage to 15 mg twice daily | Reduce selumetinib dosage to 12.5 mg twice daily |
0.90-1.09 m2 | Reduce selumetinib dosage to 20 mg twice daily | Reduce selumetinib dosage to 15 mg twice daily |
1.10-1.29 m2 | Reduce selumetinib dosage to 22.5 mg twice daily | Reduce selumetinib dosage to 15 mg twice daily |
1.30-1.49 m2 | Reduce selumetinib dosage to 25 mg twice daily | Reduce selumetinib dosage to 25 mg in the morning and 10 mg in the evening |
1.50-1.69 m2 | Reduce selumetinib dosage to 30 mg twice daily | Reduce selumetinib dosage to 25 mg in the morning and 20 mg in the evening |
1.70-1.89 m2 | Reduce selumetinib dosage to 35 mg in the morning and 30 mg in the evening | Reduce selumetinib dosage to 25 mg in the morning and 20 mg in the evening |
≥1.90 m2 | Reduce selumetinib dosage to 35 mg twice daily | Reduce selumetinib dosage to 25 mg twice daily |
If an adverse reaction occurs, modify dosage accordingly (see Table 5).
Adverse Reaction and Severity | Modification |
|---|---|
Left Ventricular Dysfunction | |
Asymptomatic decrease in LVEF of ≥10% from baseline and less than the LLN | Withhold therapy until cardiomyopathy resolves, and then resume at reduced dosage |
Symptomatic decreased LVEF | Permanently discontinue |
Grade 3 or 4 decreased LVEF | Permanently discontinue |
Ocular Toxicity | |
Retinal pigment epithelial detachment (RPED) | Withhold therapy until RPED resolves, and then resume at reduced dosage |
Retinal vein occlusion | Permanently discontinue |
GI Toxicity | |
Grade 3 diarrhea | Withhold therapy until diarrhea improves to grade 0 or 1, and then resume at same dosage |
If grade 3 diarrhea does not improve within 3 days, permanently discontinue | |
Grade 4 diarrhea | Permanently discontinue |
Grade 3 or 4 colitis | Permanently discontinue |
Dermatologic Toxicity | |
Grade 3 or 4 | Withhold therapy until toxicity improves, and then resume at reduced dosage |
Musculoskeletal Effects | |
Grade 4 elevation of CK concentration | Withhold therapy until elevated CK concentration improves to grade 0 or 1, and then resume at reduced dosage |
If grade 4 elevation of CK concentration does not improve within 3 weeks, permanently discontinue | |
Elevated CK concentration (any grade) and myalgia | Withhold therapy until elevated CK concentration and myalgia improve to grade 0 or 1, and then resume at reduced dosage |
If elevated CK concentration and myalgia do not improve within 3 weeks, permanently discontinue | |
Rhabdomyolysis | Permanently discontinue |
Other Toxicity | |
Grade 2 (intolerable) | Withhold therapy until toxicity improves to grade 0 or 1, and then resume at reduced dosage |
Grade 3 | Withhold therapy until toxicity improves to grade 0 or 1, and then resume at reduced dosage |
Grade 4 | Withhold therapy until toxicity improves to grade 0 or 1, and then resume at reduced dosage or consider discontinuance of therapy |
Dosage Modification for Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes
Avoid concomitant use of selumetinib with moderate or strong inhibitors of CYP3A4 or fluconazole.1 If concomitant use cannot be avoided, reduce the dosage of selumetinib as recommended in Table 6 (capsules) or Table 7 (granules).1 If concomitant use of the moderate or strong inhibitor of CYP3A4 or fluconazole is discontinued, the selumetinib dosage should be returned (after 3 terminal half-lives) to the dosage used prior to initiation of the moderate or strong CYP3A4 inhibitor or fluconazole.1
BSA (m2) | If current dosage is selumetinib 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily | If current dosage is selumetinib 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily |
|---|---|---|
0.55-0.69 m2 | Reduce selumetinib dosage to 10 mg twice daily | Reduce selumetinib dosage to 10 mg once daily |
0.70-0.89 m2 | Reduce selumetinib dosage to 20 mg in the morning and 10 mg in the evening | Reduce selumetinib dosage to 10 mg twice daily |
0.90-1.09 m2 | Reduce selumetinib dosage to 20 mg twice daily | Reduce selumetinib dosage to 20 mg in the morning and 10 mg in the evening |
