Highlights

Indications and usage

Selumetinib is indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas.

Dosage and administration

Recommended dosage

The recommended dosage of selumetinib is 25 mg/m² orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity.

Selumetinib can be taken with or without food. The recommended dose of selumetinib based on body surface area is shown in Table 1.

Table 1. Recommended Dosage Based on Body Surface Area

Swallow selumetinib capsules whole with water. Do not chew, dissolve, or open capsules.

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

Do not take a missed dose of selumetinib unless it is more than 6 hours until the next scheduled dose.

If vomiting occurs after selumetinib administration, do not take an additional dose, but continue with the next scheduled dose.

Dosage modifications for adverse reactions

The recommended dose reductions for adverse reactions are provided in Table 2.

Table 2. Recommended Dose Reductions for Selumetinib for Adverse Reactions

Dosage modifications for adverse reactions are in Table 3.

Table 3. Recommended Dosage Modifications for Selumetinib for Adverse Reactions

Dosage modifications for hepatic impairment

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

Table 4. Recommended Dosage of Selumetinib for Moderate Hepatic Impairment

Dosage modifications for drug interactions

Strong or moderate CYP3A4 inhibitors or fluconazole. Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with selumetinib. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the selumetinib dosage as recommended in Table 5. After discontinuation of the strong or moderate CYP3A4 inhibitor or fluconazole for three elimination half-lives, resume the selumetinib dose that was taken before initiating the inhibitor or fluconazole.

Table 5. Recommended Dosage of Selumetinib for Coadministration with Strong or Moderate CYP3A4 Inhibitors or Fluconazole

Dosage forms and strengths

Contraindications

None.

Warnings and precautions

Cardiomyopathy

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

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

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

Assess ejection fraction by echocardiogram before 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 based on the severity of the adverse reaction. In patients who interrupt selumetinib 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 lower limit of normal, obtain an echocardiogram or a cardiac MRI every 2 to 3 months or as directed by the cardiologist.

Ocular toxicity

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

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

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

Gastrointestinal toxicity

Diarrhea occurred in 77% of 74 pediatric patients who received selumetinib 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.

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 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 as a single agent.

Advise patients to start an anti-diarrheal agent (eg, 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 based on the severity of the adverse reaction.

Skin toxicity

Rash occurred in 91% of 74 pediatric patients who received selumetinib 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.

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

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

Increased creatine phosphokinase

Increased creatine phosphokinase (CPK) occurred in 76% of 74 pediatric patients who received selumetinib 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 for myalgia.

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

Obtain serum CPK before initiating selumetinib, 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 based on the severity of the adverse reaction.

Increased levels of vitamin E and risk of bleeding

Selumetinib 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 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 and supplement) will exceed the recommended or safe limits.

An increased risk of bleeding in patients may occur in patients who are coadministered vitamin-K antagonists or antiplatelet antagonists with selumetinib. 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 antiplatelet agents as appropriate.

Embryo-fetal toxicity

Based on findings from animal studies and its mechanism of action, selumetinib 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 more than five 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 and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with selumetinib and for 1 week after the last dose.

Adverse reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the Warnings and precautions section reflect exposure to selumetinib in 74 pediatric patients who received a dosage ranging from 20 mg/m² to 30 mg/m² orally twice daily in SPRINT. Among these patients, the duration of selumetinib exposure, including dose interruptions, was 12 months or longer (91%), more than 2 years (74%), or more than 4 years (23%). The Warnings and precautions also include additional data from adult and pediatric patients who received selumetinib administered at various doses across a range of tumors in other clinical trials.

