{ "meta": { "disclaimer": "Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service.", "terms": "https://open.fda.gov/terms/", "license": "https://open.fda.gov/license/", "last_updated": "2026-06-05", "results": { "skip": 0, "limit": 10, "total": 2 } }, "results": [ { "spl_product_data_elements": [ "Gomekli mirdametinib MIRDAMETINIB MIRDAMETINIB CROSCARMELLOSE SODIUM MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE FD&C BLUE NO. 1 GELATIN, UNSPECIFIED TITANIUM DIOXIDE FERRIC OXIDE YELLOW BUTYL ALCOHOL ALCOHOL ISOPROPYL ALCOHOL POTASSIUM HYDROXIDE PROPYLENE GLYCOL WATER SHELLAC AMMONIA Light Green MIR;1mg Gomekli mirdametinib MIRDAMETINIB MIRDAMETINIB CROSCARMELLOSE SODIUM MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE FD&C BLUE NO. 1 GELATIN, UNSPECIFIED TITANIUM DIOXIDE FERRIC OXIDE YELLOW BUTYL ALCOHOL ALCOHOL ISOPROPYL ALCOHOL POTASSIUM HYDROXIDE PROPYLENE GLYCOL WATER SHELLAC AMMONIA MIR;2mg Gomekli mirdametinib MIRDAMETINIB MIRDAMETINIB CROSCARMELLOSE SODIUM MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE GRAPE SUCRALOSE White to off-white S" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE GOMEKLI is indicated for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection [see Clinical Studies (14) ]. GOMEKLI is a kinase inhibitor indicated for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection. ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION The recommended dosage of GOMEKLI is 2 mg/m 2 orally twice daily, with or without food, for the first 21 days of each 28-day cycle. Continue treatment with GOMEKLI until disease progression or unacceptable toxicity. ( 2 ) 2.1 Recommended Evaluation and Testing Before Initiating GOMEKLI Prior to administration of GOMEKLI: conduct comprehensive ophthalmic assessment [see Warnings and Precautions (5.1) ]. assess ejection fraction (EF) by echocardiogram [see Warnings and Precautions (5.2) ]. 2.2 GOMEKLI Dosage Form Overview GOMEKLI is available in 2 dosage forms: capsules or tablets for oral suspension. GOMEKLI capsules: must be swallowed whole, do not open, break or chew capsules. GOMEKLI tablets for oral suspension: can be swallowed whole or can be dispersed in drinking water and administered orally as a liquid [see Dosage and Administration (2.4) ]. 2.3 Recommended Dosage The recommended dosage of GOMEKLI is 2 mg/m 2 orally twice daily (approximately every 12 hours) with or without food for the first 21 days of each 28-day cycle. The maximum dose is 4 mg twice daily. Continue treatment with GOMEKLI until disease progression or unacceptable toxicity. The recommended dose of GOMEKLI is based on body surface area (BSA) as shown in Table 1. Table 1: Recommended Dosage for GOMEKLI Body Surface Area (m 2 ) * Recommended Dosage for Capsules or Tablets for Oral Suspension 0.40 to 0.69 1 mg twice daily 0.70 to 1.04 2 mg twice daily 1.05 to 1.49 3 mg twice daily ≥1.50 4 mg twice daily * The recommended dosage for patients with a BSA less than 0.40 m 2 has not been established. Missed dose: If the patient misses a dose of GOMEKLI, do not take an additional dose. Take the next scheduled dose at the prescribed time. Vomiting: If vomiting occurs after GOMEKLI administration, do not take an additional dose. Take the next scheduled dose at the prescribed time. 2.4 GOMEKLI Preparation and Administration Instructions GOMEKLI Capsules Swallow GOMEKLI capsules whole with or without food. If more than one capsule is required for a dose, swallow one capsule at a time. Do not open, break or chew capsules. Do not administer to patients who are unable to swallow a whole capsule [see GOMEKLI Tablets for Oral Suspension]. GOMEKLI Tablets for Oral Suspension GOMEKLI tablets for oral suspension can be swallowed whole with or without food. If more than one tablet is required for a dose, swallow one tablet at a time. For patients who are not able to swallow whole tablets, prepare GOMEKLI tablets for oral suspension dispersed in drinking water and administer orally as a liquid [see Instructions for Use ]. Preparation and Administration Add the prescribed number of tablets to a dosing cup containing approximately 5 mL to 10 mL of drinking water. Gently swirl the water and tablets until the tablets are fully dispersed and an oral suspension is obtained. It takes approximately two to four minutes to fully disperse the tablets. Once the tablets are dispersed, the oral suspension will appear white and cloudy. Administer the oral suspension immediately after preparation from a dosing cup or oral syringe. After administration of the prepared suspension, add approximately 5 mL to 10 mL of drinking water to the dosing cup and gently swirl to resuspend any remaining particles. Administer the suspension to ensure the full dose is taken. Discard the oral suspension if not administered within 30 minutes after preparation. 2.5 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 2 . Table 2: Recommended Dose Reductions for GOMEKLI for Adverse Reactions Body Surface Area (m 2 ) Reduced Dose * Morning Evening 0.40 to 0.69 1 mg once daily 0.70 to 1.04 2 mg 1 mg 1.05 to 1.49 2 mg 2 mg ≥1.50 3 mg 3 mg * Permanently discontinue GOMEKLI in patients unable to tolerate GOMEKLI after one dose reduction. The recommended dosage modifications for adverse reactions are provided in Table 3 . Table 3: Recommended Dosage Modifications and Management of Adverse Reactions for GOMEKLI Adverse Reaction Severity Dosage Modification Ocular Toxicity [see Warnings and Precautions (5.1) ] Grade ≤ 2 Continue GOMEKLI at current dose level. Consider ophthalmologic examinations every 2 to 4 weeks until resolution to ≤Grade 1 or baseline. Grade ≥ 3 Withhold GOMEKLI until ≤Grade 1 or baseline. If recovery occurs ≤14 days, resume GOMEKLI at the next lower dose. If recovery occurs in >14 days, consider permanent discontinuation of GOMEKLI. Symptomatic Retinal Pigment Epithelium Detachment (RPED) Withhold GOMEKLI until ≤Grade 1 or baseline. Resume GOMEKLI at the same dose. Retinal Vein Occlusion (RVO) Permanently discontinue GOMEKLI. Left Ventricular Dysfunction [see Warnings and Precautions (5.2) ] Asymptomatic, absolute decrease in LVEF of 10% or greater from baseline and is less than the lower limit of normal Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Any absolute decrease in LVEF 20% or greater from baseline Permanently discontinue GOMEKLI. Adverse Reaction Severity Dosage Modification Dermatologic Adverse Reactions [see Warnings and Precautions (5.3) ] Intolerable Grade 2 or Grade 3 Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Grade 3 or 4 Dermatitis Acneiform or Non-Acneiform Rash Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Other Adverse Reactions [see Adverse Reactions (6.1) ] Intolerable Grade 2 or Grade 3 Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Grade 4 Consider permanent discontinuation of GOMEKLI. * Per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v. 5.0)." ], "dosage_and_administration_table": [ "
Table 1: Recommended Dosage for GOMEKLI
Body Surface Area (m2) *Recommended Dosage for Capsules or Tablets for Oral Suspension
0.40 to 0.691 mg twice daily
0.70 to 1.042 mg twice daily
1.05 to 1.493 mg twice daily
≥1.504 mg twice daily
", "
Table 2: Recommended Dose Reductions for GOMEKLI for Adverse Reactions
Body Surface Area (m2)Reduced Dose*
MorningEvening
0.40 to 0.691 mg once daily
0.70 to 1.042 mg1 mg
1.05 to 1.492 mg2 mg
≥1.503 mg3 mg
", "
Table 3: Recommended Dosage Modifications and Management of Adverse Reactions for GOMEKLI
Adverse ReactionSeverityDosage Modification
Ocular Toxicity [see Warnings and Precautions (5.1)]Grade ≤ 2Continue GOMEKLI at current dose level. Consider ophthalmologic examinations every 2 to 4 weeks until resolution to ≤Grade 1 or baseline.
Grade ≥ 3Withhold GOMEKLI until ≤Grade 1 or baseline. If recovery occurs ≤14 days, resume GOMEKLI at the next lower dose. If recovery occurs in >14 days, consider permanent discontinuation of GOMEKLI.
Symptomatic Retinal Pigment Epithelium Detachment (RPED)Withhold GOMEKLI until ≤Grade 1 or baseline. Resume GOMEKLI at the same dose.
Retinal Vein Occlusion (RVO)Permanently discontinue GOMEKLI.
Left Ventricular Dysfunction [see Warnings and Precautions (5.2)]Asymptomatic, absolute decrease in LVEF of 10% or greater from baseline and is less than the lower limit of normalWithhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose.
Any absolute decrease in LVEF 20% or greater from baselinePermanently discontinue GOMEKLI.
Adverse ReactionSeverityDosage Modification
Dermatologic Adverse Reactions [see Warnings and Precautions (5.3)]Intolerable Grade 2 or Grade 3Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose.
Grade 3 or 4 Dermatitis Acneiform or Non-Acneiform RashWithhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose.
Other Adverse Reactions [see Adverse Reactions (6.1)]Intolerable Grade 2 or Grade 3Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose.
Grade 4Consider permanent discontinuation of GOMEKLI.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Capsules: 1 mg: light green body and cap with “MIR 1 mg” printed on the cap in white ink. 2 mg: white body and a blue-green cap with “MIR 2 mg” printed on the cap in white ink. Tablets for Oral Suspension: 1 mg: white to off-white, oval, grape flavored tablet, debossed with “S” on one side. Capsules: 1 mg and 2 mg. ( 3 ) Tablets for Oral Suspension: 1 mg. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Ocular Toxicity : Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment and for new or worsening visual changes or blurred vision. Continue, withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity. ( 5.1 ) Left Ventricular Dysfunction : Assess ejection fraction by echocardiogram prior to initiating GOMEKLI, every 3 months during the first year, then as clinically indicated thereafter. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity. ( 5.2 ) Dermatologic Adverse Reactions : Initiate supportive care at first signs of dermatologic adverse reactions including rash. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity. ( 5.3 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.4 ) 5.1 Ocular Toxicity GOMEKLI can cause ocular toxicity including retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED), and blurred vision. In the pooled safety population [see Adverse Reactions (6.1) ], ocular toxicity occurred in 25% of patients treated with GOMEKLI: 20% were Grade 1 reactions, 3.8% were Grade 2 reactions, and 0.8% were Grade 3 reactions. Adult Patients In the adult pooled safety population [see Adverse Reactions (6.1) ], ocular toxicity occurred in 28% of patients treated with GOMEKLI: 21% were Grade 1 reactions, 5% were Grade 2 reactions and 1.3% were Grade 3 reactions. Retinal vein occlusion (RVO) occurred in 2.7% of adult patients, including one Grade 3 reaction which required permanent discontinuation of GOMEKLI. RPED occurred in one adult patient (1.3%). Blurred vision occurred in 9% of adult patients treated with GOMEKLI. Pediatric Patients In the pediatric pooled safety population [see Adverse Reactions (6.1) ], ocular toxicity occurred in 19% of patients: 17% were Grade 1 and 1.7% were Grade 2. Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes such as blurred vision. Continue, withhold, reduce the dose, or permanently discontinue GOMEKLI as clinically indicated [see Dosage and Administration (2.5) ]. 5.2 Left Ventricular Dysfunction GOMEKLI can cause left ventricular dysfunction. Treatment with GOMEKLI has not been studied in patients with a history of clinically significant cardiac disease or LVEF <55% prior to initiation of treatment. In the ReNeu study, in adult and pediatric patients [see Adverse Reactions (6.1) ] , decreased LVEF of 10 to <20% occurred in 20%, and decreased LVEF of ≥20% occurred in 0.9% of patients treated with GOMEKLI. All patients with decreased LVEF were identified during routine echocardiography. Decreased LVEF resolved in 75% of these patients. Adult Patients In adult patients in the ReNeu study [see Adverse Reactions (6.1) ] , decreased LVEF of 10 to <20% occurred in 16% of adult patients treated with GOMEKLI. Of the adult patients with decreased LVEF, five patients (9%) required dose interruption, one patient (1.7%) required a dose reduction and one patient required permanent discontinuation of GOMEKLI. The median time to first onset of decreased LVEF in adult patients was 70 days. Pediatric Patients In pediatric patients in the ReNeu study [see Adverse Reactions (6.1) ] , decreased LVEF of 10 to <20% occurred in 25%, and decreased LVEF of ≥20% occurred in 1.8% of patients treated with GOMEKLI. Of the pediatric patients with decreased LVEF, one patient (1.8%) required dose interruption of GOMEKLI. The median time to first onset of decreased LVEF in pediatric patients was 132 days. Before initiating GOMEKLI, assess ejection fraction (EF) by echocardiogram. Monitor EF every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on the severity of adverse reaction [see Dosage and Administration (2.5) ]. 5.3 Dermatologic Adverse Reactions GOMEKLI can cause dermatologic adverse reactions including rash. In the pooled safety population [see Adverse Reactions (6.1) ], rash occurred in 84% of patients treated with GOMEKLI: 31% were Grade 2, and 6% were Grade 3. The most frequent rashes (≥2%) included dermatitis acneiform (65%), rash (11%), eczema (8%), maculo-papular rash (4.5%) and pustular rash (3.8%). Adult Patients In the pooled adult safety population [see Adverse Reactions (6.1) ], rash occurred in 92% of patients treated with GOMEKLI: 37% were Grade 2 and 8% were Grade 3 reactions. Rash requiring permanent discontinuation of GOMEKLI occurred in 11% of adult patients. Pediatric Patients In the pooled pediatric safety population [see Adverse Reactions (6.1) ] , rash occurred in 72% of patients treated with GOMEKLI: 22% were Grade 2 and 3.4% were Grade 3 reactions. Rash resulting in permanent discontinuation of GOMEKLI occurred in 3.4% of pediatric patients. Dermatitis acneiform occurred with a higher frequency in patients aged 12 to 17 years (77%) than those aged 2 to 11 years (16%), while non-acneiform rashes occurred with a higher frequency in patients aged 2 to 11 years (53%) than those aged 12 to 17 years (15%). Initiate supportive care at first signs of dermatologic adverse reactions. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity of adverse reaction [see Dosage and Administration (2.5) ] . 5.4 Embryo-Fetal Toxicity Based on findings from clinical trials, animal studies and its mechanism of action, GOMEKLI can cause fetal harm when administered to a pregnant woman. In ReNeu, a pregnancy reported 31 days after the last dose of GOMEKLI resulted in a first trimester spontaneous abortion. In embryo-fetal development studies, oral administration of mirdametinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal mortality, structural abnormalities and alterations to growth at doses approximately equivalent to the human clinical dose of 2 mg/m 2 twice daily based on body surface area (BSA). Verify the pregnancy status of females of reproductive potential prior to the initiation of GOMEKLI. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GOMEKLI and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3 ) ]." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Ocular Toxicity [see Warnings and Precautions (5.1) ] Left Ventricular Dysfunction [see Warnings and Precautions (5.2) ] Dermatologic Adverse Reactions [see Warnings and Precautions (5.3) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.4) ] Adults: The most common adverse reactions (>25%) were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase. ( 6.1 ) Pediatric patients: The most common adverse reactions (>25%) were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased neutrophil count and increased creatine phosphokinase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact SpringWorks Therapeutics Inc. at 1-888-400-7989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to GOMEKLI in 133 patients (75 adults and 58 pediatric patients) in the ReNeu study [see Clinical Studies (14) ] (n=114) and Study NF-106 (n=19) [NCT-02096471]. Patients received GOMEKLI 2 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Among 133 patients who received GOMEKLI, 62% were exposed for one year or longer, 38% were exposed for 2 years or longer, and 12% were exposed for 3 years or longer. Neurofibromatosis Type 1-Associated Plexiform Neurofibromas The safety of GOMEKLI was evaluated in the ReNeu study [see Clinical Studies (14) ] . Eligible patients were 2 years of age and older with neurofibromatosis type 1 (NF1) who had symptomatic plexiform neurofibromas (PN). Patients were excluded for abnormal left ventricular ejection fraction (LVEF), uncontrolled hypertension, alanine transaminase (ALT) value of >2 × upper limit of normal (ULN), any current or history of retinal vein occlusion (RVO) or retinal pigment epithelium detachment (RPED), intraocular pressure >21 mmHg (or upper limit of normal adjusted by age), and history of glaucoma. Patients received GOMEKLI 2 mg/m2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Adult Patients The median age of adult patients (age ≥18) who received GOMEKLI was 35 years (range: 18-69); 64% were female; 85% were White, 9% were Black or African American, 3.4% were Asian, 3.4% were other races or race not reported; and 1.7% were Hispanic or Latino. For adult patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 0.4 to 46 months). Serious adverse reactions occurred in 17% of adult patients who received GOMEKLI. Serious adverse reactions occurring in ≥1% of patients were COVID-19 (3.4%), nephrolithiasis (3.4%), and in 1 patient each: acute kidney injury, abdominal pain, ischemic colitis, urinary tract infection, retinal vein occlusion, scoliosis, squamous cell carcinoma of skin, cerebrovascular accident and chronic obstructive pulmonary disease. One fatal adverse reaction occurred in an adult patient (1.7%) who received GOMEKLI, due to COVID-19. Permanent discontinuation of GOMEKLI due to an adverse reaction occurred in 22% of adult patients. Adverse reactions which resulted in permanent discontinuation of GOMEKLI in ≥1% of adult patients were rash, diarrhea, nausea, abdominal pain, alopecia, dry skin, left ventricular dysfunction, cough, wheezing, COVID-19, peripheral swelling, RVO, dizziness, and vomiting. Dosage interruptions of GOMEKLI due to an adverse reaction occurred in 31% of adult patients. Adverse reactions which required dosage interruption in ≥5% of patients included left ventricular dysfunction and COVID-19. Dose reductions of GOMEKLI due to an adverse reaction occurred in 17% of adult patients. Adverse reactions which required dose reductions in ≥5% of patients included rash. The most common adverse reactions (>25%) were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase. Pediatric Patients The median age of pediatric patients (age ≤17 years) who received GOMEKLI was 10 years (range: 2 to 17); 54% were female; 66% were White, 20% were Black or African American, 9% were other races or race not reported, 3.6% were Asian, 1.8% were American Indian or Alaska Native; and 14% were Hispanic or Latino. For pediatric patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 1.6 to 40 months). Serious adverse reactions occurred in 14% of pediatric patients who received GOMEKLI. Serious adverse reactions in ≥1% of patients included viral gastrointestinal infections (3.6%) and in 1 patient each: diplopia, musculoskeletal pain, seizure, fall, femoral neck fracture, dehydration and hypertension. Permanent discontinuation of GOMEKLI due to an adverse reaction occurred in 9% of pediatric patients. Adverse reactions that required permanent discontinuation of GOMEKLI in ≥1% of patients were urticaria, rash, abdominal pain, constipation, and diarrhea. Dosage interruptions of GOMEKLI due to an adverse reaction occurred in 30% of pediatric patients. Adverse reactions which required dosage interruption in ≥5% of patients included COVID-19. Dose reductions of GOMEKLI due to an adverse reaction occurred in 13% of pediatric patients. Adverse reactions which required dosage reduction in ≥3% of pediatric patients were rash and decreased neutrophil count. The most common adverse reactions (>25%) were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased neutrophil count and increased creatine phosphokinase. Table 4: Adverse Reactions (≥20%) in Adult and Pediatric Patients with NF1- Associated PN Who Received GOMEKLI in ReNeu Adult N=58 Pediatric N=56 Total N=114 All Grades (%) Grade 3 or 4 a (%) All Grades (%) Grade 3 or 4 a (%) All Grades (%) Grade 3 or 4 a (%) Skin and Subcutaneous Tissue Disorders Rash b 90 10 73 3.6 82 7 Gastrointestinal Disorders Diarrhea c 59 0 55 5 57 2.6 Nausea 52 0 27 0 40 0 Vomiting 38 0 39 0 39 0 Abdominal Pain d 24 3.4 39 3.6 32 3.5 Stomatitis e 5 0 20 0 12 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain f 41 5 41 1.8 41 3.5 General Disorders and Administration Site Conditions Fatigue 29 1.7 13 0 21 0.9 Pyrexia 7 0 20 0 13 0 Infections and Infestations COVID-19 g 22 5 25 0 24 2.6 Paronychia 1.7 0 32 0 17 0 Upper Respiratory Tract Infection 0 0 23 0 11 0 Nervous System Disorders Headache h 14 1.7 34 1.8 24 1.8 Peripheral Neuropathy i 21 0 3.6 0 12 0 Cardiac Disorders Left Ventricular Dysfunction 16 0 27 1.8 21 0.9 Respiratory, Thoracic and Mediastinal Disorders Cough j 9 0 21 0 15 0 a All reactions were Grade 3 except one fatal case of COVID-19 in an adult. b Rash includes dermatitis acneiform, eczema, maculo-papular rash, pustular rash, dermatitis, erythematous rash, palmar-plantar erythrodysaesthesia syndrome, exfoliative rash, skin exfoliation, pruritic rash, papule, papular rash and macular rash. c Diarrhea includes frequent bowel movements. d Abdominal pain includes upper abdominal pain, gastrointestinal pain and abdominal discomfort. e Stomatitis includes mouth ulceration, aphthous ulcer. f Musculoskeletal pain includes non-cardiac chest pain, back pain, pain in extremity, neck pain, musculoskeletal chest pain, myalgia, arthralgia, and bone pain. g Includes one fatal case in an adult. h Headache includes migraine. i Peripheral neuropathy includes paresthesia, hypoesthesia, neuralgia, peripheral sensory neuropathy. j Cough includes upper-airway cough syndrome. Clinically relevant adverse reactions that occurred in <20% of patients include: Skin and Subcutaneous Tissue Disorders : alopecia, hair color changes Gastrointestinal Disorders : constipation Eye Disorders : retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED) and blurred vision Table 5 summarizes the laboratory abnormalities in ReNeu. Table 5: Select Laboratory Abnormalities (≥15%) that Worsened from Baseline in Adult and Pediatric Patients with NF1-Associated PN Who Received GOMEKLI in ReNeu Adult a Pediatric b Total c Laboratory Abnormality d,e All Grades (%) Grade 3 or 4 d (%) All Grades (%) Grade 3 or 4 d (%) All Grades (%) Grade 3 or 4 d (%) Chemistry Increased Creatine Phosphokinase 55 3.6 59 5 57 4.5 Increased Triglycerides 29 0 45 0 37 0 Decreased Glucose 5 0 36 1.8 21 0.9 Decreased Calcium f 23 0 20 0 21 0 Increased Creatinine 13 0 30 0 21 0 Increased Cholesterol 23 0 16 0 20 0 Increased Alkaline Phosphatase 13 0 29 0 21 0 Decreased Bicarbonate 11 0 21 0 16 0 Increased Alanine Aminotransferase (ALT) 9 0 21 0 15 0 Increased Aspartate Aminotransferase (AST) 18 0 9 0 13 0 Hematology Decreased Hemoglobin 21 0 29 0 25 0 Decreased Leukocytes 7 0 40 0 23 0 Decreased Neutrophils 7 0 31 11 19 5 Increased Lymphocytes 7 0 27 0 17 0 Decreased Lymphocytes 16 0 1.8 0 9 0 a The denominator used to calculate the rate was 56 based on the number of patients with a baseline value and at least one post-treatment value. b The denominator used to calculate the rate varied from 55 to 56 based on the number of patients with a baseline value and at least one post-treatment value. c The denominator used to calculate the rate varied from 111 to 112 based on the number of patients with a baseline value and at least one post-treatment value. d Graded per NCI-CTCAE version 5.0. e No Grade 5 laboratory abnormalities were reported in the ReNeu study. f Calcium corrected for albumin (mmol/L)." ], "adverse_reactions_table": [ "
Table 4: Adverse Reactions (≥20%) in Adult and Pediatric Patients with NF1- Associated PN Who Received GOMEKLI in ReNeu
Adult N=58Pediatric N=56Total N=114
All Grades (%)Grade 3 or 4a (%)All Grades (%)Grade 3 or 4a (%)All Grades (%)Grade 3 or 4a (%)
Skin and Subcutaneous Tissue Disorders
Rashb9010733.6827
Gastrointestinal Disorders
Diarrheac590555572.6
Nausea520270400
Vomiting380390390
Abdominal Paind243.4393.6323.5
Stomatitise50200120
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Painf415411.8413.5
General Disorders and Administration Site Conditions
Fatigue291.7130210.9
Pyrexia70200130
Infections and Infestations
COVID-19g225250242.6
Paronychia1.70320170
Upper Respiratory Tract Infection00230110
Nervous System Disorders
Headacheh141.7341.8241.8
Peripheral Neuropathyi2103.60120
Cardiac Disorders
Left Ventricular Dysfunction160271.8210.9
Respiratory, Thoracic and Mediastinal Disorders
Coughj90210150
", "
Table 5: Select Laboratory Abnormalities (≥15%) that Worsened from Baseline in Adult and Pediatric Patients with NF1-Associated PN Who Received GOMEKLI in ReNeu
AdultaPediatricbTotalc
Laboratory Abnormalityd,eAll Grades (%)Grade 3 or 4d (%)All Grades (%)Grade 3 or 4d (%)All Grades (%)Grade 3 or 4d (%)
Chemistry
Increased Creatine Phosphokinase553.6595574.5
Increased Triglycerides290450370
Decreased Glucose50361.8210.9
Decreased Calciumf230200210
Increased Creatinine130300210
Increased Cholesterol230160200
Increased Alkaline Phosphatase130290210
Decreased Bicarbonate110210160
Increased Alanine Aminotransferase (ALT)90210150
Increased Aspartate Aminotransferase (AST)18090130
Hematology
Decreased Hemoglobin210290250
Decreased Leukocytes70400230
Decreased Neutrophils703111195
Increased Lymphocytes70270170
Decreased Lymphocytes1601.8090
" ], "clinical_studies": [ "6.1 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 pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to GOMEKLI in 133 patients (75 adults and 58 pediatric patients) in the ReNeu study [see Clinical Studies (14) ] (n=114) and Study NF-106 (n=19) [NCT-02096471]. Patients received GOMEKLI 2 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Among 133 patients who received GOMEKLI, 62% were exposed for one year or longer, 38% were exposed for 2 years or longer, and 12% were exposed for 3 years or longer. Neurofibromatosis Type 1-Associated Plexiform Neurofibromas The safety of GOMEKLI was evaluated in the ReNeu study [see Clinical Studies (14) ] . Eligible patients were 2 years of age and older with neurofibromatosis type 1 (NF1) who had symptomatic plexiform neurofibromas (PN). Patients were excluded for abnormal left ventricular ejection fraction (LVEF), uncontrolled hypertension, alanine transaminase (ALT) value of >2 × upper limit of normal (ULN), any current or history of retinal vein occlusion (RVO) or retinal pigment epithelium detachment (RPED), intraocular pressure >21 mmHg (or upper limit of normal adjusted by age), and history of glaucoma. Patients received GOMEKLI 2 mg/m2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Adult Patients The median age of adult patients (age ≥18) who received GOMEKLI was 35 years (range: 18-69); 64% were female; 85% were White, 9% were Black or African American, 3.4% were Asian, 3.4% were other races or race not reported; and 1.7% were Hispanic or Latino. For adult patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 0.4 to 46 months). Serious adverse reactions occurred in 17% of adult patients who received GOMEKLI. Serious adverse reactions occurring in ≥1% of patients were COVID-19 (3.4%), nephrolithiasis (3.4%), and in 1 patient each: acute kidney injury, abdominal pain, ischemic colitis, urinary tract infection, retinal vein occlusion, scoliosis, squamous cell carcinoma of skin, cerebrovascular accident and chronic obstructive pulmonary disease. One fatal adverse reaction occurred in an adult patient (1.7%) who received GOMEKLI, due to COVID-19. Permanent discontinuation of GOMEKLI due to an adverse reaction occurred in 22% of adult patients. Adverse reactions which resulted in permanent discontinuation of GOMEKLI in ≥1% of adult patients were rash, diarrhea, nausea, abdominal pain, alopecia, dry skin, left ventricular dysfunction, cough, wheezing, COVID-19, peripheral swelling, RVO, dizziness, and vomiting. Dosage interruptions of GOMEKLI due to an adverse reaction occurred in 31% of adult patients. Adverse reactions which required dosage interruption in ≥5% of patients included left ventricular dysfunction and COVID-19. Dose reductions of GOMEKLI due to an adverse reaction occurred in 17% of adult patients. Adverse reactions which required dose reductions in ≥5% of patients included rash. The most common adverse reactions (>25%) were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase. Pediatric Patients The median age of pediatric patients (age ≤17 years) who received GOMEKLI was 10 years (range: 2 to 17); 54% were female; 66% were White, 20% were Black or African American, 9% were other races or race not reported, 3.6% were Asian, 1.8% were American Indian or Alaska Native; and 14% were Hispanic or Latino. For pediatric patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 1.6 to 40 months). Serious adverse reactions occurred in 14% of pediatric patients who received GOMEKLI. Serious adverse reactions in ≥1% of patients included viral gastrointestinal infections (3.6%) and in 1 patient each: diplopia, musculoskeletal pain, seizure, fall, femoral neck fracture, dehydration and hypertension. Permanent discontinuation of GOMEKLI due to an adverse reaction occurred in 9% of pediatric patients. Adverse reactions that required permanent discontinuation of GOMEKLI in ≥1% of patients were urticaria, rash, abdominal pain, constipation, and diarrhea. Dosage interruptions of GOMEKLI due to an adverse reaction occurred in 30% of pediatric patients. Adverse reactions which required dosage interruption in ≥5% of patients included COVID-19. Dose reductions of GOMEKLI due to an adverse reaction occurred in 13% of pediatric patients. Adverse reactions which required dosage reduction in ≥3% of pediatric patients were rash and decreased neutrophil count. The most common adverse reactions (>25%) were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased neutrophil count and increased creatine phosphokinase. Table 4: Adverse Reactions (≥20%) in Adult and Pediatric Patients with NF1- Associated PN Who Received GOMEKLI in ReNeu Adult N=58 Pediatric N=56 Total N=114 All Grades (%) Grade 3 or 4 a (%) All Grades (%) Grade 3 or 4 a (%) All Grades (%) Grade 3 or 4 a (%) Skin and Subcutaneous Tissue Disorders Rash b 90 10 73 3.6 82 7 Gastrointestinal Disorders Diarrhea c 59 0 55 5 57 2.6 Nausea 52 0 27 0 40 0 Vomiting 38 0 39 0 39 0 Abdominal Pain d 24 3.4 39 3.6 32 3.5 Stomatitis e 5 0 20 0 12 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain f 41 5 41 1.8 41 3.5 General Disorders and Administration Site Conditions Fatigue 29 1.7 13 0 21 0.9 Pyrexia 7 0 20 0 13 0 Infections and Infestations COVID-19 g 22 5 25 0 24 2.6 Paronychia 1.7 0 32 0 17 0 Upper Respiratory Tract Infection 0 0 23 0 11 0 Nervous System Disorders Headache h 14 1.7 34 1.8 24 1.8 Peripheral Neuropathy i 21 0 3.6 0 12 0 Cardiac Disorders Left Ventricular Dysfunction 16 0 27 1.8 21 0.9 Respiratory, Thoracic and Mediastinal Disorders Cough j 9 0 21 0 15 0 a All reactions were Grade 3 except one fatal case of COVID-19 in an adult. b Rash includes dermatitis acneiform, eczema, maculo-papular rash, pustular rash, dermatitis, erythematous rash, palmar-plantar erythrodysaesthesia syndrome, exfoliative rash, skin exfoliation, pruritic rash, papule, papular rash and macular rash. c Diarrhea includes frequent bowel movements. d Abdominal pain includes upper abdominal pain, gastrointestinal pain and abdominal discomfort. e Stomatitis includes mouth ulceration, aphthous ulcer. f Musculoskeletal pain includes non-cardiac chest pain, back pain, pain in extremity, neck pain, musculoskeletal chest pain, myalgia, arthralgia, and bone pain. g Includes one fatal case in an adult. h Headache includes migraine. i Peripheral neuropathy includes paresthesia, hypoesthesia, neuralgia, peripheral sensory neuropathy. j Cough includes upper-airway cough syndrome. Clinically relevant adverse reactions that occurred in <20% of patients include: Skin and Subcutaneous Tissue Disorders : alopecia, hair color changes Gastrointestinal Disorders : constipation Eye Disorders : retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED) and blurred vision Table 5 summarizes the laboratory abnormalities in ReNeu. Table 5: Select Laboratory Abnormalities (≥15%) that Worsened from Baseline in Adult and Pediatric Patients with NF1-Associated PN Who Received GOMEKLI in ReNeu Adult a Pediatric b Total c Laboratory Abnormality d,e All Grades (%) Grade 3 or 4 d (%) All Grades (%) Grade 3 or 4 d (%) All Grades (%) Grade 3 or 4 d (%) Chemistry Increased Creatine Phosphokinase 55 3.6 59 5 57 4.5 Increased Triglycerides 29 0 45 0 37 0 Decreased Glucose 5 0 36 1.8 21 0.9 Decreased Calcium f 23 0 20 0 21 0 Increased Creatinine 13 0 30 0 21 0 Increased Cholesterol 23 0 16 0 20 0 Increased Alkaline Phosphatase 13 0 29 0 21 0 Decreased Bicarbonate 11 0 21 0 16 0 Increased Alanine Aminotransferase (ALT) 9 0 21 0 15 0 Increased Aspartate Aminotransferase (AST) 18 0 9 0 13 0 Hematology Decreased Hemoglobin 21 0 29 0 25 0 Decreased Leukocytes 7 0 40 0 23 0 Decreased Neutrophils 7 0 31 11 19 5 Increased Lymphocytes 7 0 27 0 17 0 Decreased Lymphocytes 16 0 1.8 0 9 0 a The denominator used to calculate the rate was 56 based on the number of patients with a baseline value and at least one post-treatment value. b The denominator used to calculate the rate varied from 55 to 56 based on the number of patients with a baseline value and at least one post-treatment value. c The denominator used to calculate the rate varied from 111 to 112 based on the number of patients with a baseline value and at least one post-treatment value. d Graded per NCI-CTCAE version 5.0. e No Grade 5 laboratory abnormalities were reported in the ReNeu study. f Calcium corrected for albumin (mmol/L).", "14 CLINICAL STUDIES 14.1 Neurofibromatosis Type 1 Associated Plexiform Neurofibromas The efficacy of GOMEKLI was evaluated in the ReNeu study (NCT03962543), a multicenter, single-arm study in 114 patients ≥2 years of age with symptomatic, inoperable neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) causing significant morbidity. An inoperable PN was defined as a PN that cannot be completely surgically removed without risk for substantial morbidity due to: encasement of or close proximity to vital structures, invasiveness, or high vascularity of the PN. Patients received GOMEKLI 2 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measure was confirmed overall response rate (ORR), defined as the percentage of patients with complete response (disappearance of the target PN) or partial response (≥20% reduction in PN volume). Responses were assessed by blinded independent central review (BICR) using volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria modified to be confirmed at a subsequent tumor assessment within 2 to 6 months during the 24-cycle treatment phase. A secondary efficacy outcome measure was duration of response for patients who achieved a confirmed response. Adults A total of 58 adult patients received GOMEKLI. The median age was 35 years (range 18 to 69 years); 64% were female, 85% were White, 9% were Black or African American, 3.4% were Asian, 3.4% were other races; and 1.7% were Hispanic or Latino. Approximately half of the patients (53%) had a progressing PN at study entry, 7% had prior treatment with a MEK inhibitor and 69% had prior surgery. Morbidities reported in >25% of patients were pain (90%), disfigurement or major deformity (52%), and motor dysfunction (40%). Pediatric Patients A total of 56 pediatric patients received GOMEKLI. The median age was 10 years (range: 2 to 17); 54% were female; 66% were White, 20% were Black or African American, 9% were other races, 3.6% were Asian, 1.8% were American Indian or Alaska Native; and 14% were Hispanic or Latino. Most patients (63%) had a progressing PN at study entry, 11% had prior treatment with a MEK inhibitor and 36% had prior surgery. Morbidities reported in >25% of patients were pain (70%), disfigurement or major deformity (50%), and motor dysfunction (27%). Efficacy results are provided in Table 7. The median time to onset of response was 7.8 months (range: 4 months to 19 months) for the adult cohort and 7.9 months (range: 4.1 months to 18.8 months) for the pediatric cohort. Table 7: Efficacy Results by BICR from ReNeu GOMEKLI Adult (N=58) GOMEKLI Pediatric (N=56) Confirmed Overall Response Rate a,b,c ,n (%) 24 (41%) 29 (52%) 95% CI d (29, 55) (38, 65) Duration of Response (DoR) DoR ≥12 months e 21 (88%) 26 (90%) DoR ≥24 months e 12 (50%) 14 (48%) Abbreviations: CI: confidence interval. a Confirmed overall response was defined as two consecutive assessments of PR or CR assessed within 2- 6 months during the Treatment Phase. b Patients who had no post-baseline MRI assessment or no confirmed overall response were treated as non-responders. c All partial responses. d Obtained using the Clopper-Pearson approach. e Duration of response was assessed based on observed time." ], "clinical_studies_table": [ "