1.10-1.29 m2 | Reduce selumetinib dosage to 25 mg twice daily | Reduce selumetinib dosage to 25 mg in the morning and 10 mg in the evening |
1.30-1.49 m2 | Reduce selumetinib dosage to 30 mg in the morning and 25 mg in the evening | Reduce selumetinib dosage to 25 mg in the morning and 20 mg in the evening |
1.50-1.69 m2 | Reduce selumetinib dosage to 35 mg in the morning and 30 mg in the evening | Reduce selumetinib dosage to 25 mg twice daily |
1.70-1.89 m2 | Reduce selumetinib dosage to 35 mg twice daily | Reduce selumetinib dosage to 30 mg in the morning and 25 mg in the evening |
≥1.90 m2 | Reduce selumetinib dosage to 40 mg twice daily | Reduce selumetinib dosage to 30 mg twice daily |
BSA (m2) | If current dosage is selumetinib 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily | If current dosage is selumetinib 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily |
|---|---|---|
0.40-0.59 m2 | Reduce selumetinib dosage to 10 mg twice daily | Reduce selumetinib dosage to 7.5 mg twice daily |
0.60-0.69 m2 | Reduce selumetinib dosage to 12.5 mg twice daily | Reduce selumetinib dosage to 10 mg in the morning and 7.5 mg in the evening |
0.70-0.89 m2 | Reduce selumetinib dosage to 15 mg twice daily | Reduce selumetinib dosage to 10 mg twice daily |
0.90-1.09 m2 | Reduce selumetinib dosage to 20 mg twice daily | Reduce selumetinib dosage to 15 mg twice daily |
1.10-1.29 m2 | Reduce selumetinib dosage to 25 mg twice daily | Reduce selumetinib dosage to 25 mg in the morning and 10 mg in the evening |
1.30-1.49 m2 | Reduce selumetinib dosage to 30 mg in the morning and 25 mg in the evening | Reduce selumetinib dosage to 25 mg in the morning and 20 mg in the evening |
1.50-1.69 m2 | Reduce selumetinib dosage to 35 mg in the morning and 30 mg in the evening | Reduce selumetinib dosage to 25 mg twice daily |
1.70-1.89 m2 | Reduce selumetinib dosage to 35 mg twice daily | Reduce selumetinib dosage to 30 mg in the morning and 25 mg in the evening |
≥1.90 m2 | Reduce selumetinib dosage to 40 mg twice daily | Reduce selumetinib dosage to 30 mg twice daily |
An appropriate dosage for patients with severe hepatic impairment (Child-Pugh class C) has not been established.1
In patients with moderate hepatic impairment (Child-Pugh class B), reduce the dosage of selumetinib to 20 mg/m2 twice daily.1 The calculated dosage based on BSA in patients with moderate hepatic impairment is shown in Table 8 (capsules) and Table 9 (granules).1
BSA (m2) | Recommended Dosage Reduction |
|---|---|
0.55-0.69 m2 | Reduce selumetinib dosage to 10 mg twice daily |
0.70-0.89 m2 | Reduce selumetinib dosage to 20 mg in the morning and 10 mg in the evening |
0.90-1.09 m2 | Reduce selumetinib dosage to 20 mg twice daily |
1.10-1.29 m2 | Reduce selumetinib dosage to 25 mg twice daily |
1.30-1.49 m2 | Reduce selumetinib dosage to 30 mg in the morning and 25 mg in the evening |
1.50-1.69 m2 | Reduce selumetinib dosage to 35 mg in the morning and 30 mg in the evening |
1.70-1.89 m2 | Reduce selumetinib dosage to 35 mg twice daily |
≥1.90 m2 | Reduce selumetinib dosage to 40 mg twice daily |
BSA (m2) | Recommended Dosage Reduction |
|---|---|
0.40-0.59 m2 | Reduce selumetinib dosage to 10 mg twice daily |
0.60-0.69 m2 | Reduce selumetinib dosage to 12.5 mg twice daily |
0.70-0.89 m2 | Reduce selumetinib dosage to 15 mg twice daily |
0.90-1.09 m2 | Reduce selumetinib dosage to 20 mg twice daily |
1.10-1.29 m2 | Reduce selumetinib dosage to 25 mg twice daily |
1.30-1.49 m2 | Reduce selumetinib dosage to 30 mg in the morning and 25 mg in the evening |
1.50-1.69 m2 | Reduce selumetinib dosage to 35 mg in the morning and 30 mg in the evening |
1.70-1.89 m2 | Reduce selumetinib dosage to 35 mg twice daily |
≥1.90 m2 | Reduce selumetinib dosage to 40 mg twice daily |