Neurofibromatosis type 1 with inoperable plexiform neurofibromas. The safety of selumetinib was evaluated in SPRINT Phase II Stratum 1. Eligible patients were 2 to 18 years of age with neurofibromatosis type 1 who had inoperable plexiform neurofibromas that were causing significant morbidity. Patients were excluded for abnormal LVEF, uncontrolled hypertension (blood pressure greater than the 95th percentile for age, height, and sex), any current or past history of retinal vein occlusion or retinal pigment epithelial detachment, intraocular pressure greater than 21 mmHg (or upper limit of normal adjusted by age), uncontrolled glaucoma, and inability to swallow whole capsules. Patients received selumetinib 25 mg/m² orally twice daily (n=50). Among these patients, 88% were exposed for 12 months or longer, and 66% were exposed for greater than 2 years.

Serious adverse reactions occurred in 24% of patients who received selumetinib. Serious adverse reactions that occurred in two or more patients were anemia, hypoxia, and diarrhea.

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received selumetinib. Adverse reactions resulting in permanent discontinuation of selumetinib included increased blood creatinine, increased weight, diarrhea, paronychia, malignant peripheral nerve sheath tumor, acute kidney injury, and skin ulcer.

Dosage interruptions and dose reductions due to adverse reactions occurred in 80% and 24% of patients who received selumetinib, respectively. Adverse reactions requiring a dosage interruption or reduction in 5% or more of patients were vomiting, paronychia, diarrhea, nausea, abdominal pain, rash, skin infection, influenza-like illness, pyrexia, and weight gain.

The most common adverse reactions (40% or more) were vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.

Table 6 presents the adverse reactions in SPRINT Phase II Stratum 1.

Table 6. Adverse Reactions (20% or greater) in Patients Who Received Selumetinib in SPRINT Phase II Stratum 1

Clinically relevant adverse reactions that occurred in fewer than 20% of patients include:

Table 7 presents the laboratory abnormalities in SPRINT Phase II Stratum 1.

Table 7. Select Laboratory Abnormalities (15% or more) Worsening from Baseline in Patients Who Received Selumetinib in SPRINT Phase II Stratum 1

Drug interactions

Effect of other drugs on selumetinib

Use in specific populations

Pregnancy

Risk summary. Based on findings from animal studies and its mechanism of action, selumetinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of selumetinib 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 greater than five times the human exposure at the clinical dose of 25 mg/m² twice daily (see Data). Advise pregnant women of the potential risk to the fetus.

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.

Data.

Animal data. In embryo-fetal development studies in mice at doses greater than 2.5 mg/kg twice daily (approximately five 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.

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 (eg, prematurely open eye[s] and cleft palate) was increased even at the lowest dose of 0.5 mg/kg twice daily (maternal maximal concentration [C_max] of approximately 0.6 times the human C_max at the clinical dose of 25 mg/m² twice daily).

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 (see Data). Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with selumetinib and for 1 week after the last dose.

Data.

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.

Females and males of reproductive potential

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

Pregnancy testing. Verify the pregnancy status of females of reproductive potential before initiating selumetinib.

Contraception.

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

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

Pediatric use

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

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

Geriatric use

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

Renal impairment

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

Hepatic impairment

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

Overdosage

Dialysis is not helpful as selumetinib is highly protein-bound and is extensively metabolized.

Clinical pharmacology

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.

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

Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of selumetinib have not been fully characterized.

Cardiac electrophysiology. At a dose 1.5 times the maximum recommended dose, selumetinib does not prolong the QT/QTc interval to any clinically relevant extent.

Pharmacokinetics

At the recommended dosage of 25 mg/m² twice daily in pediatric patients (2 to 18 years old), the mean maximum plasma concentration (Cmax) (coefficient of variation [CV%]) following the first dose and at steady state was 731 (62%) ng/mL and 798 (52%) ng/mL, respectively. The mean area under the plasma drug concentration curve (AUC_0-12h) following the first dose was 2009 (35%) ng•h/mL, and the AUC_0-6h at steady state was 1958 (41%) ng•h/mL. Selumetinib AUC and C_max increase proportionally over a dose range from 20 mg/m² to 30 mg/m² (0.8 to 1.2 times the recommended dose). The accumulation was 1.1-fold following administration of selumetinib 25 mg/m² twice daily.