Table 4: Adverse Reactions (≥20%) in Adult and Pediatric Patients with NF1- Associated PN Who Received GOMEKLI in ReNeu
Adult N=58Pediatric N=56Total N=114
All Grades (%)Grade 3 or 4a (%)All Grades (%)Grade 3 or 4a (%)All Grades (%)Grade 3 or 4a (%)
Skin and Subcutaneous Tissue Disorders
Rashb9010733.6827
Gastrointestinal Disorders
Diarrheac590555572.6
Nausea520270400
Vomiting380390390
Abdominal Paind243.4393.6323.5
Stomatitise50200120
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Painf415411.8413.5
General Disorders and Administration Site Conditions
Fatigue291.7130210.9
Pyrexia70200130
Infections and Infestations
COVID-19g225250242.6
Paronychia1.70320170
Upper Respiratory Tract Infection00230110
Nervous System Disorders
Headacheh141.7341.8241.8
Peripheral Neuropathyi2103.60120
Cardiac Disorders
Left Ventricular Dysfunction160271.8210.9
Respiratory, Thoracic and Mediastinal Disorders
Coughj90210150
", "
Table 5: Select Laboratory Abnormalities (≥15%) that Worsened from Baseline in Adult and Pediatric Patients with NF1-Associated PN Who Received GOMEKLI in ReNeu
AdultaPediatricbTotalc
Laboratory Abnormalityd,eAll Grades (%)Grade 3 or 4d (%)All Grades (%)Grade 3 or 4d (%)All Grades (%)Grade 3 or 4d (%)
Chemistry
Increased Creatine Phosphokinase553.6595574.5
Increased Triglycerides290450370
Decreased Glucose50361.8210.9
Decreased Calciumf230200210
Increased Creatinine130300210
Increased Cholesterol230160200
Increased Alkaline Phosphatase130290210
Decreased Bicarbonate110210160
Increased Alanine Aminotransferase (ALT)90210150
Increased Aspartate Aminotransferase (AST)18090130
Hematology
Decreased Hemoglobin210290250
Decreased Leukocytes70400230
Decreased Neutrophils703111195
Increased Lymphocytes70270170
Decreased Lymphocytes1601.8090
", "
Table 7: Efficacy Results by BICR from ReNeu
GOMEKLI Adult (N=58)GOMEKLI Pediatric (N=56)
Confirmed Overall Response Rate a,b,c,n (%)24 (41%)29 (52%)
95% CId(29, 55)(38, 65)
Duration of Response (DoR)
DoR ≥12 monthse21 (88%)26 (90%)
DoR ≥24 monthse12 (50%)14 (48%)
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Infertility: May impair fertility in females. ( 8.3 ) 8.1 Pregnancy Risk Summary Based on findings from clinical trials, animal studies, and its mechanism of action [see Clinical Pharmacology (12.1) ] , GOMEKLI can cause fetal harm or loss of pregnancy when administered to a pregnant woman. In embryo-fetal development studies, oral administration of mirdametinib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal mortality, structural abnormalities and alterations to growth at doses that were approximately equivalent to the human clinical dose of 2 mg/m 2 twice daily based on BSA (see Data). Advise pregnant women of the potential risk to a 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 Human Data In ReNeu, a pregnancy reported 31 days after the last dose of GOMEKLI resulted in a first trimester spontaneous abortion. Animal Data In an embryo-fetal developmental toxicity study, mirdametinib was administered orally to pregnant rats during the period of organogenesis (gestation days 6 to 17) at doses of 0.3, 0.6, 3 or 5 mg/kg/day. Mirdametinib caused post-implantation loss and decreased fetal body weights at doses ≥3 mg/kg/day (≥5 times the human clinical dose of 2 mg/m 2 twice daily based on BSA). Multiple malformations, including shortening of limbs and absence or shortening of digits, were observed in one fetus and another with hyperflexion variation at the dose of 3 mg/kg/day. In an embryo-fetal developmental toxicity study, mirdametinib was administered orally to pregnant rabbits during the period of organogenesis (gestation day 7 to 19) at doses of 0.3, 1, 3, or 6 mg/kg/day. Maternal toxicity (decreased body weight and moribund condition) was observed at doses ≥1 mg/kg/day (≥3 times the human clinical dose of 2 mg/m 2 twice daily based on BSA). Two animals had spontaneous abortions at the 1 mg/kg dose on Days 20 and 23. Mirdametinib caused post-implantation loss at doses ≥0.3 mg/kg/day (approximately equivalent to the human clinical dose of 2 mg/m 2 twice daily based on BSA). 8.2 Lactation Risk Summary There are no data on the presence of mirdametinib or its metabolites in human milk or their effects on a breastfed child or on milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential GOMEKLI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating GOMEKLI. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with GOMEKLI and for 3 months after the last dose. Infertility Based on findings in animals, GOMEKLI may impair fertility in females of reproductive potential. The reversibility of the effects on female fertility in animals is unknown [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of GOMEKLI have been established in pediatric patients 2 years of age and older with NF1-PN based on the results of the ReNeu study, a single-arm trial conducted in 58 pediatric patients age ≥2 years [see Clinical Studies (14.1) ] . The ReNeu study demonstrated improvement in overall response rate per REiNS criteria and duration of response. The safety and effectiveness of GOMEKLI have not been established in pediatric patients younger than 2 years old. Animal Toxicity Data In a 3-month repeat-dose toxicology study in rats, oral administration of mirdametinib at doses ≥0.3 mg/kg/day (≥2 times the human exposure at the clinical dose of 2 mg/m2 twice daily based on AUC) resulted in dysplasia in femoral epiphyseal growth plate, metaphyseal hypocellularity of the bone marrow of long bones, and metaphyseal thickening of bone trabeculae of long bones; male rats were more sensitive to these effects. 8.5 Geriatric Use Of the 133 patients with neurofibromatosis type 1 (NF1) with symptomatic plexiform neurofibromas (PN) who received GOMEKLI 2 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity, 2 (1.5%) were 65 years of age and older and none were 75 years of age and older. Clinical studies of GOMEKLI did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger adult patients. 8.6 Renal Impairment No dosage adjustment is required in patients with mild (creatinine clearance: 60-89 mL/min) or moderate (creatinine clearance: 30-59 mL/min) renal impairment. GOMEKLI has not been studied in patients with severe (creatinine clearance <30 mL/min) renal impairment [see Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment No dosage adjustment is required in patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or total bilirubin in 1-1.5 x ULN). The pharmacokinetics of mirdametinib in patients with moderate (bilirubin >1.5 to 3 x ULN and any AST) or severe (bilirubin >3 x ULN and any AST) hepatic impairment has not been evaluated [see Clinical Pharmacology (12.3) ]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Based on findings from clinical trials, animal studies, and its mechanism of action [see Clinical Pharmacology (12.1) ] , GOMEKLI can cause fetal harm or loss of pregnancy when administered to a pregnant woman. In embryo-fetal development studies, oral administration of mirdametinib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal mortality, structural abnormalities and alterations to growth at doses that were approximately equivalent to the human clinical dose of 2 mg/m 2 twice daily based on BSA (see Data). Advise pregnant women of the potential risk to a 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 Human Data In ReNeu, a pregnancy reported 31 days after the last dose of GOMEKLI resulted in a first trimester spontaneous abortion. Animal Data In an embryo-fetal developmental toxicity study, mirdametinib was administered orally to pregnant rats during the period of organogenesis (gestation days 6 to 17) at doses of 0.3, 0.6, 3 or 5 mg/kg/day. Mirdametinib caused post-implantation loss and decreased fetal body weights at doses ≥3 mg/kg/day (≥5 times the human clinical dose of 2 mg/m 2 twice daily based on BSA). Multiple malformations, including shortening of limbs and absence or shortening of digits, were observed in one fetus and another with hyperflexion variation at the dose of 3 mg/kg/day. In an embryo-fetal developmental toxicity study, mirdametinib was administered orally to pregnant rabbits during the period of organogenesis (gestation day 7 to 19) at doses of 0.3, 1, 3, or 6 mg/kg/day. Maternal toxicity (decreased body weight and moribund condition) was observed at doses ≥1 mg/kg/day (≥3 times the human clinical dose of 2 mg/m 2 twice daily based on BSA). Two animals had spontaneous abortions at the 1 mg/kg dose on Days 20 and 23. Mirdametinib caused post-implantation loss at doses ≥0.3 mg/kg/day (approximately equivalent to the human clinical dose of 2 mg/m 2 twice daily based on BSA)." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of GOMEKLI have been established in pediatric patients 2 years of age and older with NF1-PN based on the results of the ReNeu study, a single-arm trial conducted in 58 pediatric patients age ≥2 years [see Clinical Studies (14.1) ] . The ReNeu study demonstrated improvement in overall response rate per REiNS criteria and duration of response. The safety and effectiveness of GOMEKLI have not been established in pediatric patients younger than 2 years old. Animal Toxicity Data In a 3-month repeat-dose toxicology study in rats, oral administration of mirdametinib at doses ≥0.3 mg/kg/day (≥2 times the human exposure at the clinical dose of 2 mg/m2 twice daily based on AUC) resulted in dysplasia in femoral epiphyseal growth plate, metaphyseal hypocellularity of the bone marrow of long bones, and metaphyseal thickening of bone trabeculae of long bones; male rats were more sensitive to these effects." ], "geriatric_use": [ "8.5 Geriatric Use Of the 133 patients with neurofibromatosis type 1 (NF1) with symptomatic plexiform neurofibromas (PN) who received GOMEKLI 2 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity, 2 (1.5%) were 65 years of age and older and none were 75 years of age and older. Clinical studies of GOMEKLI did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger adult patients." ], "description": [ "11 DESCRIPTION GOMEKLI capsules and tablets for oral suspension contain mirdametinib, a kinase inhibitor. Mirdametinib is chemically known as (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-((2- fluoro-4-iodophenyl)amino) benzamide. The molecular formula is C 16 H 14 F 3 IN 2 O 4 and the molecular weight is 482.20 g/mol. The structural formula for mirdametinib is: Mirdametinib is a white to tan or pink solid with an aqueous solubility of 0.25 mg/mL and a pH of 7.2 in water at 25°C. The molecule has a pKa of 7.96. GOMEKLI capsules and tablets for oral suspension are immediate release (IR) dosage forms intended for oral administration. GOMEKLI (mirdametinib) 1 mg and 2 mg capsules contain 1 mg and 2 mg mirdametinib, respectively, in gelatin capsule and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The gelatin capsule shell contains FD&C blue #1, gelatin, titanium dioxide, and yellow iron oxide. The capsule is imprinted with white ink that contains butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, strong ammonia solution, and titanium dioxide. GOMEKLI (mirdametinib) 1 mg tablets for oral suspension contain 1 mg mirdametinib and the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, grape flavor, and sucralose. The grape flavor includes corn syrup solids, modified corn starch, and triacetin. GOMEKLI capsules and tablets for oral suspension contain mirdametinib, a kinase inhibitor. Mirdametinib is chemically known as (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-((2- fluoro-4-iodophenyl)amino) benzamide. The molecular formula is C16H14 F3IN2O4 and the molecular weight is 482.20 g/mol. The structural formula for mirdametinib is:" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Mirdametinib 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. In vitro, mirdametinib inhibited kinase activity of MEK1 and MEK2 and downstream phosphorylation of ERK. In a mouse model of NF1, oral dosing of mirdametinib inhibited ERK phosphorylation and reduced neurofibroma tumor volume and proliferation. 12.2 Pharmacodynamics Mirdametinib exposure-response relationships and the time course of pharmacodynamic response are not fully characterized. Cardiac Electrophysiology At approximately six times the steady-state exposure associated with the recommended dose of 2 mg/m 2 , clinically significant QTc interval prolongation was not observed. 12.3 Pharmacokinetics GOMEKLI pharmacokinetic parameters are summarized in Table 6. Table 6: Pharmacokinetic Parameters and Characteristics of Mirdametinib General Information Steady-state [mean (%CV)] Cmax Adult patients (≥18 years): 188 (52%) ng/mL Pediatric patients (2 to17 years): 191 (62%) ng/mL AUC Adult patients (≥18 years): 431 (43%) ng·h/mL Pediatric patients (2 to 17 years): 459 (46%) ng·h/mL Time to steady-state Approximately 6 days Accumulation ratio (AUC) [mean] 1.1 to 1.9 Absorption Tmax [median (min, max)] Tablet: 0.8 (0.4-3) hours post-dose Capsule: 1.1 (0-4) hours post-dose Absolute bioavailability No data are available in humans Food effect [GMR% (90% CI)] (high-fat, high-calorie meal) Cmax 57% (54%, 61%) AUCinf 93% (90%, 96%) Distribution Human plasma protein binding Greater than 99% Apparent volume of distribution [mean (%CV)] 255 L (13%) Elimination Apparent systemic clearance [mean (%CV)] 6.3 L/h (13%) Terminal elimination half-life [mean (%CV)] 28 h (12%) Metabolism Primary pathway Metabolism involves glucuronidation and oxidation via UGT (primarily UGT1A6 and UGT2B7) and CES enzymes. Excretion Radioactivity In urine: 68% In feces: 27% Unchanged mirdametinib In urine and feces: 9% In urine: 0.7% Abbreviations: AUC: area under the plasma concentration-time curve; AUCinf: AUC from dosing extrapolated to infinity; CI: confidence interval; CES: carboxyl esterase enzyme; Cmax: maximum plasma concentration; CV: coefficient of variation; GMR: geometric least squares mean ratio; UGT: uridine diphosphate (UDP)- glycosyltransferase Specific Populations Effects of Age, Sex, and Race No clinically significant differences in mirdametinib pharmacokinetics were observed based on age (2 to 86 years), sex, and race (11% African American or Black, 12% Asian, 72% White). The effects of moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease (ESRD) on mirdametinib pharmacokinetics are unknown. Drug Interaction Studies No clinical DDI studies have been conducted. The effect of concomitant strong CYP3A4 inducers (that also co-induce UGTs, P-gp, and CES enzymes) on mirdametinib PK is currently unknown. In Vitro Studies CYP Enzymes : Mirdametinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Mirdametinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4. Transporter Systems : Mirdametinib does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters. Mirdametinib is a substrate of BCRP and P-gp transporters." ], "clinical_pharmacology_table": [ "
Table 6: Pharmacokinetic Parameters and Characteristics of Mirdametinib
General Information
Steady-state [mean (%CV)]CmaxAdult patients (≥18 years): 188 (52%) ng/mL Pediatric patients (2 to17 years): 191 (62%) ng/mL
AUCAdult patients (≥18 years): 431 (43%) ng·h/mL Pediatric patients (2 to 17 years): 459 (46%) ng·h/mL
Time to steady-stateApproximately 6 days
Accumulation ratio (AUC) [mean]1.1 to 1.9
Absorption
Tmax [median (min, max)]Tablet: 0.8 (0.4-3) hours post-dose Capsule: 1.1 (0-4) hours post-dose
Absolute bioavailabilityNo data are available in humans
Food effect [GMR% (90% CI)] (high-fat, high-calorie meal)Cmax57% (54%, 61%)
AUCinf93% (90%, 96%)
Distribution
Human plasma protein bindingGreater than 99%
Apparent volume of distribution [mean (%CV)]255 L (13%)
Elimination
Apparent systemic clearance [mean (%CV)]6.3 L/h (13%)
Terminal elimination half-life [mean (%CV)]28 h (12%)
Metabolism
Primary pathwayMetabolism involves glucuronidation and oxidation via UGT (primarily UGT1A6 and UGT2B7) and CES enzymes.