No dosage adjustment is necessary in patients with renal impairment or in those with end-stage renal disease.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Cardiomyopathy (defined as a decrease in left ventricular ejection fraction [LVEF] from baseline of ≥10%), has been reported.1 Selumetinib has not been evaluated in patients with a history of clinically significant cardiac disease or LVEF <55% prior to therapy.1
In the NF1 PN pediatric safety pool involving 134 patients, a Grade 2 LVEF decrease (40 to 50%; 10 to 19% drop from baseline) occurred in 17% of evaluable patients.1 Decreased LVEF of ≥20% occurred in 0.7% of patients, resulting in dose interruption and reduction.1 Resolution of decreased LVEF occurred in 75% of these patients.1 The median time to first onset of LVEF decrease was approximately 12 months (median duration approximately 3 months).1
In the KOMET adult NF1 PN study involving 71 patients, a Grade 2 LVEF decrease (40% to 50%; 10 to 19% drop from baseline) occurred in 14% of evaluable patients.1 A dose interrruption as a result of decreased LVEF occurred in 1.4% of patients.1 The median time to first onset of LVEF decrease was approximately 4 months (median duration approximately 4 months).1
LVEF should be assessed using echocardiogram prior to initiating therapy, every 3 months during the first year of therapy, then every 6 months thereafter and as clinically indicated.1 If left ventricular dysfunction occurs, temporary interruption of therapy, dosage reduction, or discontinuance of selumetinib may be necessary.1 In patients who interrupt selumetinib because of decreased LVEF, obtain an echocardiogram or cardiac MRI every 3-6 weeks until resolution.1 When decreased LVEF resolves to the institutional LLN or greater, obtain an echocardiogram or cardiac MRI every 2-3 months or as directed by the cardiologist.1
Adverse ocular effects, including retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), central serous retinopathy, and blurred vision have been reported in patients receiving selumetinib.1
In the NF1 PN pediatric safety pool involving 134 patients, blurred vision, photophobia, cataracts, ocular hypertension, and retinal tear occurred in 13% of patients administered selumetinib.1 Dose interruption due to blurred vision occurred in 1.5% of patients; resolution of ocular toxicity occurred in 72% of these patients.1 Grade 1 asymptomatic tranisent subretinal fluid was seen in 6% of patients, none required a dose modification, and 88% of these patients experienced resolution of the event.1 Grade 1 retinopathy occurred in 0.7% of patients with all events resolving without dose modification.1 RPED occured during treatment with selumetinib and resulted in permanent discontinuation of therapy.1
In the KOMET adult NF1 PN study involving 71 patients, blurred vision and vitreous floaters occurred in 6% of patients administered selumetinib.1 Serious ocular toxicities (e.g., RVO and RPED) occurred in an unapproved population of adults with multiple tumor types administered selumetinib as monotherapy or in combination with other anti-cancer agents.1
Comprehensive ophthalmologic examinations should be performed prior to initiating selumetinib, regularly during therapy, and as clinically indicated (i.e., if new or worsening visual disturbances occur).1 If RVO occurs, selumetinib should be permanently discontinued.1 If RPED occurs, selumetinib therapy should be temporarily interrupted and optical coherence tomography assessments should be performed every 3 weeks until RPED resolves; selumetinib may then be resumed at a reduced dosage.1 Temporary interruption, dosage reduction, or discontinuance of selumetinib may be necessary based on severity of adverse reaction.1
GI effects, including diarrhea and colitis, have occurred in patients receiving selumetinib.1
In the NF1 PN pediatric safety pool involving 134 patients, diarrhea was reported in 59% of selumetinib-treated patients, including Grade 3 diarrhea in 10% of patients.1 Permanent discontinuation or dose interruption of therapy due to diarrhea occurred in 0.7% and 10% of patients, respectively.1 The median time to first onset of diarrhea was approximately 2 months; the median duration was 5 days.1 Colitis occurred in an unapproved population of pediatric patients with multiple tumor types who received semuletinib as monotherapy.1