Absorption. The mean absolute oral bioavailability of selumetinib was 62% in healthy adults. The median time to peak plasma concentrations (T_max) at steady-state in pediatric patients was 1 to 1.5 hours.

Effect of food. Selumetinib Cmax and AUC decreased by 24% and 8%, respectively, following a low-fat meal (400 calories, 25% fat) in adolescent patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas who were administered multiple doses of 25 mg/m² twice daily, and T_max was delayed by approximately 0.6 hours.

A population PK analysis including children and adolescent patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas, adult patients with cancers, and healthy adults showed that a low- or high-fat meal had no clinically relevant effect on the AUC of selumetinib.

Distribution. The mean apparent volume of distribution at steady state (V_ss) of selumetinib across a dose range of 20 mg/m² to 30 mg/m² (0.8- to 1.2 times the recommended dosage) ranged from 78 L to 171 L in pediatric patients.

The plasma protein binding was 98.4% in humans in vitro. Selumetinib binds to serum albumin (96%) and alpha-1 acid glycoprotein (less than 35%).

Elimination. In pediatric patients, selumetinib had an apparent oral clearance (CL/F) of 8.8 L/hr and a mean elimination half-life of approximately 6.2 hours following a dose of 25 mg/m².

Metabolism. Selumetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. It is estimated that 56% of the observed intrinsic clearance of selumetinib could be attributed to CYP metabolism, and about 29% to direct glucuronidation by UGT enzymes in vitro. The active metabolite, N-desmethyl selumetinib, is generated by CYP2C19 and CYP1A2, with additional contribution by CYP2C9 and CYP2A6, and metabolized through the same routes as selumetinib.

N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma, but is approximately three to five times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.

Excretion. After a single oral dose of radiolabeled selumetinib 75 mg (1.5 times the recommended dose) to healthy adults, 59% of the dose was recovered in feces (19% as unchanged) and 33% in urine (less than 1% as parent).

Specific populations.

Racial or ethnic groups. No clinically meaningful effect on the pharmacokinetics of selumetinib or N-desmethyl selumetinib was observed based on race (White, Asian, Black).

Patients with renal impairment. Following administration of a single dose of 50 mg, selumetinib exposures were similar in subjects with end-stage renal disease (CLcr < 15 mL/min) who required dialysis compared to subjects with normal renal function (CLcr ≥ 90 mL/min).

Patients with hepatic impairment. Following administration of a single-dose of selumetinib, dose normalized total AUC0-INF decreased by 14% in subjects with mild hepatic impairment (Child-Pugh A) and increased by 59% in subjects with moderate hepatic impairment (Child-Pugh B) and by 57% in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal hepatic function. Selumetinib unbound AUC0-INF decreased by 31% in subjects with mild hepatic impairment (Child-Pugh A) and increased by 41% in subjects with moderate hepatic impairment (Child-Pugh B), and 3.2-fold in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function.

Drug interaction studies.

Clinical studies and model-informed approaches.

Effect of strong or moderate CYP3A4 inhibitors. Concomitant use of itraconazole (strong CYP3A4 inhibitor) increased selumetinib AUC by 49% and C_max by 19%. Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 41% and C_max by 23%.

Effect of fluconazole. Concomitant use of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor) increased selumetinib AUC by 53% and C_max by 26%.

Effect of strong or moderate CYP3A4 inducers. Concomitant use of rifampicin (strong CYP3A4 inducer) decreased selumetinib AUC by 51% and C_max by 26%. Concomitant use of efavirenz (moderate CYP3A4 inducer) is predicted to decrease selumetinib AUC by 38% and C_max by 22%.

In vitro studies.

CYP enzymes. Selumetinib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1. Selumetinib does not induce CYP3A4, CYP1A2, or CYP2B6.