Excretion
RadioactivityIn urine: 68% In feces: 27%
Unchanged mirdametinibIn urine and feces: 9% In urine: 0.7%
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Mirdametinib 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. In vitro, mirdametinib inhibited kinase activity of MEK1 and MEK2 and downstream phosphorylation of ERK. In a mouse model of NF1, oral dosing of mirdametinib inhibited ERK phosphorylation and reduced neurofibroma tumor volume and proliferation." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Mirdametinib exposure-response relationships and the time course of pharmacodynamic response are not fully characterized. Cardiac Electrophysiology At approximately six times the steady-state exposure associated with the recommended dose of 2 mg/m 2 , clinically significant QTc interval prolongation was not observed." ], "pharmacokinetics": [ "12.3 Pharmacokinetics GOMEKLI pharmacokinetic parameters are summarized in Table 6. Table 6: Pharmacokinetic Parameters and Characteristics of Mirdametinib General Information Steady-state [mean (%CV)] Cmax Adult patients (≥18 years): 188 (52%) ng/mL Pediatric patients (2 to17 years): 191 (62%) ng/mL AUC Adult patients (≥18 years): 431 (43%) ng·h/mL Pediatric patients (2 to 17 years): 459 (46%) ng·h/mL Time to steady-state Approximately 6 days Accumulation ratio (AUC) [mean] 1.1 to 1.9 Absorption Tmax [median (min, max)] Tablet: 0.8 (0.4-3) hours post-dose Capsule: 1.1 (0-4) hours post-dose Absolute bioavailability No data are available in humans Food effect [GMR% (90% CI)] (high-fat, high-calorie meal) Cmax 57% (54%, 61%) AUCinf 93% (90%, 96%) Distribution Human plasma protein binding Greater than 99% Apparent volume of distribution [mean (%CV)] 255 L (13%) Elimination Apparent systemic clearance [mean (%CV)] 6.3 L/h (13%) Terminal elimination half-life [mean (%CV)] 28 h (12%) Metabolism Primary pathway Metabolism involves glucuronidation and oxidation via UGT (primarily UGT1A6 and UGT2B7) and CES enzymes. Excretion Radioactivity In urine: 68% In feces: 27% Unchanged mirdametinib In urine and feces: 9% In urine: 0.7% Abbreviations: AUC: area under the plasma concentration-time curve; AUCinf: AUC from dosing extrapolated to infinity; CI: confidence interval; CES: carboxyl esterase enzyme; Cmax: maximum plasma concentration; CV: coefficient of variation; GMR: geometric least squares mean ratio; UGT: uridine diphosphate (UDP)- glycosyltransferase Specific Populations Effects of Age, Sex, and Race No clinically significant differences in mirdametinib pharmacokinetics were observed based on age (2 to 86 years), sex, and race (11% African American or Black, 12% Asian, 72% White). The effects of moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease (ESRD) on mirdametinib pharmacokinetics are unknown. Drug Interaction Studies No clinical DDI studies have been conducted. The effect of concomitant strong CYP3A4 inducers (that also co-induce UGTs, P-gp, and CES enzymes) on mirdametinib PK is currently unknown. In Vitro Studies CYP Enzymes : Mirdametinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Mirdametinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4. Transporter Systems : Mirdametinib does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters. Mirdametinib is a substrate of BCRP and P-gp transporters." ], "pharmacokinetics_table": [ "
Table 6: Pharmacokinetic Parameters and Characteristics of Mirdametinib
General Information
Steady-state [mean (%CV)]CmaxAdult patients (≥18 years): 188 (52%) ng/mL Pediatric patients (2 to17 years): 191 (62%) ng/mL
AUCAdult patients (≥18 years): 431 (43%) ng·h/mL Pediatric patients (2 to 17 years): 459 (46%) ng·h/mL
Time to steady-stateApproximately 6 days
Accumulation ratio (AUC) [mean]1.1 to 1.9
Absorption
Tmax [median (min, max)]Tablet: 0.8 (0.4-3) hours post-dose Capsule: 1.1 (0-4) hours post-dose
Absolute bioavailabilityNo data are available in humans
Food effect [GMR% (90% CI)] (high-fat, high-calorie meal)Cmax57% (54%, 61%)
AUCinf93% (90%, 96%)
Distribution
Human plasma protein bindingGreater than 99%
Apparent volume of distribution [mean (%CV)]255 L (13%)
Elimination
Apparent systemic clearance [mean (%CV)]6.3 L/h (13%)
Terminal elimination half-life [mean (%CV)]28 h (12%)
Metabolism
Primary pathwayMetabolism involves glucuronidation and oxidation via UGT (primarily UGT1A6 and UGT2B7) and CES enzymes.
Excretion
RadioactivityIn urine: 68% In feces: 27%
Unchanged mirdametinibIn urine and feces: 9% In urine: 0.7%
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Mirdametinib was not carcinogenic in a 6-month study in transgenic rasH2 mice that received oral doses up to 5 mg/kg/day (approximately 15 times the human exposure at the clinical dose of 2 mg/m 2 twice daily based on AUC). Mirdametinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mirdametinib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow chromosomal aberration assay. Mirdametinib was positive in the in vivo micronucleus assay in rats. In a dedicated fertility study, male rats were treated with mirdametinib for 28 days before mating with untreated females to Gestational Day 1. Female rats were treated with mirdametinib for 14 days before mating with untreated males to Gestational Day 7. No effects on mating performance or fertility in males or females were observed at doses up to 1 mg/kg/day (approximately 2 times the human clinical dose of 2 mg/m 2 twice daily based on BSA). In a 3-month repeat-dose toxicology study in rats, mirdametinib caused decreased ovarian organ weight and increased follicular cysts associated with decreases in the number of corpora lutea at doses ≥0.3 mg/kg/day (approximately 2 times the human exposure at the clinical dose of 2 mg/m 2 twice daily based on AUC). Findings in male rats included hypoplasia of the spermatogenic epithelium in the testis, decreased content in the epididymis, and inflammation of the prostate at 1 mg/kg (approximately 8-times the human exposure at the clinical dose of 2 mg/m 2 based on AUC). The reversibility of effects on ovary and male reproductive organs was not assessed." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Mirdametinib was not carcinogenic in a 6-month study in transgenic rasH2 mice that received oral doses up to 5 mg/kg/day (approximately 15 times the human exposure at the clinical dose of 2 mg/m 2 twice daily based on AUC). Mirdametinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mirdametinib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow chromosomal aberration assay. Mirdametinib was positive in the in vivo micronucleus assay in rats. In a dedicated fertility study, male rats were treated with mirdametinib for 28 days before mating with untreated females to Gestational Day 1. Female rats were treated with mirdametinib for 14 days before mating with untreated males to Gestational Day 7. No effects on mating performance or fertility in males or females were observed at doses up to 1 mg/kg/day (approximately 2 times the human clinical dose of 2 mg/m 2 twice daily based on BSA). In a 3-month repeat-dose toxicology study in rats, mirdametinib caused decreased ovarian organ weight and increased follicular cysts associated with decreases in the number of corpora lutea at doses ≥0.3 mg/kg/day (approximately 2 times the human exposure at the clinical dose of 2 mg/m 2 twice daily based on AUC). Findings in male rats included hypoplasia of the spermatogenic epithelium in the testis, decreased content in the epididymis, and inflammation of the prostate at 1 mg/kg (approximately 8-times the human exposure at the clinical dose of 2 mg/m 2 based on AUC). The reversibility of effects on ovary and male reproductive organs was not assessed." ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING How supplied GOMEKLI Capsules are supplied as follows: Capsule Strength Capsule Description Package Configuration NDC 1 mg Light green body and cap with “MIR 1 mg” printed on the cap in white ink. Bottle of 42 capsules 82448-130-42 2 mg White body and a blue green cap with “MIR 2 mg” printed on the cap in white ink. Bottle of 42 capsules 82448-260-42 Bottle of 84 capsules 82448-260-84 GOMEKLI Tablets for Oral Suspension are supplied as follows: Tablet Strength Tablet Description Package Configuration NDC 1 mg White to off-white, oval, grape flavored tablet, debossed with “S” on one side. Bottle of 42 tablets 82448-134-42 Bottle of 84 tablets 82448-134-84 Storage and Handling Store capsules and tablets for oral suspension at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature. Protect from light." ], "how_supplied_table": [ "
Capsule StrengthCapsule DescriptionPackage ConfigurationNDC
1 mgLight green body and cap with “MIR 1 mg” printed on the cap in white ink.Bottle of 42 capsules82448-130-42
2 mgWhite body and a blue green cap with “MIR 2 mg” printed on the cap in white ink.Bottle of 42 capsules82448-260-42
Bottle of 84 capsules82448-260-84
", "
Tablet StrengthTablet DescriptionPackage ConfigurationNDC
1 mg White to off-white, oval, grape flavored tablet, debossed with “S” on one side.Bottle of 42 tablets82448-134-42
Bottle of 84 tablets82448-134-84
" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Ocular Toxicity Advise patients and caregivers that GOMEKLI can cause serious ocular effects and to immediately contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.1) ] . Left Ventricular Dysfunction Advise patients and caregivers that GOMEKLI can cause decreased LVEF and to immediately report any signs or symptoms of left ventricular dysfunction to their healthcare provider [see Warnings and Precautions (5.2) ] . Dermatologic Adverse Reactions Advise patients and caregivers that GOMEKLI can cause severe dermatologic adverse reactions and to contact their healthcare provider if they experience any skin reactions [see Warnings and Precautions (5.3) ] . Advise patients and caregivers that GOMEKLI can cause alopecia. 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 [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose [see Warnings and Precautions (5.4) and Use in Specific Populations (8.3) ] . Males Advise males with female partners of reproductive potential to use effective contraception during treatment with GOMEKLI and for 3 months after the last dose [see Warnings and Precautions (5.4) and Use in Specific Populations (8.3) ] . Lactation Advise women not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose [see Use in Specific Populations (8.2) ] . Infertility Advise females of reproductive potential that GOMEKLI may impair fertility [see Nonclinical Toxicology (13.1) ]. Administration Advise patients to swallow GOMEKLI capsules whole (do not open, break or chew capsules) [see Dosage and Administration (2.2) ] . Advise patients to either swallow GOMEKLI tablets whole or to disperse GOMEKLI tablets in water and administer orally as a liquid [see Dosage and Administration (2.2) and Instructions for Use ] . Manufactured for: SpringWorks Therapeutics, Inc. Stamford, CT 06902 GOMEKLI TM is a trademark of SpringWorks Therapeutics, Inc. © 2025 SpringWorks Therapeutics, Inc." ], "spl_patient_package_insert": [ "GOMEKLI™ (go-MEK-lee) (mirdametinib) capsules PATIENT INFORMATION GOMEKLI™ (go-MEK- lee) (mirdametinib) tablets for oral suspension What is GOMEKLI? GOMEKLI is a prescription medicine used to treat adults and children 2 years of age and older with neurofibromatosis type 1 (NF1) who have plexiform neurofibromas that cause symptoms and cannot be completely removed by surgery. It is not known if GOMEKLI is safe and effective in children under 2 years of age. Before taking GOMEKLI tell your healthcare provider about all of your medical conditions, including if you: have eye problems have heart problems are pregnant or plan to become pregnant. GOMEKLI can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should check to see if you are pregnant before you begin treatment with GOMEKLI. Use effective birth control (contraception) during treatment with GOMEKLI and for 6 weeks after your last dose. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with GOMEKLI. Males with female partners who are able to become pregnant: Use effective birth control (contraception) during treatment with GOMEKLI and for 3 months after your last dose. Tell your healthcare provider right away if your female partner becomes pregnant or thinks she may be pregnant during treatment with GOMEKLI. are breastfeeding or plan to breastfeed. It is not known if GOMEKLI passes into your breastmilk. Do not breastfeed during treatment with GOMEKLI and for 1 week after your last dose. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I take GOMEKLI? Take GOMEKLI exactly as your healthcare provider tells you to take it. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with GOMEKLI if you develop certain side effects. Take GOMEKLI twice a day, about 12 hours apart, for 21 days, followed by 7 days off treatment, to complete a 28- day treatment cycle. Your healthcare provider will decide how many treatment cycles are right for you. Take GOMEKLI with or without food. GOMEKLI comes in 2 different dosage forms, GOMEKLI capsules and GOMEKLI tablets for oral suspension. Your healthcare provider will decide the dosage form and dose of GOMEKLI that is right for you. If you take GOMEKLI capsules : Swallow each capsule whole with drinking water. If more than 1 capsule is required, swallow 1 capsule at a time. Do not open, break, or chew the capsules If you take GOMEKLI tablets for oral suspension , either : Swallow each tablet for oral suspension whole with drinking water. If more than 1 tablet is required, swallow 1 tablet at a time. OR Disperse the tablets for oral suspension in drinking water to make a liquid (suspension) before you take or give GOMEKLI. See the “Instructions for Use” that come with your medicine for instructions on how to prepare and take GOMEKLI tablets for oral suspension. If you miss a dose of GOMEKLI, skip the missed dose and take your next dose at your regularly scheduled time. If you vomit at any time after taking GOMEKLI, do not take an additional dose. Take your next dose at your regularly scheduled time. What are the possible side effects of GOMEKLI? GOMEKLI may cause serious side effects, including: eye problems. GOMEKLI may cause eye problems that can lead to blindness. Your healthcare provider will check your vision before and during treatment with GOMEKLI. Tell your healthcare provider right away if you get any of the following signs or symptoms of eye problems: blurred vision loss of vision other changes to your vision heart problems. GOMEKLI may lower the amount of blood pumped by your heart, which is common in children during treatment with GOMEKLI and can also be severe . Your healthcare provider will do tests before you start GOMEKLI treatment, every 3 months during your first year of treatment, and then as needed to make sure your heart is working properly. Tell your healthcare provider right away if you get any of the following signs or symptoms of heart problems: coughing or wheezing tiredness shortness of breath increased heart rate swelling of your ankles and feet skin problems. Skin rashes are common with GOMEKLI in both adults and children and can also be severe. GOMEKLI can also cause hair loss (alopecia). Tell your healthcare provider if you develop any of the following signs or symptoms of skin problems: flat skin rash skin redness raised bumps on the skin itchy rash skin bumps that look like acne peeling skin The most common side effects of GOMEKLI in adults include: diarrhea vomiting nausea tiredness muscle, joint, and bone pain The most common severe abnormal blood tests in adults include an increased enzyme called creatine phosphokinase (CPK). The most common side effects of GOMEKLI in children include: diarrhea headache muscle, joint, and bone pain skin redness, swelling, or pain around the fingernails or toenails stomach (abdominal) pain nausea vomiting The most common severe abnormal blood tests in children include decreased white blood cell (neutrophil) counts and increased CPK. GOMEKLI may cause fertility problems in females, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility. These are not all of the possible side effects of GOMEKLI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store GOMEKLI? Store GOMEKLI at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light. Keep GOMEKLI and all medicines out of the reach of children. General information about the safe and effective use of GOMEKLI. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use GOMEKLI for a condition for which it is not prescribed. Do not give GOMEKLI to other people even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about GOMEKLI that is written for health professionals. What are the ingredients in GOMEKLI? Active ingredient: mirdametinib Inactive ingredients: capsule contains: croscarmellose sodium, magnesium stearate and microcrystalline cellulose. The capsule shell contains: FD&C blue #1, gelatin, titanium dioxide, and yellow iron oxide. The printing ink contains: butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, strong ammonia solution, and titanium dioxide. tablet for oral suspension contains: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, grape flavor, and sucralose. The grape flavor includes corn syrup solids, modified corn starch, and triacetin. Manufactured for SpringWorks Therapeutics, Inc. Stamford, CT 06902 GOMEKLI TM is a trademark of SpringWorks Therapeutics, Inc. © 2025 SpringWorks Therapeutics, Inc. For more information call 1-888-400-7989 or visit www.GOMEKLI.com This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 02/2025" ], "spl_patient_package_insert_table": [ "
GOMEKLI™ (go-MEK-lee) (mirdametinib) capsulesPATIENT INFORMATIONGOMEKLI™ (go-MEK-lee) (mirdametinib) tablets for oral suspension
What is GOMEKLI? GOMEKLI is a prescription medicine used to treat adults and children 2 years of age and older with neurofibromatosis type 1 (NF1) who have plexiform neurofibromas that cause symptoms and cannot be completely removed by surgery. It is not known if GOMEKLI is safe and effective in children under 2 years of age.
Before taking GOMEKLI tell your healthcare provider about all of your medical conditions, including if you: have eye problems have heart problems are pregnant or plan to become pregnant. GOMEKLI can harm your unborn baby. Females who are able to become pregnant:Your healthcare provider should check to see if you are pregnant before you begin treatment with GOMEKLI. Use effective birth control (contraception) during treatment with GOMEKLI and for 6 weeks after your last dose. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with GOMEKLI. Males with female partners who are able to become pregnant: Use effective birth control (contraception) during treatment with GOMEKLI and for 3 months after your last dose. Tell your healthcare provider right away if your female partner becomes pregnant or thinks she may be pregnant during treatment with GOMEKLI. are breastfeeding or plan to breastfeed. It is not known if GOMEKLI passes into your breastmilk.Do not breastfeed during treatment with GOMEKLI and for 1 week after your last dose. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should I take GOMEKLI?Take GOMEKLI exactly as your healthcare provider tells you to take it. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with GOMEKLI if you develop certain side effects. Take GOMEKLI twice a day, about 12 hours apart, for 21 days, followed by 7 days off treatment, to complete a 28- day treatment cycle. Your healthcare provider will decide how many treatment cycles are right for you. Take GOMEKLI with or without food. GOMEKLI comes in 2 different dosage forms, GOMEKLI capsules and GOMEKLI tablets for oral suspension. Your healthcare provider will decide the dosage form and dose of GOMEKLI that is right for you. If you take GOMEKLI capsules:Swallow each capsule whole with drinking water. If more than 1 capsule is required, swallow 1 capsule at a time. Do not open, break, or chew the capsules If you take GOMEKLI tablets for oral suspension, either:Swallow each tablet for oral suspension whole with drinking water. If more than 1 tablet is required, swallow 1 tablet at a time. OR Disperse the tablets for oral suspension in drinking water to make a liquid (suspension) before you take or give GOMEKLI. See the “Instructions for Use” that come with your medicine for instructions on how to prepare and take GOMEKLI tablets for oral suspension. If you miss a dose of GOMEKLI, skip the missed dose and take your next dose at your regularly scheduled time. If you vomit at any time after taking GOMEKLI, do not take an additional dose. Take your next dose at your regularly scheduled time.
What are the possible side effects of GOMEKLI? GOMEKLI may cause serious side effects, including:eye problems. GOMEKLI may cause eye problems that can lead to blindness. Your healthcare provider will check your vision before and during treatment with GOMEKLI. Tell your healthcare provider right away if you get any of the following signs or symptoms of eye problems:
blurred visionloss of visionother changes to your vision
heart problems. GOMEKLI may lower the amount of blood pumped by your heart, which is common in children during treatment with GOMEKLI and can also be severe. Your healthcare provider will do tests before you start GOMEKLI treatment, every 3 months during your first year of treatment, and then as needed to make sure your heart is working properly. Tell your healthcare provider right away if you get any of the following signs or symptoms of heart problems:
coughing or wheezingtiredness
shortness of breathincreased heart rate
swelling of your ankles and feet
skin problems. Skin rashes are common with GOMEKLI in both adults and children and can also be severe. GOMEKLI can also cause hair loss (alopecia). Tell your healthcare provider if you develop any of the following signs or symptoms of skin problems:
flat skin rashskin redness
raised bumps on the skinitchy rash
skin bumps that look like acnepeeling skin
The most common side effects of GOMEKLI in adults include:
diarrheavomiting
nauseatiredness
muscle, joint, and bone pain
The most common severe abnormal blood tests in adults include an increased enzyme called creatine phosphokinase (CPK).
The most common side effects of GOMEKLI in children include:
diarrheaheadache
muscle, joint, and bone painskin redness, swelling, or pain around the fingernails or toenails
stomach (abdominal) painnausea
vomiting
The most common severe abnormal blood tests in children include decreased white blood cell (neutrophil) counts and increased CPK. GOMEKLI may cause fertility problems in females, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility. These are not all of the possible side effects of GOMEKLI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store GOMEKLI? Store GOMEKLI at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light.Keep GOMEKLI and all medicines out of the reach of children.