In the KOMET adult NF1 PN study involving 71 patients, diarrhea was reported in 42% of selumetinib-treated patients.1 Dose interruption of therapy due to diarrhea occurred in 1.4% of patients.1 The median time to first onset of diarrhea was approximately 1 month; the median duration was 7 days.1 Serious GI toxicities (e.g., perforation, colitis, ileus, intestinal obstruction) occurred in an unapproved population of adults with multiple tumor types administered selumetinib as monotherapy or in combination with other anti-cancer agents.1
Fluid intake should be increased and an antidiarrheal agent (e.g., loperamide) should be initiated immediately following the first episode of unformed, loose stool.1, 6 Temporary interruption, dosage reduction, or discontinuance of selumetinib may be necessary based on severity of adverse reaction.1
Severe dermatologic effects (e.g., dermatitis acneiform) have been reported in patients receiving selumetinib.1
In the NF1 PN pediatric safety pool including 134 patients, rash occurred in 68% of selumetinib-treated patients.1 The most frequent rashes included dermatitis acneiform (47%) and maculopapular rash (31%); pruritus (30%), alopecia (26%), and eczema (24%) were also reported.1 Grade 3 rash occurred in 5% of patients.1 Dose interruption and dose reduction due to rash occurred in 8% and 3.7% of patients, respectively.1
In the KOMET adult NF1 PN study involving 71 patients, rash occurred in 85% of selumetinib-treated patients.1 The most frequent rash included dermatitis acneiform (66%); alopecia (18%) and pruritus (10%) were also reported.1 Grade 3 rash occurred in 4.2% of patients.1 Dose interruption, dose reduction, or permanent discontinuation of therapy due to rash occurred in a similar percentage of patients (2.8%).1 Other skin toxicities (e.g., severe palmar-plantar erythrodysesthesia syndrome) occurred in an unapproved population of adults with multiple tumor types administered selumetinib as monotherapy or in combination with other anti-cancer agents.1
Monitor for severe skin rash.1 Temporary interruption, dosage reduction, or discontinuance of selumetinib may be necessary based on severity of adverse reaction.1
Increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, myalgia, and rhabdomyolysis have been reported in patients receiving selumetinib.1
In the NF1 PN pediatric safety pool involving 134 patients, increased CPK occurred in 73% of selumetinib-treated patients, including Grade 3 or 4 in 8% of patients.1 Dose interruption and dose reduction of selumetinib due to increased CPK occurred in 4% of patients.1 Increased CPK concurrent with myalgia occurred in 5% of patients; a single patients permanently discontinued selumetinib for myalgia.1
In the KOMET adult NF1 PN study involving 71 patients, increased CPK occurred in 70% of selumetinib-treated patients, including Grade 3 or 4 in 7% of patients.1 Dose interruption and dose reduction of selumetinib due to increased CPK occurred in 4.2% and 2.8% of patients, respectively.1 Increased CPK concurrent with myalgia occurred in 1.4% of patients.1 Rhabdomyolysis was reported in an unapproved adult population who received selumetinib monotherapy.1
Serum CK concentrations should be evaluated at baseline, periodically during selumetinib therapy, and as clinically indicated.1 If elevated CK concentrations occur, the patient should be evaluated for rhabdomyolysis or other etiology.1 Temporary interruption, dosage reduction, or discontinuance of selumetinib may be necessary based on severity of adverse reaction.1
Vitamin E Intake and Increased Risk of Bleeding (Selumetinib Capsules)
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]).1 Because vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors, the risk of bleeding may be increased if the daily vitamin E intake exceeds the daily recommended or safe limits.1 Supplemental vitamin E during selumetinib capsule 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.1