Transporter systems. Selumetinib does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters.

Selumetinib is a substrate of BCRP and P-gp transporters.

Nonclinical toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenicity. Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice at exposures 24 times (males) and 36 times (females) and in a 2-year carcinogenicity study in rats at exposures 20 times (males) and 15 times the human exposure (AUC) at the clinical dose of 25 mg/m².

Mutagenicity. Selumetinib was not mutagenic or clastogenic in vitro. Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses greater than 160 mg/kg (approximately 38 times the human C_max at the clinical dose of 25 mg/m²).

Impairment of fertility. In a 6-month mouse study, selumetinib did not affect male mating performance at any dose up to 20 mg/kg twice daily (approximately 33 times the human exposure based on AUC at the clinical dose of 25 mg/m² twice daily). In female mice exposed to selumetinib at 12.5 mg/kg twice daily, mating performance and fertility were not affected. The NOAEL for both maternal toxicity and effects on reproductive performance was 2.5 mg/kg twice daily (approximately five times the human exposure based on AUC at the clinical dose of 25 mg/m² twice daily).

Animal toxicology and/or pharmacology

In a 26-week repeat-dose toxicology study, selumetinib at a dose of 20 mg/kg (approximately 33 times the human exposure based on AUC at the clinical dose of 25 mg/m² twice daily) led to significant urinary tract obstruction as well as inflammation and luminal hemorrhage of the urethra leading to early death in male mice.

Clinical studies

Neurofibromatosis type 1 with inoperable plexiform neurofibromas

The efficacy of selumetinib was evaluated in SPRINT Phase II Stratum 1, an open-label, multicenter, single-arm trial (NCT01362803). Eligible patients were required to have neurofibromatosis type 1 with inoperable plexiform neurofibroma, defined as a plexiform neurofibroma that could not be removed entirely without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the plexiform neurofibromas. Patients were also required to have significant morbidity related to the target plexiform neurofibromas. Morbidities that were present in 20% or more of patients included disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction. Patients received selumetinib 25 mg/m² orally twice daily until disease progression or unacceptable toxicity.

The primary efficacy outcome measure was overall response rate, defined as the percentage of patients with complete response (defined as disappearance of the target plexiform neurofibromas) or confirmed partial response (defined as 20% or more reduction in plexiform neurofibromas volume confirmed at a subsequent tumor assessment within 3-6 months). The target plexiform neurofibroma, defined as the plexiform neurofibroma that caused relevant clinical symptoms or complications (plexiform neurofibroma-related morbidities), was evaluated for response rate using centrally read volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. Tumor response was evaluated at baseline and during treatment after every four cycles for 2 years, and then every six cycles. An additional efficacy outcome measure was duration of response (DoR).

A total of 50 pediatric patients received selumetinib. The median age was 10.2 years (range 3.5 to 17.4 years); 60% were male; and 84% were White, 8% were Black, and 2% were Asian.

Efficacy results are provided in Table 8. The median time to onset of response was 7.2 months (range: 3.3 months to 1.6 years).

Table 8. Efficacy Results from SPRINT Phase II Stratum 1

How supplied/storage and handling

How supplied

Storage

Store at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F).

Dispense in the original bottle. Keep the bottle tightly closed. Do not remove the desiccant. Protect from moisture.

Patient counseling information

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

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

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

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

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

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

Increased vitamin E levels and risk of bleeding. Advise patients and caregivers to notify their healthcare provider if they are taking a supplement containing vitamin E, a vitamin-K antagonist, or an antiplatelet agent.

Embryo-fetal toxicity.

• 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 and for 1 week after the last dose.

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

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

Drug interactions. 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.

Dosing and administration. Inform patients and caregivers on how to take selumetinib and what to do for missed or vomited doses.

Koselugo® is a trademark of AstraZeneca.

Patient package insert

For the patient package insert and instructions of use, see the relevant sections of the DAILYMED drug label information.