General information about the safe and effective use of GOMEKLI. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use GOMEKLI for a condition for which it is not prescribed. Do not give GOMEKLI to other people even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about GOMEKLI that is written for health professionals.
What are the ingredients in GOMEKLI? Active ingredient: mirdametinib Inactive ingredients: capsule contains: croscarmellose sodium, magnesium stearate and microcrystalline cellulose. The capsule shell contains: FD&C blue #1, gelatin, titanium dioxide, and yellow iron oxide. The printing ink contains: butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, strong ammonia solution, and titanium dioxide. tablet for oral suspension contains: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, grape flavor, and sucralose. The grape flavor includes corn syrup solids, modified corn starch, and triacetin. Manufactured for SpringWorks Therapeutics, Inc. Stamford, CT 06902 GOMEKLITM is a trademark of SpringWorks Therapeutics, Inc. ©2025 SpringWorks Therapeutics, Inc. For more information call 1-888-400-7989 or visit www.GOMEKLI.com
" ], "instructions_for_use": [ "INSTRUCTIONS FOR USE GOMEKLI™ (go-MEK-lee) (mirdametinib) tablets for oral suspension GOMEKLI tablets for oral suspension can be swallowed whole or prepared and taken as a liquid (oral suspension). This Instructions for Use contains information on how to prepare and take GOMEKLI tablets for oral suspension as an oral suspension. Important Information You Need to Know Before Taking GOMEKLI Tablets for Oral Suspension Read these Instructions for Use before you or your child start taking GOMEKLI tablets for oral suspension for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment. GOMEKLI tablets for oral suspension is for oral use only (taken by mouth). Take GOMEKLI tablets for oral suspension with or without food. Your healthcare provider will tell you how many GOMEKLI tablets for oral suspension you will need for your or your child’s dose. Always take GOMEKLI tablets for oral suspension exactly as your healthcare provider tells you. If you have any questions about how to prepare and take or give a dose of GOMEKLI tablets for oral suspension, talk to your healthcare provider or pharmacist. Supplies you will need to take or give GOMEKLI tablets for oral suspension To prepare and take or give GOMEKLI tablets for oral suspension, you will need: the prescribed number of GOMEKLI tablets for oral suspension a dosing cup provided by your healthcare provider or pharmacist if necessary, a 10 mL oral syringe provided by your healthcare provider or pharmacist about 10 mL to 20 mL of drinking water Preparing GOMEKLI tablets for oral suspension Step 1: Wash and dry your hands before preparing GOMEKLI tablets for oral suspension. Step 2: Add about 5 mL to 10 mL of drinking water to the dosing cup. Note: The amount of water does not need to be exact. Only use water to prepare the dose. Step 3: Count the prescribed number of tablets into your hand. Step 4: Add the prescribed number of tablets to the water. Step 5: Swirl the dosing cup gently to disperse the tablets until no lumps remain. It will take about 2 to 4 minutes to fully disperse the tablets in the water. GOMEKLI oral suspension will be white and cloudy and there will be some medicine (residue) visible. Try not to spill any of the prepared oral suspension. If you spill the oral suspension, see “ Section C. Cleaning up spilled GOMEKLI oral suspension .“ Important: Take or give GOMEKLI oral suspension right away after preparing the dose. If you cannot take or give it right way, take or give GOMEKLI oral suspension within 30 minutes of preparing the dose. Section A. Taking or giving GOMEKLI oral suspension by swallowing the oral suspension directly from the dosing cup. Note: To use an oral syringe to take or give GOMEKLI oral suspension, skip to Section B . Step A1: Take or give the GOMEKLI oral suspension from the dosing cup right away after preparing the dose . If more than 30 minutes have passed since you prepared the dose, throw away (dispose of) the GOMEKLI oral suspension and start over from Step 1 . See “ Section D. Disposing of GOMEKLI tablets for oral suspension .” If you are not sure how to throw away the GOMEKLI oral suspension, ask your healthcare provider or pharmacist. Important: After swallowing the oral suspension, there will be some medicine (residue) still inside the dosing cup. The residue may be hard to see. Follow Steps A2 through A4 to make sure that the full dose of GOMEKLI is taken or given. Step A2: Add another 5 mL to 10 mL of drinking water to the same dosing cup. Step A3: Swirl the dosing cup gently. Step A4: Drink or give the water and residue mixture from the dosing cup. Step A5 : Wash the dosing cup with clean water. Allow the dosing cup to dry completely before storing. Wash your hands when you are finished. Section B. Taking or giving GOMEKLI oral suspension from an oral syringe. Step B1: Place the tip (open end) of the oral syringe into the prepared medicine and draw up all the GOMEKLI oral suspension from the dosing cup into the oral syringe by pulling back on the plunger. Important: Take or give the GOMEKLI oral suspension from the oral syringe right away after preparing the dose . If more than 30 minutes have passed since you prepared the dose, throw away the GOMEKLI oral suspension and start over from Step 1 . See “ Section D. Disposing of GOMEKLI oral suspension or GOMEKLI tablets for oral suspension .” If you are not sure how to throw away the GOMEKLI oral suspension, ask your healthcare provider or pharmacist. Step B2 : Place the tip of the oral syringe inside the mouth pointing toward the inside of either cheek. If you are giving a dose of GOMEKLI oral suspension to a child, make sure they are sitting upright until all the liquid has been swallowed. Step B3: Slowly push the plunger all the way down to give the full dose of GOMEKLI. Allow time for all the medicine to be swallowed. Important : After swallowing the oral suspension, there will be some medicine (residue) still inside the dosing cup and oral syringe. The residue may be hard to see. Follow Steps B4 through B6 to make sure that the full dose of GOMEKLI is given. Step B4 : Add another 5 to 10 mL of drinking water to the same dosing cup. Step B5 : Swirl the dosing cup gently. Step B6 : Place the tip of the oral syringe into the dosing cup and draw the water and residue mixture into the oral syringe by pulling back on the plunger. Take or give all of the water and residue mixture to the child. Allow time for the water and residue mixture to be swallowed. Step B7 : Wash the dosing cup and oral syringe with clean water. Pull the plunger out of the oral syringe and wash the oral syringe parts separately. Allow the parts to dry completely before reassembling and storing. Wash your hands when you are finished. Section C. Cleaning up spilled GOMEKLI oral suspension If you accidentally spill any GOMEKLI oral suspension, soak up the spilled GOMEKLI oral suspension completely using an absorbent material, such as paper towels, and throw away (dispose of) in the trash. Wash your hands with soap and water. Section D. Disposing of GOMEKLI oral suspension or GOMEKLI tablets for oral suspension If it has been more than 30 minutes since you prepared your dose of GOMEKLI oral suspension or if you have any unused prepared oral suspension, throw away the prepared oral suspension in the trash. Throw away unused or expired GOMEKLI tablets for oral suspension in the trash. Section E. Storing GOMEKLI tablets for oral suspension Store GOMEKLI tablets for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light. Keep GOMEKLI tablets for oral suspension and all medicines out of the reach of children. Manufactured for SpringWorks Therapeutics, Inc. Stamford, CT 06902 GOMEKLI TM is a trademark of SpringWorks Therapeutics, Inc. © 2025 SpringWorks Therapeutics, Inc. For more information call 1-888-400-7989 or visit www.GOMEKLI.com This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 02/2025 STEP 2 step 3 step 4 step 5 2-4 min step a1 step a2 step a3 step a4 step a5 step b1 step b2 step b3 step b4 step b5 step b6 step b7" ], "instructions_for_use_table": [ "
INSTRUCTIONS FOR USE GOMEKLI™ (go-MEK-lee) (mirdametinib) tablets for oral suspension
GOMEKLI tablets for oral suspension can be swallowed whole or prepared and taken as a liquid (oral suspension).
This Instructions for Use contains information on how to prepare and take GOMEKLI tablets for oral suspension as an oral suspension.
Important Information You Need to Know Before Taking GOMEKLI Tablets for Oral SuspensionRead these Instructions for Use before you or your child start taking GOMEKLI tablets for oral suspension for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment. GOMEKLI tablets for oral suspension is for oral use only (taken by mouth). Take GOMEKLI tablets for oral suspension with or without food. Your healthcare provider will tell you how many GOMEKLI tablets for oral suspension you will need for your or your child’s dose. Always take GOMEKLI tablets for oral suspension exactly as your healthcare provider tells you. If you have any questions about how to prepare and take or give a dose of GOMEKLI tablets for oral suspension, talk to your healthcare provider or pharmacist.
Supplies you will need to take or give GOMEKLI tablets for oral suspension To prepare and take or give GOMEKLI tablets for oral suspension, you will need:the prescribed number of GOMEKLI tablets for oral suspension a dosing cup provided by your healthcare provider or pharmacist if necessary, a 10 mL oral syringe provided by your healthcare provider or pharmacist about 10 mL to 20 mL of drinking water
Preparing GOMEKLI tablets for oral suspension
Step 1: Wash and dry your hands before preparing GOMEKLI tablets for oral suspension.
Step 2: Add about 5 mL to 10 mL of drinking water to the dosing cup. Note: The amount of water does not need to be exact. Only use water to prepare the dose.
Step 3: Count the prescribed number of tablets into your hand.
Step 4: Add the prescribed number of tablets to the water.
Step 5: Swirl the dosing cup gently to disperse the tablets until no lumps remain. It will take about 2 to 4 minutes to fully disperse the tablets in the water. GOMEKLI oral suspension will be white and cloudy and there will be some medicine (residue) visible. Try not to spill any of the prepared oral suspension. If you spill the oral suspension, see “Section C. Cleaning up spilled GOMEKLI oral suspension.“ Important: Take or give GOMEKLI oral suspension right away after preparing the dose. If you cannot take or give it right way, take or give GOMEKLI oral suspension within 30 minutes of preparing the dose.
Section A. Taking or giving GOMEKLI oral suspension by swallowing the oral suspension directly from the dosing cup. Note: To use an oral syringe to take or give GOMEKLI oral suspension, skip to Section B.
Step A1: Take or give the GOMEKLI oral suspension from the dosing cup right away after preparing the dose. If more than 30 minutes have passed since you prepared the dose, throw away (dispose of) the GOMEKLI oral suspension and start over from Step 1. See “Section D. Disposing of GOMEKLI tablets for oral suspension.” If you are not sure how to throw away the GOMEKLI oral suspension, ask your healthcare provider or pharmacist. Important: After swallowing the oral suspension, there will be some medicine (residue) still inside the dosing cup. The residue may be hard to see. Follow Steps A2 through A4 to make sure that the full dose of GOMEKLI is taken or given.
Step A2: Add another 5 mL to 10 mL of drinking water to the same dosing cup.
Step A3: Swirl the dosing cup gently.
Step A4: Drink or give the water and residue mixture from the dosing cup.
Step A5: Wash the dosing cup with clean water. Allow the dosing cup to dry completely before storing. Wash your hands when you are finished.
Section B. Taking or giving GOMEKLI oral suspension from an oral syringe.
Step B1: Place the tip (open end) of the oral syringe into the prepared medicine and draw up all the GOMEKLI oral suspension from the dosing cup into the oral syringe by pulling back on the plunger. Important: Take or give the GOMEKLI oral suspension from the oral syringe right away after preparing the dose. If more than 30 minutes have passed since you prepared the dose, throw away the GOMEKLI oral suspension and start over from Step 1. See “Section D. Disposing of GOMEKLI oral suspension or GOMEKLI tablets for oral suspension.” If you are not sure how to throw away the GOMEKLI oral suspension, ask your healthcare provider or pharmacist.
Step B2: Place the tip of the oral syringe inside the mouth pointing toward the inside of either cheek. If you are giving a dose of GOMEKLI oral suspension to a child, make sure they are sitting upright until all the liquid has been swallowed.
Step B3: Slowly push the plunger all the way down to give the full dose of GOMEKLI. Allow time for all the medicine to be swallowed. Important: After swallowing the oral suspension, there will be some medicine (residue) still inside the dosing cup and oral syringe. The residue may be hard to see. Follow Steps B4 through B6 to make sure that the full dose of GOMEKLI is given.
Step B4: Add another 5 to 10 mL of drinking water to the same dosing cup.
Step B5: Swirl the dosing cup gently.
Step B6: Place the tip of the oral syringe into the dosing cup and draw the water and residue mixture into the oral syringe by pulling back on the plunger. Take or give all of the water and residue mixture to the child. Allow time for the water and residue mixture to be swallowed.
Step B7: Wash the dosing cup and oral syringe with clean water. Pull the plunger out of the oral syringe and wash the oral syringe parts separately. Allow the parts to dry completely before reassembling and storing. Wash your hands when you are finished.
Section C. Cleaning up spilled GOMEKLI oral suspension
If you accidentally spill any GOMEKLI oral suspension, soak up the spilled GOMEKLI oral suspension completely using an absorbent material, such as paper towels, and throw away (dispose of) in the trash. Wash your hands with soap and water.
Section D. Disposing of GOMEKLI oral suspension or GOMEKLI tablets for oral suspension
If it has been more than 30 minutes since you prepared your dose of GOMEKLI oral suspension or if you have any unused prepared oral suspension, throw away the prepared oral suspension in the trash. Throw away unused or expired GOMEKLI tablets for oral suspension in the trash.
Section E. Storing GOMEKLI tablets for oral suspension Store GOMEKLI tablets for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light.Keep GOMEKLI tablets for oral suspension and all medicines out of the reach of children.