Patients receiving concomitant warfarin or antiplatelet agents have an increased risk of bleeding; such patients should be monitored for bleeding and international normalized ratio (INR) or prothrombin time should be assessed more frequently.1 The dosage of warfarin or antiplatelet agents should be adjusted as appropriate.1
Selumetinib granules do not contain vitamin E.1
Fetal/Neonatal Morbidity and Mortality
Based on data from clinical trials, animal findings, and its mechanism of action, selumetinib may cause fetal harm when administered to a pregnant woman.1 In the KOMET study, a patient experienced a first trimester spontaneous abortion while receiving selumetinib.1 Embryofetal toxicity (i.e., reduced fetal weight, structural abnormalities, effects on embryofetal survival) have been observed in mice receiving selumetinib during organogenesis at exposures approximately >5 times the human exposure at recommended dosage of 25 mg/m2 twice daily.1
Pregnancy status should be verified in females of reproductive potential prior to initiation of selumetinib therapy.1 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.1 Advise pregnant females of the potential risk to the fetus.1
Selumetinib may cause fetal harm if administered to pregnant women based on its mechanism of action, animal findings, and data from clinical trials.1 In the KOMET study, a patient experienced a first trimester spontaneous abortion while receiving selumetinib.1
Pregnancy status should be verified in females of reproductive potential prior to initiation of selumetinib therapy.1
Selumetinib and its active metabolites are distributed into milk in rats; it is not known whether selumetinib or its active metabolites are distributed into human milk.1 Because of the potential for serious adverse reactions to selumetinib in breast-fed infants, women should be advised not to breast-feed while receiving the drug and for 1 week after the last dose.1 The effects of the drug on breast-fed infants or on the production of milk are unknown.1
Females and Males of Reproductive Potential
Pregnancy status should be verified in females of reproductive potential prior to initiation of selumetinib therapy.1
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.1 Advise pregnant females of the potential risk to the fetus.1
The safety and efficacy of selumetinib have been established in pediatric patients ≥1 year of age with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas.1
The safety and efficacy of selumetinib have not been established in pediatric patients <1 year of age.1
The expanded approval of selumetinib capsules and granules to pediatric patients ≥1 year of age was based on adequate bridging between the oral granule and approved capsule formulations in a relative bioavailability study in healthy adults and exposure matching between the pediatric patient populations in the SPRINT study (capsule formulation, ≥2 years of age) and the SPRINKLE study (oral granule formulation, ≥1 year of age).7 Similar exposure between the formulations supported extrapolation of efficacy from pediatric patients ≥2 to ≥1 year of age.7
In 3-month general toxicology studies, growth plate dysplasia occurred in male rats receiving selumetinib at a dosage approximately 60 times the human exposure based on AUC at the recommended dosage of 25 mg/m2 twice daily).1
Because of the intended chronic use of the drug for pediatric patients with NF-1 plexiform neurofibromas, growth and development should be monitored long-term.6
Clinical studies did not include a sufficient number of patients ≥65 years of age to determine whether response to selumetinib is different from younger patients.1
Unbound systemic exposure of selumetinib is increased by 1.4-fold in individuals with moderate (Child-Pugh class B) and 3.2-fold in individuals with severe (Child-Pugh class C) hepatic impairment.1