Manufactured for SpringWorks Therapeutics, Inc. Stamford, CT 06902 GOMEKLITM is a trademark of SpringWorks Therapeutics, Inc. ©2025 SpringWorks Therapeutics, Inc. For more information call 1-888-400-7989 or visit www.GOMEKLI.com
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 1 mg Capsule Bottle Label - 82448-130-42 NDC 82448-130-42 42 Capsules Rx only GOMEKLI ® (mirdametinib) Capsules 1 mg per capsule PRINCIPAL DISPLAY PANEL - 1 mg Capsule Bottle Label - 82448-130-42", "PRINCIPAL DISPLAY PANEL - 1 mg Capsule Bottle Carton - 82448-130-42 NDC 82448-130-42 42 Capsules GOMEKLI ® (mirdametinib) Capsules 1 mg per capsule Rx only SpringWorks ® THERAPEUTICS PRINCIPAL DISPLAY PANEL - 1 mg Capsule Bottle Carton - 82448-130-42", "PRINCIPAL DISPLAY PANEL - 2 mg Capsule Bottle Label - 82448-260-42 NDC 82448-260-42 42 Capsules Rx only GOMEKLI ® (mirdametinib) Capsules 2 mg per capsule PRINCIPAL DISPLAY PANEL - 2 mg Capsule Bottle Label - 82448-260-42", "PRINCIPAL DISPLAY PANEL - 2 mg Capsule Bottle Carton - 82448-260-42 NDC 82448-260-42 42 Capsules GOMEKLI ® (mirdametinib) Capsules 2 mg per capsule Rx only SpringWorks ® THERAPEUTICS PRINCIPAL DISPLAY PANEL - 2 mg Capsule Bottle Carton - 82448-260-42", "PRINCIPAL DISPLAY PANEL - 2 mg Capsule Bottle Label - 82448-260-84 NDC 82448-260-84 84 Capsules Rx only GOMEKLI ® (mirdametinib) Capsules 2 mg per capsule PRINCIPAL DISPLAY PANEL - 2 mg Capsule Bottle Label - 82448-260-84", "PRINCIPAL DISPLAY PANEL - 2 mg Capsule Bottle Carton - 82448-260-84 NDC 82448-260-84 84 Capsules GOMEKLI ® (mirdametinib) Capsules 2 mg per capsule Rx only SpringWorks ® THERAPEUTICS PRINCIPAL DISPLAY PANEL - 2 mg Capsule Bottle Carton - 82448-260-84", "PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label - 82448-134-42 NDC 82448-134-42 42 Tablets Rx only GOMEKLI ® (mirdametinib) Tablets for Oral Suspension 1 mg per tablet PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label - 82448-134-42", "PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Carton - 82448-134-42 NDC 82448-134-42 42 Tablets GOMEKLI ® (mirdametinib) Tablets for Oral Suspension 1 mg per tablet Rx only SpringWorks ® THERAPEUTICS PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Carton - 82448-134-42", "PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label - 82448-134-84 NDC 82448-134-84 84 Tablets Rx only GOMEKLI ® (mirdametinib) Tablets for Oral Suspension 1 mg per tablet PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label - 82448-134-84", "PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Carton - 82448-134-84 NDC 82448-134-84 84 Tablets GOMEKLI ® (mirdametinib) Tablets for Oral Suspension 1 mg per tablet Rx only SpringWorks ® THERAPEUTICS PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Carton - 82448-134-84" ], "set_id": "4c41bf90-5fa7-4935-a95c-e047ea6bbf8e", "id": "849abb0f-1b19-4b4f-a3fe-113869a59653", "effective_time": "20260511", "version": "6", "openfda": { "application_number": [ "NDA219389", "NDA219379" ], "brand_name": [ "Gomekli" ], "generic_name": [ "MIRDAMETINIB" ], "manufacturer_name": [ "SpringWorks Therapeutics, Inc." ], "product_ndc": [ "82448-130", "82448-260", "82448-134" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "MIRDAMETINIB" ], "rxcui": [ "2705617", "2705623", "2705626", "2705628", "2705632", "2705635" ], "spl_id": [ "849abb0f-1b19-4b4f-a3fe-113869a59653" ], "spl_set_id": [ "4c41bf90-5fa7-4935-a95c-e047ea6bbf8e" ], "package_ndc": [ "82448-130-42", "82448-260-42", "82448-260-84", "82448-134-42", "82448-134-84" ], "is_original_packager": [ true ], "nui": [ "N0000175605", "N0000193943", "N0000193944" ], "pharm_class_epc": [ "Kinase Inhibitor [EPC]" ], "pharm_class_moa": [ "Mitogen-Activated Protein Kinase Kinase 1 Inhibitors [MoA]", "Mitogen-Activated Protein Kinase Kinase 2 Inhibitors [MoA]" ], "unii": [ "86K0J5AK6M" ] } }, { "spl_product_data_elements": [ "KOSELUGO SELUMETINIB SELUMETINIB SELUMETINIB VITAMIN E POLYETHYLENE GLYCOL SUCCINATE HYPROMELLOSE, UNSPECIFIED CARRAGEENAN POTASSIUM CHLORIDE TITANIUM DIOXIDE SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA WATER SEL;10 KOSELUGO SELUMETINIB SELUMETINIB SELUMETINIB VITAMIN E POLYETHYLENE GLYCOL SUCCINATE HYPROMELLOSE, UNSPECIFIED CARRAGEENAN POTASSIUM CHLORIDE FD&C BLUE NO. 2 FERRIC OXIDE YELLOW TITANIUM DIOXIDE FERRIC OXIDE RED CARNAUBA WAX SHELLAC 1,4-BUTANEDIOL MONOVINYL ETHER ALCOHOL WATER GLYCERYL OLEATE SEL;25 KOSELUGO SELUMETINIB SELUMETINIB SELUMETINIB GLYCERYL DIBEHENATE STEAROYL POLYOXYL-32 GLYCERIDES HYPROMELLOSE ACETATE SUCCINATE, UNSPECIFIED STEARIC ACID ACETONE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE FERRIC OXIDE YELLOW KOSELUGO SELUMETINIB SELUMETINIB SELUMETINIB GLYCERYL DIBEHENATE STEAROYL POLYOXYL-32 GLYCERIDES HYPROMELLOSE ACETATE SUCCINATE, UNSPECIFIED STEARIC ACID ACETONE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE FERRIC OXIDE RED" ], "recent_major_changes": [ "Indications and Usage ( 1 ) 11/2025 Dosage and Administration ( 2.1 ) 11/2025 Warnings and Precautions ( 5.2 ) 05/2026 Warnings and Precautions ( 5.4 , 5.5 , 5.7 ) 11/2025" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE KOSELUGO is indicated for the treatment of adult and pediatric patients 1 year of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) [see Dosage and Administration (2) ]. KOSELUGO is a kinase inhibitor indicated for the treatment of adult and pediatric patients 1 year of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION • KOSELUGO capsules: The recommended dosage is 25 mg/m 2 , swallowed whole, taken orally twice daily with or without food (see Table 1) . (2.1 , 2.2 ) • KOSELUGO oral granules: The recommended dosage is equivalent to 25 mg/m 2 , sprinkled onto or mixed with soft food and taken orally twice daily (see Table 2). ( 2.1 , 2.2 ) • Moderate hepatic impairment (Child-Pugh B): The recommended dosage is 20 mg/m 2 orally twice daily (see Tables 6 and 7) . ( 2.2 , 2.4 ) • Severe hepatic impairment (Child-Pugh C): The recommended dosage has not been established. ( 2.4 , 8.6 ) • Strong or Moderate CYP3A4 Inhibitors or Fluconazole: If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the dose of KOSELUGO (see Tables 8 and 9) . ( 2.5 ) 2.1 Recommended Dosage The recommended dosage of KOSELUGO capsules ( see Table 1 ) and KOSELUGO oral granules ( see Table 2 ) for adult and pediatric patients 1 year of age and older, based on body surface area, is 25 mg/m 2 orally twice daily, until disease progression or unacceptable toxicity [see Dosage and Administration (2.2)]. Table 1 Recommended Dosage: KOSELUGO Capsules Body Surface Area The recommended dosage of KOSELUGO capsules for patients with a BSA less than 0.55 m 2 has not been established. KOSELUGO Capsules 0.55 – 0.69 m 2 20 mg in the morning and 10 mg in the evening 0.70 – 0.89 m 2 20 mg twice daily 0.90 – 1.09 m 2 25 mg twice daily 1.10 – 1.29 m 2 30 mg twice daily 1.30 – 1.49 m 2 35 mg twice daily 1.50 – 1.69 m 2 40 mg twice daily 1.70 – 1.89 m 2 45 mg twice daily ≥ 1.90 m 2 50 mg twice daily Table 2 Recommended Dosage: KOSELUGO Oral Granules Body Surface Area The recommended dosage of KOSELUGO oral granules for patients with a BSA less than 0.40 m 2 has not been established. KOSELUGO Oral Granules 0.40 – 0.59 m 2 12.5 mg twice daily 0.60 – 0.69 m 2 15 mg twice daily 0.70 – 0.89 m 2 20 mg twice daily 0.90 – 1.09 m 2 25 mg twice daily 1.10 – 1.29 m 2 30 mg twice daily 1.30 – 1.49 m 2 35 mg twice daily 1.50 – 1.69 m 2 40 mg twice daily 1.70 – 1.89 m 2 45 mg twice daily ≥ 1.90 m 2 50 mg twice daily 2.2 Administration KOSELUGO is available in two dosage forms: KOSELUGO capsules and KOSELUGO oral granules. Prescribe KOSELUGO oral granules for patients who have difficulty swallowing whole capsules. KOSELUGO Capsules • Administer KOSELUGO capsules to patients who can swallow a whole capsule. • Swallow KOSELUGO capsules whole. Do not open, chew or crush KOSELUGO capsules. • KOSELUGO capsules may be administered with or without food. KOSELUGO Oral Granules Administer KOSELUGO oral granules to patients who have difficulty swallowing a whole capsule. Sprinkle KOSELUGO oral granules on or mix with a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry and consume within 30 minutes of preparation. If not consumed within 30 minutes of preparation, discard and prepare a new dose. If a dose has been partially consumed within 30 minutes of preparation, discard the remainder of the dose and do not prepare a new dose, aim to complete dosing within 30 minutes next time. The KOSELUGO oral granules should be free-flowing. Do NOT use if the oral granules are clumped or stuck inside the capsule shell. Instruct the patient or caregiver to contact their pharmacy if this happens. Discard the empty capsule shells after use. Do NOT swallow, chew, or dissolve the capsule shells of KOSELUGO oral granules. Do NOT chew or crush the KOSELUGO oral granules. Do NOT add oral granules to liquids. Do NOT mix KOSELUGO oral granules in grapefruit or any juice, fruit puree or jam containing Seville orange. Missed Dose If a dose of KOSELUGO capsules or KOSELUGO oral granules is missed, make up that dose unless the next dose is due within 6 hours. Vomiting If vomiting occurs after taking a dose of KOSELUGO capsules or KOSELUGO oral granules, do not take an additional dose. Take the next dose at the regular scheduled time. 2.3 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions for KOSELUGO capsules and KOSELUGO oral granules are provided in Tables 3 and 4, respectively. Table 3 Recommended Dose Reductions for KOSELUGO Capsules for Adverse Reactions Body Surface Area First Dose Reduction (mg/dose) Second Dose Reduction (mg/dose) Morning Evening Morning Evening 0.55 – 0.69 m 2 10 10 10 mg once daily 0.70 – 0.89 m 2 20 10 10 10 0.90 – 1.09 m 2 25 10 10 10 1.10 – 1.29 m 2 25 20 20 10 1.30 – 1.49 m 2 25 25 25 10 1.50 – 1.69 m 2 30 30 25 20 1.70 – 1.89 m 2 35 30 25 20 ≥ 1.90 m 2 35 35 25 25 Permanently discontinue KOSELUGO capsules in patients unable to tolerate two dose reductions. Table 4 Recommended Dose Reductions for KOSELUGO Oral Granules for Adverse Reactions Body Surface Area First Dose Reduction (mg/dose) Second Dose Reduction (mg/dose) Morning Evening Morning Evening 0.40 – 0.59 m 2 10 10 7.5 7.5 0.60 – 0.69 m 2 12.5 12.5 10 10 0.70 – 0.89 m 2 15 15 12.5 12.5 0.90 – 1.09 m 2 20 20 15 15 1.10 – 1.29 m 2 22.5 22.5 15 15 1.30 – 1.49 m 2 25 25 25 10 1.50 – 1.69 m 2 30 30 25 20 1.70 – 1.89 m 2 35 30 25 20 ≥ 1.90 m 2 35 35 25 25 Permanently discontinue KOSELUGO oral granules in patients unable to tolerate two dose reductions. The recommended dosage modifications of KOSELUGO capsules and KOSELUGO oral granules for adverse reactions are provided in Table 5. Table 5 Recommended Dosage Modifications for Adverse Reactions Severity of Adverse Reaction Recommended Dosage Modifications for KOSELUGO capsules and KOSELUGO oral granules Left Ventricular Dysfunction [see Warnings and Precautions (5.1) ] • Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normal Withhold until resolution. Resume at reduced dose. • Symptomatic decreased LVEF • Grade 3 or 4 decreased LVEF Permanently discontinue. Ocular Toxicity [see Warnings and Precautions (5.2) ] • Retinal Pigment Epithelial Detachment (RPED) Withhold until resolution. Resume at reduced dose. • Retinal vein occlusion (RVO) Permanently discontinue. Gastrointestinal Toxicity [see Warnings and Precautions (5.3) ] • Grade 3 Diarrhea Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days. • Grade 4 Diarrhea Permanently discontinue. • Grade 3 or 4 Colitis Permanently discontinue. Skin Toxicity [see Warnings and Precautions (5.4) ] • Grade 3 or 4 Withhold until improvement. Resume at reduced dose. Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5) ] • Grade 4 Increased CPK • Any Increased CPK and myalgia Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks. • Rhabdomyolysis Permanently discontinue. Other Adverse Reactions [see Adverse Reactions (6.1)] • Intolerable Grade 2 • Grade 3 Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose. • Grade 4 Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose. Consider discontinuation. * Per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. 2.4 Recommended Dosage in Patients with Hepatic Impairment Severe Hepatic Impairment The recommended dosage of KOSELUGO for use in patients with severe hepatic impairment (Child-Pugh C) has not been established [see Use in Specific Populations (8.6) ] . Moderate Hepatic Impairment The recommended dosage of KOSELUGO capsules (see Table 6) and KOSELUGO oral granules (see Table 7) for pediatric patients 1 year of age or older with moderate hepatic impairment (Child-Pugh B) is based on body surface area; 20 mg/m 2 orally twice daily, until disease progression or unacceptable toxicity [see Dosage and Administration (2.2) ]. Table 6 Recommended Dosage of KOSELUGO Capsules for Moderate Hepatic Impairment Body Surface Area Moderate Hepatic Impairment (Child-Pugh B) (mg/dose) Morning Evening 0.55 – 0.69 m 2 10 10 0.70 – 0.89 m 2 20 10 0.90 – 1.09 m 2 20 20 1.10 – 1.29 m 2 25 25 1.30 – 1.49 m 2 30 25 1.50 – 1.69 m 2 35 30 1.70 – 1.89 m 2 35 35 ≥ 1.90 m 2 40 40 Table 7 Recommended Dosage of KOSELUGO Oral Granules for Moderate Hepatic Impairment Body Surface Area Moderate Hepatic Impairment (Child‑Pugh B) (mg/dose) Morning Evening 0.40 – 0.59 m 2 10 10 0.60 – 0.69 m 2 12.5 12.5 0.70 – 0.89 m 2 15 15 0.90 – 1.09 m 2 20 20 1.10 – 1.29 m 2 25 25 1.30 – 1.49 m 2 30 25 1.50 – 1.69 m 2 35 30 1.70 – 1.89 m 2 35 35 ≥ 1.90 m 2 40 40 2.5 Dosage Modifications for Drug Interactions Strong or Moderate CYP3A4 Inhibitors or Fluconazole Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the KOSELUGO dosage as recommended in Table 8 (KOSELUGO capsules) and Table 9 (KOSELUGO oral granules). After discontinuation of the strong or moderate CYP3A4 inhibitor or fluconazole for 3-elimination half-lives, resume the KOSELUGO dose that was taken prior to initiating the inhibitor or fluconazole [see Drug Interactions (7.1) ] . Table 8 Recommended Dosage of KOSELUGO Capsules for Coadministration with Strong or Moderate CYP3A4 Inhibitors or Fluconazole Body Surface Area If the current dosage is 25 mg/m 2 twice daily, reduce to 20 mg/m 2 twice daily (mg/dose) If the current dosage is 20 mg/m 2 twice daily, reduce to 15 mg/m 2 twice daily (mg/dose) Morning Evening Morning Evening 0.55 – 0.69 m 2 10 10 10 mg once daily 0.70 – 0.89 m 2 20 10 10 10 0.90 – 1.09 m 2 20 20 20 10 1.10 – 1.29 m 2 25 25 25 10 1.30 – 1.49 m 2 30 25 25 20 1.50 – 1.69 m 2 35 30 25 25 1.70 – 1.89 m 2 35 35 30 25 ≥ 1.90 m 2 40 40 30 30 Table 9 Recommended Dosage of KOSELUGO Oral Granules for Coadministration with Strong or Moderate CYP3A4 Inhibitors or Fluconazole Body Surface Area If the current dosage is 25 mg/m 2 twice daily, reduce to 20 mg/m 2 twice daily (mg/dose) If the current dosage is 20 mg/m 2 twice daily, reduce to 15 mg/m 2 twice daily (mg/dose) Morning Evening Morning Evening 0.40 – 0.59 m 2 10 10 7.5 7.5 0.60 – 0.69 m 2 12.5 12.5 10 7.5 0.70 – 0.89 m 2 15 15 10 10 0.90 – 1.09 m 2 20 20 15 15 1.10 – 1.29 m 2 25 25 25 10 1.30 – 1.49 m 2 30 25 25 20 1.50 – 1.69 m 2 35 30 25 25 1.70 – 1.89 m 2 35 35 30 25 ≥ 1.90 m 2 40 40 30 30" ], "dosage_and_administration_table": [ "
Table 1 Recommended Dosage: KOSELUGO Capsules
Body Surface AreaThe recommended dosage of KOSELUGO capsules for patients with a BSA less than 0.55 m2 has not been established.KOSELUGO Capsules
0.55 – 0.69 m220 mg in the morning and 10 mg in the evening
0.70 – 0.89 m220 mg twice daily
0.90 – 1.09 m225 mg twice daily
1.10 – 1.29 m230 mg twice daily
1.30 – 1.49 m235 mg twice daily
1.50 – 1.69 m240 mg twice daily
1.70 – 1.89 m245 mg twice daily
≥ 1.90 m250 mg twice daily
", "
Table 2 Recommended Dosage: KOSELUGO Oral Granules
Body Surface AreaThe recommended dosage of KOSELUGO oral granules for patients with a BSA less than 0.40 m2 has not been established.KOSELUGO Oral Granules
0.40 – 0.59 m212.5 mg twice daily
0.60 – 0.69 m215 mg twice daily
0.70 – 0.89 m220 mg twice daily
0.90 – 1.09 m225 mg twice daily
1.10 – 1.29 m230 mg twice daily
1.30 – 1.49 m235 mg twice daily
1.50 – 1.69 m240 mg twice daily
1.70 – 1.89 m245 mg twice daily
≥ 1.90 m250 mg twice daily
", "
Table 3 Recommended Dose Reductions for KOSELUGO Capsules for Adverse Reactions
Body Surface AreaFirst Dose Reduction (mg/dose)Second Dose Reduction (mg/dose)
MorningEveningMorningEvening
0.55 – 0.69 m2101010 mg once daily
0.70 – 0.89 m220101010
0.90 – 1.09 m225101010
1.10 – 1.29 m225202010
1.30 – 1.49 m225252510
1.50 – 1.69 m230302520
1.70 – 1.89 m235302520
≥ 1.90 m235352525
Permanently discontinue KOSELUGO capsules in patients unable to tolerate two dose reductions.
", "
Table 4 Recommended Dose Reductions for KOSELUGO Oral Granules for Adverse Reactions
Body Surface AreaFirst Dose Reduction (mg/dose)Second Dose Reduction (mg/dose)
MorningEveningMorningEvening
0.40 – 0.59 m210107.57.5
0.60 – 0.69 m212.512.51010
0.70 – 0.89 m2151512.512.5
0.90 – 1.09 m220201515
1.10 – 1.29 m222.522.51515
1.30 – 1.49 m225252510
1.50 – 1.69 m230302520
1.70 – 1.89 m235302520
≥ 1.90 m235352525
Permanently discontinue KOSELUGO oral granules in patients unable to tolerate two dose reductions.
", "Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normalSymptomatic decreased LVEFGrade 3 or 4 decreased LVEFRetinal Pigment Epithelial Detachment (RPED) Retinal vein occlusion (RVO) Grade 3 DiarrheaGrade 4 DiarrheaGrade 3 or 4 ColitisGrade 3 or 4Grade 4 Increased CPKAny Increased CPK and myalgiaRhabdomyolysisIntolerable Grade 2 Grade 3Grade 4
Table 5 Recommended Dosage Modifications for Adverse Reactions
Severity of Adverse ReactionRecommended Dosage Modifications for KOSELUGO capsules and KOSELUGO oral granules
Left Ventricular Dysfunction [see Warnings and Precautions (5.1)]
•
Withhold until resolution. Resume at reduced dose.
••
Permanently discontinue.
Ocular Toxicity [see Warnings and Precautions (5.2)]
•
Withhold until resolution. Resume at reduced dose.
•
Permanently discontinue.
Gastrointestinal Toxicity [see Warnings and Precautions (5.3)]
•
Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days.
•
Permanently discontinue.
•
Permanently discontinue.
Skin Toxicity [see Warnings and Precautions (5.4)]
•
Withhold until improvement. Resume at reduced dose.
Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5)]
••
Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.
•
Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (6.1)]
••
Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose.
•
Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose. Consider discontinuation.
", "
Table 6 Recommended Dosage of KOSELUGO Capsules for Moderate Hepatic Impairment
Body Surface Area Moderate Hepatic Impairment (Child-Pugh B) (mg/dose)
MorningEvening
0.55 – 0.69 m21010
0.70 – 0.89 m22010
0.90 – 1.09 m22020
1.10 – 1.29 m22525
1.30 – 1.49 m23025
1.50 – 1.69 m23530
1.70 – 1.89 m23535
≥ 1.90 m24040
", "
Table 7 Recommended Dosage of KOSELUGO Oral Granules for Moderate Hepatic Impairment
Body Surface AreaModerate Hepatic Impairment (Child‑Pugh B) (mg/dose)
MorningEvening
0.40 – 0.59 m21010
0.60 – 0.69 m212.512.5
0.70 – 0.89 m21515
0.90 – 1.09 m22020
1.10 – 1.29 m22525
1.30 – 1.49 m23025
1.50 – 1.69 m23530
1.70 – 1.89 m23535
≥ 1.90 m24040
", "
Table 8 Recommended Dosage of KOSELUGO Capsules for Coadministration with Strong or Moderate CYP3A4 Inhibitors or Fluconazole
Body Surface AreaIf the current dosage is 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily (mg/dose)If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily (mg/dose)
MorningEveningMorningEvening
0.55 – 0.69 m2101010 mg once daily
0.70 – 0.89 m220101010
0.90 – 1.09 m220202010
1.10 – 1.29 m225252510
1.30 – 1.49 m230252520
1.50 – 1.69 m235302525
1.70 – 1.89 m235353025
≥ 1.90 m240403030
", "
Table 9 Recommended Dosage of KOSELUGO Oral Granules for Coadministration with Strong or Moderate CYP3A4 Inhibitors or Fluconazole
Body Surface AreaIf the current dosage is 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily (mg/dose)If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily (mg/dose)
MorningEveningMorningEvening
0.40 – 0.59 m210107.57.5
0.60 – 0.69 m212.512.5107.5
0.70 – 0.89 m215151010
0.90 – 1.09 m220201515
1.10 – 1.29 m225252510
1.30 – 1.49 m230252520
1.50 – 1.69 m235302525
1.70 – 1.89 m235353025
≥ 1.90 m240403030
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Capsules: • 10 mg selumetinib: white to off-white, opaque, hard capsule sealed with a clear band and marked with “SEL 10” in black ink. • 25 mg selumetinib: blue, opaque, hard capsule sealed with a clear band and marked with “SEL 25” in black ink. Oral Granules: • 5 mg selumetinib: off-white to light-yellow free-flowing oral granules contained within capsules. The capsules have a yellow cap and white body. The cap is printed with “sel 5” in black ink, and body is printed with a sprinkle capsule image indicating opening. • 7.5 mg selumetinib: off-white to light-yellow free-flowing oral granules contained within capsules. The capsules have a pink cap and white body. The cap is printed with “sel 7.5” in black ink, and body is printed with a sprinkle capsule image indicating opening. • Capsules: 10 mg and 25 mg of selumetinib. ( 3 ) • Oral Granules: 5 mg and 7.5 mg of selumetinib. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS • Left Ventricular Dysfunction : Assess ejection fraction prior to initiating treatment, every 3 months during the first year, then every 6 months thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. ( 2.3 , 5.1 ) • Ocular Toxicity : Conduct ophthalmic assessments prior to initiating KOSELUGO, at regular intervals during treatment and for new or worsening visual changes. Permanently discontinue KOSELUGO for retinal vein occlusion (RVO). Withhold KOSELUGO for retinal pigment epithelial detachment (RPED), monitor with optical coherence tomography assessments until resolution, and resume at reduced dose. ( 2.3 , 5.2 ) • Gastrointestinal Toxicity : Advise patients to start an anti-diarrheal agent immediately after the first episode of loose stool and to increase fluid intake. Withhold, reduce the dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. ( 2.3 , 5.3 ) • Skin Toxicity : Monitor for severe skin rashes. Withhold, reduce the dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. ( 2.3 , 5.4 ) • Increased Creatine Phosphokinase (CPK) : Increased CPK and rhabdomyolysis can occur. Obtain serum CPK prior to initiating KOSELUGO, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate for rhabdomyolysis or other causes. Withhold, reduce the dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. ( 2.3 , 5.5 ) • Increased Vitamin E Levels and Increased Risk of Bleeding (KOSELUGO Capsules) : KOSELUGO capsules contain vitamin E and daily intake of vitamin E that exceeds the recommended or safe limits may increase the risk of bleeding. An increased risk of bleeding may occur in patients co-administered vitamin-K antagonists or anti-platelet agents. KOSELUGO oral granules do not contain vitamin E. ( 5.6 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception ( 5.7 , 8.1 , 8.3 ). 5.1 Left Ventricular Dysfunction KOSELUGO can cause cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥ 10% below baseline. KOSELUGO has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 55% prior to treatment. Pediatric Patients In the NF1 PN pediatric safety pool (N = 134) [see Adverse Reactions (6.1) ], Grade 2 LVEF decrease [Grade 2 LVEF decrease (40% to 50%; 10 to 19% drop from baseline)], based on reported adverse reactions, occurred in 17% of evaluable patients. Decreased LVEF of ≥ 20% occurred in 0.7% of patients and resulted in dose interruption and dose reduction. Decreased LVEF resolved in 75% of these patients. The median time to first onset of maximum CTCAE grade LVEF decrease was approximately 12 months (median duration approximately 3 months). Adult Patients In the KOMET adult NF1 PN study (N = 71) [see Adverse Reactions (6.1) ], Grade 2 LVEF decrease [Grade 2 LVEF decrease (40% to 50%; 10 to 19% drop from baseline)], based on echocardiogram results, occurred in 14% of evaluable patients. Decreased LVEF resulted in dose interruption in 1.4% of patients. The median time to first onset of maximum CTCAE grade LVEF decrease was approximately 4 months (median duration approximately 4 months). 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 KOSELUGO based on severity of adverse reaction [see Dosage and Administration (2.3)]. In patients who interrupt KOSELUGO for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks until resolution. 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. 5.2 Ocular Toxicity KOSELUGOcan cause ocular toxicity, including retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), central serous retinopathy (CSR), and blurred vision. Pediatric Patients In the NF1 PN pediatric safety pool (N = 134) [see Adverse Reactions (6.1)], blurred vision, photophobia, cataracts, ocular hypertension, and retinal tear occurred in 13% of pediatric patients receiving KOSELUGO. Blurred vision resulted in dose interruption in 1.5% of patients. Ocular toxicity resolved in 72% of these patients. Grade 1 asymptomatic transient subretinal fluid was observed in 6% of patients, none required dose modification and of these 88% resolved. Grade 1 retinopathy occurred in 0.7% of patients, and all events resolved without dose modification. RPED occurred in the pediatric population during treatment with single agent KOSELUGO and resulted in permanent discontinuation. Adult Patients In the KOMET adult NF1 PN study (N = 71) [see Adverse Reactions (6.1)], blurred vision and vitreous floaters occurred in 6% of patients receiving KOSELUGO. Serious ocular toxicities including RVO and RPED, occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO as a single agent or in combination with other anti cancer agents. Postmarketing Experience In postmarketing experience [see Adverse Reactions (6.2)], cases of RPED/CSR occurred. Conduct comprehensive ophthalmic assessments prior to initiating KOSELUGO, at regular intervals during treatment, and for new or worsening visual changes. Permanently discontinue KOSELUGO in patients with RVO. Withhold KOSELUGO in patients with RPED, follow up with optical coherence tomography assessments every 3 weeks until resolution, and resume KOSELUGO at a reduced dose. For other ocular toxicities, withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of the adverse reaction [see Dosage and Administration (2.3) ]. 5.3 Gastrointestinal Toxicity KOSELUGO can cause gastrointestinal toxicities, including diarrhea and colitis. Pediatric Patients In the NF1 PN pediatric safety pool (N = 134) [see Adverse Reactions (6.1) ] , diarrhea occurred in 59% of patients who received KOSELUGO, including Grade 3 in 10% of patients. Diarrhea resulting in permanent discontinuation occurred in 0.7% of patients. Diarrhea resulting in dose interruption occurred in 10% of patients. The median time to first onset of maximum CTCAE grade diarrhea was approximately 2 months and the median duration was 5 days. Colitis occurred in an unapproved population of pediatric patients with multiple tumor types who received KOSELUGO as a single agent. Adult Patients In the KOMET adult NF1 PN study (N = 71) [see Adverse Reactions (6.1) ] , diarrhea occurred in 42% patients who received KOSELUGO. Diarrhea resulting in dose interruption occurred in 1.4% of patients. The median time to first onset of maximum CTCAE grade diarrhea was approximately1 month and the median duration was 7 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 KOSELUGO as a single agent or in combination with other anti-cancer agents. 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 KOSELUGO based on severity of adverse reaction [see Dosage and Administration (2.3) ]. 5.4 Skin Toxicity KOSELUGO can cause severe rashes, including dermatitis acneiform. Pediatric Patients In the NF1 PN pediatric safety pool (N = 134) [see Adverse Reactions (6.1) ] , rash occurred in 68% of patients who received KOSELUGO. The most frequent rashes included dermatitis acneiform (47%) and maculopapular rash (31%). Pruritus (30%), alopecia (26%), and eczema (24%) occurred in patients who received KOSELUGO. Grade 3 rash occurred in 5% of patients. Rash resulted in dose interruption in 8% of patients and dose reduction in 3.7% of patients. Adult Patients In the KOMET adult NF1 PN study (N = 71) [see Adverse Reactions (6.1) ], rash occurred in 85% of patients who received KOSELUGO. The most frequent rash included dermatitis acneiform (66%). Alopecia (18%) and pruritus (10%) occurred in patients who received KOSELUGO. Grade 3 rash occurred in 4.2% of patients. Rash resulted in dose interruption in 2.8% of patients, dose reduction in 2.8% of patients, and permanent discontinuation in 2.8% 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 KOSELUGO as a single agent or in combination with other anti-cancer agents. Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction [see Dosage and Administration (2.3) ]. 5.5 Increased Creatine Phosphokinase KOSELUGO can cause increased creatine phosphokinase (CPK), myalgia, and rhabdomyolysis. Pediatric Patients In the NF1 PN pediatric safety pool (N = 134) [see Adverse Reactions (6.1) ] , increased creatine phosphokinase (CPK), based on laboratory data, occurred in 73% of patients who received KOSELUGO, including Grade 3 or 4 in 8% of patients. Increased CPK resulted in dose interruption and dose reduction in 4% of patients. Increased CPK concurrent with myalgia occurred in 5% of patients, including one patient who permanently discontinued KOSELUGO for myalgia. Adults In the KOMET adult NF1 PN study (N = 71) [see Adverse Reactions (6.1 )] , increased creatine phosphokinase (CPK), based on laboratory data, occurred in 70% of patients who received KOSELUGO, including Grade 3 or 4 in 7% of patients. Increased CPK resulted in dose interruption and dose reduction in 4.2% and 2.8% of patients, respectively. Increased CPK concurrent with myalgia occurred in 1.4% of patients. Rhabdomyolysis occurred in an unapproved adult population who received KOSELUGO as a single agent. Obtain serum CPK prior to initiating KOSELUGO, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction [see Dosage and Administration (2.3) ] . 5.6 Increased Levels of Vitamin E and Increased Risk of Bleeding (KOSELUGO Capsules) KOSELUGO capsules can cause increased levels of vitamin E and increased risk of bleeding. KOSELUGO capsules contain vitamin E (10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS); while KOSELUGO 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 KOSELUGO and supplement) will exceed the recommended or safe limits. An increased risk of bleeding in patients may occur in patients who are co-administered vitamin K antagonists or anti-platelet antagonists with KOSELUGO capsules. 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. KOSELUGO oral granules do not contain vitamin E [see Drug Interactions (7.1) ]. 5.7 Embryo-Fetal Toxicity Based on findings from clinical trials, animal studies and its mechanism of action, KOSELUGO can cause fetal harm when administered to a pregnant woman. In KOMET, a first trimester spontaneous abortion was reported in a patient receiving KOSELUGO. 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/m 2 twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose [see Use in Specific Populations (8.1 , 8.3) ] ." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Left Ventricular Dysfunction [see Warnings and Precautions (5.1) ] • Ocular Toxicity [see Warnings and Precautions (5.2) ] • Gastrointestinal Toxicity [see Warnings and Precautions (5.3) ] • Skin Toxicity [see Warnings and Precautions (5.4) ] • Increased Creatine Phosphokinase [see Warnings and Precautions (5.5) ] Most common adverse reactions in pediatric patients (≥ 40%) are: vomiting, diarrhea, increased creatine phosphokinase, dry skin, paronychia, nausea, dermatitis acneiform, and pyrexia. ( 6.1 ) Most common adverse reactions in adult patients (≥ 40%) are rash (all), dermatitis acneiform, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 NF1 PN pediatric safety pool described in the WARNINGS AND PRECAUTIONS reflects exposure to KOSELUGO at the recommended dosage in 134 pediatric patients in SPRINKLE (N = 36) (NCT05309668), SPRINT Phase I (N = 24) (NCT01362803), SPRINT Phase II Stratum 1 (N = 50) [see Clinical Studies (14.1) ] , and Phase I Food Effect Study (N = 24) (NCT05101148). Among pediatric patients, the duration of KOSELUGO exposure was 12 months or longer (80%), more than 2 years (44%), or more than 3 years (37%). The most common adverse reactions in pediatric patients (≥ 40%) are vomiting, diarrhea, increased creatine phosphokinase, dry skin, paronychia, nausea, dermatitis acneiform, and pyrexia. In the KOMET adult NF1 PN study, 71 adult patients received KOSELUGO at the recommended dosage [see Clinical Studies (14.1) ] . Among adult patients, the duration of KOSELUGO exposure in the randomized period was 6 months or longer (92%), and 11 months or longer (66%). The most common adverse reactions in adult patients (≥ 40%) are rash (all), dermatitis acneiform, and diarrhea. Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN) Pediatrics 2-18 years of Age (SPRINT Phase II Stratum 1) The safety of KOSELUGO was evaluated in SPRINT Phase II Stratum 1 [see Clinical Studies (14.1) ] . Eligible patients were 2-18 years of age with neurofibromatosis type 1 (NF1) who had inoperable plexiform neurofibromas (PN) that was causing significant morbidity. Patients were excluded for abnormal LVEF, uncontrolled hypertension (blood pressure ≥ the 95th percentile for age, height, and sex), any current or past history of RVO or RPED, intraocular pressure > 21 mmHg (or upper limit of normal adjusted by age), uncontrolled glaucoma, and inability to swallow whole capsules. Patients received KOSELUGO 25 mg/m 2 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 KOSELUGO. Serious adverse reactions that occurred in 2 or more patients were anemia, hypoxia and diarrhea. Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received KOSELUGO. Adverse reactions resulting in permanent discontinuation of KOSELUGO 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 KOSELUGO, respectively. Adverse reactions requiring a dosage interruption or reduction in ≥ 5% 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%) were vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus. Table 10 presents the adverse reactions in SPRINT Phase II Stratum 1. Table 10 Adverse Reactions (≥ 20%) in Patients Who Received KOSELUGO in SPRINT Phase II Stratum 1 Adverse Reaction KOSELUGO (N = 50) All Grades (%) Grade ≥ 3 (%) * Gastrointestinal Vomiting 82 6 Abdominal pain Abdominal pain includes abdominal pain; abdominal pain upper 76 0 Diarrhea 70 16 Nausea 66 2 Stomatitis Stomatitis includes stomatitis; mouth ulceration 50 0 Constipation 34 0 Skin and Subcutaneous Tissue Rash (all) Rash (all) includes dermatitis acneiform; rash maculo-papular; erythema; rash pustular; rash; urticaria; exfoliative rash; rash pruritic; rash erythematous 80 6 Dry skin 60 0 Rash acneiform Rash (acneiform) includes dermatitis acneiform 50 4 Paronychia Paronychia includes paronychia; nail infection 48 6 Pruritus 46 0 Dermatitis Dermatitis includes dermatitis; dermatitis atopic; dermatitis diaper; eczema; seborrheic dermatitis; skin irritation 36 4 Hair changes Hair changes include alopecia; hair color change 32 0 Musculoskeletal and Connective Tissue Musculoskeletal pain Musculoskeletal pain includes pain in extremity; back pain; neck pain; musculoskeletal pain 58 0 General Fatigue Fatigue includes fatigue; malaise 56 0 Pyrexia 56 8 Edema Edema includes peripheral swelling; edema; localized edema 20 0 Nervous System Headache 48 2 Respiratory, Thoracic and Mediastinal Epistaxis 28 0 Renal and Urinary System Hematuria 22 2 Proteinuria 22 0 Metabolism and Nutrition Decreased appetite 22 0 Cardiac System Decreased ejection fraction 22 0 Sinus tachycardia 20 0 Infections Skin infection Skin infection includes skin infection; abscess; cellulitis; impetigo; staphylococcal skin infection 20 2 * All events were Grade 3. Clinically relevant adverse reactions that occurred < 20% of patients include: • Eye: visual impairment and subretinal fluid. • Gastrointestinal Disorders: dry mouth. • General Disorders: facial edema, including periorbital edema and face edema. • Metabolism and Nutrition: increased weight. • Renal and Urinary System: acute kidney injury. • Respiratory, Thoracic & Mediastinal: dyspnea, including exertional dyspnea and dyspnea at rest. • Vascular: hypertension. Table 11 presents the laboratory abnormalities in SPRINT Phase II Stratum 1. Table 11 Select Laboratory Abnormalities (≥ 15%) Worsening from Baseline in Patients Who Received KOSELUGO in SPRINT Phase II Stratum 1 Laboratory Abnormality KOSELUGO All Grades (%) The denominator used to calculate the rate varied from 39 to 49 based on the number of patients with a baseline value and at least one post-treatment value. Grade ≥ 3 (%) Chemistry Increased creatine phosphokinase (CPK) 79 7 Includes one Grade 4 increased CPK and one Grade 4 increased potassium. Decreased albumin 51 0 Increased aspartate aminotransferase (AST) 41 2 Increased alanine aminotransferase (ALT) 35 4 Increased lipase 32 5 Increased potassium 27 4 Decreased potassium 18 2 § Increased alkaline phosphatase 18 0 Increased amylase 18 0 Increased sodium 18 0 Decreased sodium 16 0 Hematology Decreased hemoglobin 41 4 Decreased neutrophils 33 4 Decreased lymphocytes 20 2 Adults ≥ 18 years of Age (KOMET) The safety of KOSELUGO was evaluated in KOMET [see Clinical Studies (14.1) ] . Eligible patients were 18 years of age or older with NF1 who had symptomatic, inoperable PN. Patients were excluded for abnormal LVEF, uncontrolled hypertension, any current or past history of RVO or RPED/CSR, intraocular pressure > 21 mmHg (or upper limit of normal adjusted by age), uncontrolled glaucoma, and inability to swallow whole capsules. Among the patients (N = 137) who have received KOSELUGO, the median duration of KOSELUGO treatment was 11 months with a range of 10 days to 31 months. Serious adverse reactions occurred in 14% of patients who received KOSELUGO. Serious adverse reactions occurring in more than one patient included cellulitis (2.8%). Permanent discontinuation due to an adverse reaction occurred in 13% of patients who received KOSELUGO. Adverse reactions resulting in permanent discontinuation of KOSELUGO included dermatitis acneiform, cellulitis, nausea, wound, neurofibrosarcoma, neurofibrosarcoma recurrent, psychiatric decompensation, ulcerative keratitis, and nail disorder. Dosage interruptions and dose reductions due to adverse reactions occurred in 27% and 14% of patients who received KOSELUGO, respectively. Adverse reactions requiring a dosage reduction in 2 or more patients were paronychia, increased CPK, increased ALT, increased AST, rash, and alopecia. Adverse reactions requiring a dosage interruption in 2 or more patients were increased CPK, rash, headache, abdominal pain, nausea, and COVID‑19. The most common adverse reactions (≥ 40%) were rash (all), rash (acneiform), and diarrhea. Table 12 presents the adverse reactions in the KOMET study. The 12 cycle (48 weeks) randomization period for KOSELUGO versus placebo was followed by a single arm treatment period where all patients received KOSELUGO (placebo patients crossed over to KOSELUGO at end of the randomized period). No new adverse reactions were identified during the open-label period. Table 12 Adverse Reactions (≥ 20%) in Patients Who Received KOSELUGO Compared with Placebo in KOMET Adverse Reactions Randomized to KOSELUGO * (N = 71) Randomized to Placebo * (N = 74) All Grades (%) Grades ≥ 3 (%) All Grades (%) Grades ≥ 3 (%) Skin and Subcutaneous Tissue Rash (all) Rash (all): acne, dermatitis, dermatitis acneiform, erythema, exfoliative rash, rash, rash erythematous, rash follicular, rash maculo-papular, rash pruritic, rash pustular, urticaria, rash macular, and rash papular. 