In patients with moderate hepatic impairment (Child-Pugh class B), reduce the dosage of selumetinib to 20 mg/m2 twice daily.1
An appropriate dosage for patients with severe hepatic impairment (Child-Pugh class C) has not been established.1
No clinically significant differences in selumetinib exposures were seen in patients with end stage renal disease (creatinine clearance <15 mL/minute) who require dialysis.1
Adverse effects reported in ≥40% of pediatric patients include vomiting, diarrhea, increased CPK, dry skin, paronychia, nausea, dermatitis acneiform, and pyrexia.1
Adverse effects reported in ≥40% of adult patients include rash (all), dermatitis acneiform, and diarrhea.1
Selumetinib is primarily metabolized by cytochrome P-450 (CYP) 3A4 and, to a lesser extent, by CYP isoenzymes 2C19, 1A2, 2C9, 2E1, and 3A5.1 Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3.1 Metabolism of selumetinib to the active metabolite N -desmethyl selumetinib is mediated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6.1 N -Desmethyl selumetinib is metabolized via the same routes as selumetinib.1
In vitro, selumetinib does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, or 2E1.1 Selumetinib does not induce CYP isoenzymes 3A4, 1A2, or 2B6.1
Selumetinib does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K transporters.1 The drug is a substrate of BCRP and P-gp transporters.1
Drugs Affecting Hepatic Microsomal Enzymes
Moderate or Strong CYP3A4 Inhibitors
Concomitant use of selumetinib with strong or moderate inhibitors of CYP3A4 may result in increased systemic exposure (area under the concentration-time curve [AUC]) of selumetinib, and increased risk of adverse effects to selumetinib.1 Concomitant administration of the strong CYP3A4 inhibitor itraconazole increased AUC and peak plasma concentrations of selumetinib by 49% and 19%, respectively.1 Concomitant administration of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor) increased AUC and peak plasma concentrations of selumetinib by 53% and 26%, respectively.1 Concomitant administration of the moderate CYP3A4 inhibitor erythromycin is predicted to increase AUC and peak plasma concentrations of selumetinib by 41% and 23%, respectively.1
Avoid concomitant use of selumetinib with moderate or strong inhibitors of CYP3A4 or fluconazole.1 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.1 The calculated dosage based on BSA is shown in Table 6 (capsules) or Table 7 (granules).1 If concomitant use of the moderate or strong inhibitor of CYP3A4 or fluconazole is discontinued, the selumetinib dosage should be returned (after 3 terminal half-lives) to the dosage used prior to initiation of the moderate or strong CYP3A4 inhibitor or fluconazole.1
Moderate or Strong CYP3A4 Inducers
Concomitant use of selumetinib with strong or moderate inducers of CYP3A4 may result in decreased systemic exposure (AUC) of selumetinib and reduced selumetinib efficacy.1 Concomitant administration of the strong CYP3A4 inducer rifampin decreased AUC and peak plasma concentrations of selumetinib by 51% and 26%, respectively.1 Concomitant administration of the moderate CYP3A4 inducer efavirenz is predicted to decrease AUC and peak plasma concentrations of selumetinib by 38% and 22%, respectively.1
Avoid concomitant use of selumetinib with moderate or strong inducers of CYP3A4.1
Anticoagulant or Antiplatelet Agents
Patients receiving concomitant warfarin or antiplatelet agents with selumetinib capsules have an increased risk of bleeding; such patients should be monitored for bleeding and international normalized ratio (INR) or prothrombin time should be assessed more frequently.1 The dosage of warfarin or antiplatelet agents should be adjusted as appropriate.1
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]).1 Because vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors, the risk of bleeding may be increased if the daily vitamin E intake exceeds the daily recommended or safe limits.1 Supplemental vitamin E during selumetinib capsule 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.1
Selumetinib, an inhibitor of mitogen-activated extracellular signal-regulated kinases 1 and 2 (MEK1/2), is an antineoplastic agent.1, 3 MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.1 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 Neurofibromatosis type 1 (NF1) is a progressive multi-system disease characterized by progressive cutaneous, neurologic, skeletal, and neoplastic manifestations.6 Loss of NF1 gene expression in neural stem cells results in activation of the RAF/MEK/ERK pathway, which can be the cause of or sustain the growth of various tumor types, such as benign or malignant tumors.1, 6, 12 Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system.6 Plexiform neurofibromas are one of the most common benign tumors, which occur in approximately 20% to 50% of NF1 patients.6 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.1
The bioavailability of selumetinib is 62%.1 A low- or high-fat meal resulted in no clinically relevant effect on selumetinib pharmacokinetics.1 The median time to peak plasma concentrations is 1.5 hours.1 Plasma protein binding was 98.4%; predominantly to serum albumin.1 Selumetinib is primarily metabolized by cytochrome P-450 (CYP) 3A4 and, to a lesser extent, by CYP isoenzymes 2C19, 1A2, 2C9, 2E1, and 3A5.1 Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3.1 Metabolism of selumetinib to the active metabolite N -desmethyl selumetinib is mediated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6.1 N -Desmethyl selumetinib is metabolized via the same routes as selumetinib.1 The active metabolite is 3-5 times more potent than selumetinib and is estimated to represent <10% of drug levels in human plasma, contributing approximately 21 to 35% of the overall pharmacologic activity.1 Following a single oral selumetinib dose in a healthy adult, 33% was recovered in urine (<1% as unchanged drug) and 59% in feces (19% unchanged drug).1 The elimination half-life of selumetinib is 9 hours.1 No clinically significant differences in selumetinib pharmacokinetics were seen between pediatric and adult patients.1
No clinically meaningful effect on the pharmacokinetics of selumetinib or N -desmethyl selumetinib were observed based on age (1-79 years) or race (white, Asian, Black).1 No clinically relevant differences in selumetinib pharmacokinetics were seen following administration of a single-dose of either the granule or capsule dosage forms at equivalent dosages, under fasted and fed conditions, in healthy adults.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Granules | 5 mg (of selumetinib) | ||
7.5 mg (of selumetinib) | Koselugo® | AstraZeneca Pharmaceuticals LP | ||
Capsule | 10 mg (of selumetinib) | Koselugo® | AstraZeneca Pharmaceuticals LP | |
25 mg (of selumetinib) | Koselugo® | AstraZeneca Pharmaceuticals LP |
1. AstraZeneca Pharmaceuticals LP. Koselugo® (selumetinib) capsules prescribing information. Wilmington, DE; 2026 May. [Web]
2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
3. Dombi E, Baldwin A, Marcus LJ et al. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med . 2016; 375:2550-2560. [PubMed 28029918]
5. Gross AM, Wolters PL, Dombi E et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med . 2020; 382:1430-1442. [PubMed 32187457]
6. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 213756Orig1s000: Multi-discipline review. From FDA website. [Web]
7. Food and Drug Administration. FDA approves selumetinib for pediatric patients 1 year of age and older with neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. September 10, 2025. [Web]
12. Bergoug M, Doudeau M, Godin F et al. Neurofibromin Structure, Functions and Regulation. Cells . 2020; 9 [PubMed 33121128]
13. Chen AP, Coyne GO, Walters PL, et al. Efficacy and safety of selumetinib in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas (KOMET): a multicenter, international, randomized, placebo-controlled, parallel, double-blind, phase 3 study. Lancet . 2025;405:2217-30.