85 4.2 23 0 Rash acneiform Rash acneiform: acne and dermatitis acneiform 66 2.8 11 0 Musculoskeletal and Connective Tissue Musculoskeletal pain Musculoskeletal pain: arthralgia, back pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, and pain in extremity. 23 0 22 0 Gastrointestinal Diarrhea 42 0 12 0 Vomiting 25 0 8 0 Nausea 25 0 16 0 General Edema Edema: localized edema, edema, edema peripheral, and peripheral swelling. 21 0 1.4 0 Fatigue Fatigue: asthenia and fatigue. 24 0 14 0 * ADRs of patients during the 12 Cycle (48 weeks) randomization period. Clinically relevant adverse reactions in < 20% of patients who received KOSELUGO versus placebo based on reported adverse reactions included hair changes (18% vs 11%), paronychia (13% vs 4%), pyrexia (7% vs 4%), stomatitis (18% vs 5%), and skin infection (6% vs 1%), respectively. Decreased ejection fraction in patients who received KOSELUGO versus placebo based on reported echocardiogram results occurred in 14% and 11% of patients, respectively. Table 13 presents the laboratory abnormalities in the KOMET study. Table 13 Select Laboratory Abnormalities (≥ 15%) That Worsened from Baseline in Patients Who Received KOSELUGO with a Difference Between Arms of > 10% Compared to Placebo in KOMET Laboratory Abnormalities Randomized to KOSELUGO * (N = 71) Randomized to Placebo * (N = 74) All Grades (%) Grades ≥ 3 (%) All Grades (%) Grades ≥ 3 (%) Chemistry Increase creatine phosphokinase 70 7 15 1.4 Increased aspartate aminotransferase (AST) 48 2.9 12 0 Increased alanine aminotransferase (ALT) 39 4.3 14 0 Decreased albumin 24 1.4 6 0 Increased alkaline phosphatase 17 1.4 7 0 Increased amylase 17 1.4 5 0 Decreased magnesium 16 0 5 0 Hematology Decreased hemoglobin 24 0 14 0 * Lab abnormalities of patients during the 12 Cycle (48 weeks) randomization period. Pediatrics > 1 year of Age on KOSELUGO Granules (SPRINKLE) The safety of KOSELUGO oral granules was evaluated in SPRINKLE (NCT05309668), a dose-finding and activity estimating, single-arm, multicenter study in 36 pediatric patients ages 1 year to less than 7 years with a clinical diagnosis of NF1- related symptomatic, inoperable PN. The study evaluated the pharmacokinetics (PK), safety, efficacy, and tolerability of KOSELUGO oral granules. Study patients were to receive KOSELUGO oral granules for 25 cycles at a dose equivalent to 25 mg/m 2 BSA twice daily until disease progression or unacceptable toxicity. The median age was approximately 4 years (range: 1 to 7 years), 61% were male, 61% were White, 14% were Asian and 3% were Black or African American. In the SPRINKLE study, the median duration of KOSELUGO oral granules treatment in pediatric patients with neurofibromatosis type 1 (NF1) plexiform neurofibromas (PN) was 11 months (range: 3-25 months). Serious adverse reactions occurred in 6% of patients who received KOSELUGO oral granules. Serious adverse reactions occurred in 1 patient each and included pyrexia, gastroenteritis and upper respiratory infection. A total of 31% of patients had an adverse reaction leading to a dosage interruption. Adverse reactions requiring a dosage interruption in ≥ 5% of patients were pyrexia, vomiting, diarrhea, upper respiratory infection, gastroenteritis and eczema. The most common adverse reactions (≥ 40%) were pyrexia, dry skin, and paronychia. The observed safety profile of KOSELUGO oral granules in the SPRINKLE study was consistent with the known safety profile of KOSELUGO capsules. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of KOSELUGO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Eye disorders: RPED/CSR including detachment of retinal pigment epithelium, central serous chorioretinopathy, serous retinal detachment, serous retinopathy, and retinal detachment [see Warnings and Precautions (5.2) ] ." ], "adverse_reactions_table": [ "
Table 10 Adverse Reactions (≥ 20%) in Patients Who Received KOSELUGO in SPRINT Phase II Stratum 1
Adverse ReactionKOSELUGO (N = 50)
All Grades(%)Grade ≥ 3 (%)*
Gastrointestinal
Vomiting826
Abdominal painAbdominal pain includes abdominal pain; abdominal pain upper760
Diarrhea7016
Nausea662
StomatitisStomatitis includes stomatitis; mouth ulceration500
Constipation340
Skin and Subcutaneous Tissue
Rash (all)Rash (all) includes dermatitis acneiform; rash maculo-papular; erythema; rash pustular; rash; urticaria; exfoliative rash; rash pruritic; rash erythematous806
Dry skin600
Rash acneiformRash (acneiform) includes dermatitis acneiform504
ParonychiaParonychia includes paronychia; nail infection486
Pruritus460
DermatitisDermatitis includes dermatitis; dermatitis atopic; dermatitis diaper; eczema; seborrheic dermatitis; skin irritation364
Hair changesHair changes include alopecia; hair color change320
Musculoskeletal and Connective Tissue
Musculoskeletal painMusculoskeletal pain includes pain in extremity; back pain; neck pain; musculoskeletal pain580
General
FatigueFatigue includes fatigue; malaise560
Pyrexia568
EdemaEdema includes peripheral swelling; edema; localized edema200
Nervous System
Headache482
Respiratory, Thoracic and Mediastinal
Epistaxis280
Renal and Urinary System
Hematuria222
Proteinuria220
Metabolism and Nutrition
Decreased appetite220
Cardiac System
Decreased ejection fraction 220
Sinus tachycardia200
Infections
Skin infectionSkin infection includes skin infection; abscess; cellulitis; impetigo; staphylococcal skin infection202
* All events were Grade 3.
", "
Table 11 Select Laboratory Abnormalities (≥ 15%) Worsening from Baseline in Patients Who Received KOSELUGO in SPRINT Phase II Stratum 1
Laboratory AbnormalityKOSELUGO
All Grades (%)The denominator used to calculate the rate varied from 39 to 49 based on the number of patients with a baseline value and at least one post-treatment value.Grade ≥ 3 (%)
Chemistry
Increased creatine phosphokinase (CPK)797Includes one Grade 4 increased CPK and one Grade 4 increased potassium.
Decreased albumin510
Increased aspartate aminotransferase (AST)412
Increased alanine aminotransferase (ALT)354
Increased lipase325
Increased potassium274
Decreased potassium182§
Increased alkaline phosphatase180
Increased amylase180
Increased sodium180
Decreased sodium160
Hematology
Decreased hemoglobin414
Decreased neutrophils334
Decreased lymphocytes202
", "Skin and Subcutaneous TissueRash (all)Rash (all): acne, dermatitis, dermatitis acneiform, erythema, exfoliative rash, rash, rash erythematous, rash follicular, rash maculo-papular, rash pruritic, rash pustular, urticaria, rash macular, and rash papular.Rash acneiformRash acneiform: acne and dermatitis acneiformMusculoskeletal and Connective TissueMusculoskeletal painMusculoskeletal pain: arthralgia, back pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, and pain in extremity.GastrointestinalDiarrheaVomitingNauseaGeneralEdemaEdema: localized edema, edema, edema peripheral, and peripheral swelling.FatigueFatigue: asthenia and fatigue.
Table 12 Adverse Reactions (≥ 20%) in Patients Who Received KOSELUGO Compared with Placebo in KOMET
Adverse Reactions Randomized to KOSELUGO* (N = 71)Randomized to Placebo* (N = 74)
All Grades (%) Grades ≥ 3 (%) All Grades (%) Grades ≥ 3 (%)
854.2230
662.8110
230220
420120
25080
250160
2101.40
240140
* ADRs of patients during the 12 Cycle (48 weeks) randomization period.
", "Laboratory AbnormalitiesChemistryHematology
Table 13 Select Laboratory Abnormalities (≥ 15%) That Worsened from Baseline in Patients Who Received KOSELUGO with a Difference Between Arms of > 10% Compared to Placebo in KOMET
Randomized toKOSELUGO*(N = 71)Randomized toPlacebo*(N = 74)
All Grades (%) Grades ≥ 3 (%) All Grades (%) Grades ≥ 3 (%)
Increase creatine phosphokinase707151.4
Increased aspartate aminotransferase (AST)482.9120
Increased alanine aminotransferase (ALT)394.3140
Decreased albumin241.460
Increased alkaline phosphatase171.470
Increased amylase171.450
Decreased magnesium16050
Decreased hemoglobin240140
* Lab abnormalities of patients during the 12 Cycle (48 weeks) randomization period.
" ], "drug_interactions": [ "7 DRUG INTERACTIONS • Strong or Moderate CYP3A4 Inhibitors or Fluconazole : Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration cannot be avoided, reduce the dose of KOSELUGO. ( 2.5 , 7.1 ) • Strong or Moderate CYP3A4 Inducers : Avoid concomitant use of strong and moderate CYP3A4 inducers. ( 7.1 ) 7.1 Effect of Other Drugs on KOSELUGO Strong or Moderate CYP3A4 Inhibitors or Fluconazole Management • Avoid concomitant use of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce KOSELUGO dosage [see Dosage Modifications for Drug Interactions (2.5) ]. Clinical Impact • Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inhibitor or fluconazole increased selumetinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions. Strong or Moderate CYP3A4 Inducers Management • Avoid concomitant use of strong or moderate CYP3A4 inducers with KOSELUGO. Clinical Impact • Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may reduce KOSELUGO efficacy. Vitamin E Management • Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in KOSELUGO capsules and supplement) will exceed the recommended or safe limits. • Monitor for bleeding in patients administered a vitamin‑K antagonist or an anti‑platelet agent with KOSELUGO capsules. Increase INR monitoring, as appropriate, in patients taking a vitamin‑K antagonist [see Warnings and Precautions (5.3) ] . Clinical Impact • KOSELUGO capsules contain vitamin E and daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. An increased risk of bleeding may occur in patients taking a vitamin‑K antagonist or an anti‑platelet agent with KOSELUGO capsules." ], "drug_interactions_table": [ "Avoid concomitant use of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce KOSELUGO dosage [see Dosage Modifications for Drug Interactions (2.5)].Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inhibitor or fluconazole increased selumetinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions.Avoid concomitant use of strong or moderate CYP3A4 inducers with KOSELUGO.Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce KOSELUGO efficacy.Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in KOSELUGO capsules and supplement) will exceed the recommended or safe limits.Monitor for bleeding in patients administered a vitamin‑K antagonist or an anti‑platelet agent with KOSELUGO capsules. Increase INR monitoring, as appropriate, in patients taking a vitamin‑K antagonist [see Warnings and Precautions (5.3)].KOSELUGO capsules contain vitamin E and daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. An increased risk of bleeding may occur in patients taking a vitamin‑K antagonist or an anti‑platelet agent with KOSELUGO capsules.
Strong or Moderate CYP3A4 Inhibitors or Fluconazole
Management
•
Clinical Impact
•
Strong or Moderate CYP3A4 Inducers
Management
•
Clinical Impact
•
Vitamin E
Management
••
Clinical Impact
•
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , KOSELUGO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KOSELUGO 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/m 2 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 Human Data In KOMET, a first trimester spontaneous abortion was reported in a patient receiving KOSELUGO. 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/m 2 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 (e.g., 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 ~0.6 times the human C max at the clinical dose of 25 mg/m 2 twice daily). 8.2 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 KOSELUGO 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 [see Use in Specific Populations (8.1) ]. 8.3 Females and Males of Reproductive Potential KOSELUGO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating KOSELUGO [see Use in Specific Populations (8.1) ] . 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 KOSELUGO and for 1 week after the last dose. 8.4 Pediatric Use The safety and effectiveness have been established in pediatric patients 1 year 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 KOSELUGO have not been established in pediatric patients younger than 1 year of age. Animal Toxicity Data 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/m 2 twice daily) showed growth plate dysplasia. 8.5 Geriatric Use Clinical studies of KOSELUGO did not include a sufficient number of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment Selumetinib exposures increased in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) ] . Reduce the dose of KOSELUGO for patients with moderate hepatic impairment (Child-Pugh B). A recommended dosage of KOSELUGO for use in patients with severe hepatic impairment (Child-Pugh C) has not been established [see Dosage and Administration (2.4) ]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , KOSELUGO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KOSELUGO 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/m 2 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 Human Data In KOMET, a first trimester spontaneous abortion was reported in a patient receiving KOSELUGO. 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/m 2 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 (e.g., 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 ~0.6 times the human C max at the clinical dose of 25 mg/m 2 twice daily)." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness have been established in pediatric patients 1 year 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 KOSELUGO have not been established in pediatric patients younger than 1 year of age. Animal Toxicity Data 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/m 2 twice daily) showed growth plate dysplasia." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of KOSELUGO did not include a sufficient number of patients aged 65 and over to determine whether they respond differently from younger patients." ], "overdosage": [ "10 OVERDOSAGE Dialysis is not effective as KOSELUGO is highly protein bound and is extensively metabolized." ], "description": [ "11 DESCRIPTION KOSELUGO contains selumetinib sulfate, a kinase inhibitor. The chemical name is 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-[(2-hydroxyethoxy)carbamoyl]-1-methyl-1 H -benzimidazol-3-ium hydrogen sulfate. The molecular formula for selumetinib sulfate is C 17 H 17 BrClFN 4 O 7 S and the relative molecular mass is 555.76 g/mol. Selumetinib sulfate has the following structural formula: Selumetinib sulfate is a white to yellow monomorphic crystalline powder that exhibits a pH dependent solubility. Selumetinib sulfate is freely soluble at pH < 1.5, sparingly soluble in the pH range at 1.5 to 3 and slightly soluble at pH > 3. Selumetinib sulfate has two ionizable functions with pKa values of 2.8 and 8.4. KOSELUGO (selumetinib) 10 mg capsules for oral use, contain 10 mg selumetinib (equivalent to 12.1 mg selumetinib sulfate) and the excipient, vitamin E polyethylene glycol succinate. The capsule shell contains carnauba wax, carrageenan, hypromellose, potassium chloride, purified water, and titanium dioxide. The capsule is imprinted with black ink that contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. KOSELUGO (selumetinib) 25 mg capsules for oral use, contain 25 mg selumetinib (equivalent to 30.25 mg selumetinib sulfate) and the excipient, vitamin E polyethylene glycol succinate. The capsule shell contains carnauba wax and/or cornstarch, carrageenan, FD&C blue 2, ferric oxide yellow, hypromellose, potassium chloride, purified water, and titanium dioxide. The capsule is imprinted with black ink that contains carnauba wax, FD&C Blue 2 aluminum lake, ferric oxide red, ferric oxide yellow, glyceryl monooleate, and shellac. KOSELUGO (selumetinib) 5 mg oral granules contain 5 mg selumetinib (equivalent to 6.05 mg selumetinib sulfate). The uncoated cores contain selumetinib sulfate, glyceryl dibehenate, and stearoyl polyoxylglycerides. The granule coating contains acetone, hypromellose acetate succinate, and stearic acid. The capsule shell contains ferric oxide yellow, hypromellose, and titanium dioxide. The capsule shell is imprinted with black ink that contains butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution. KOSELUGO (selumetinib) 7.5 mg oral granules contain 7.5 mg selumetinib (equivalent to 9.08 mg selumetinib sulfate). The uncoated cores contain selumetinib sulfate, glyceryl dibehenate, and stearoyl polyoxylglycerides. The granule coating contains acetone, hypromellose acetate succinate, and stearic acid. The capsule shell contains ferric oxide red, hypromellose, and titanium dioxide. The capsule shell is imprinted with black ink that contains butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution. structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 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 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. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KOSELUGO have not been fully characterized. Cardiac Electrophysiology At a dose 1.5-times the maximum recommended dose, clinically significant QTc interval prolongation was not observed. 12.3 Pharmacokinetics Selumetinib pharmacokinetics were observed at steady state in adult and pediatric patients with NF1 and are presented as mean (CV%) unless otherwise indicated. The maximum plasma concentration (C max ) is 792 (49) ng/mL and systemic exposure (AUC) is 2141 (55) ng•h/mL following KOSELUGO 25 mg/m 2 twice daily. Selumetinib AUC and C max increases in a dose proportional manner over a dose range from 20 mg/m 2 to 30 mg/m 2 (0.8 to 1.2 times the recommended dose). Selumetinib accumulation range is 1.2-1.5 fold following administration of KOSELUGO at 25 mg/m 2 . At the recommended dosage of 25 mg/m 2 of KOSELUGO oral granules (sprinkled on smooth yogurt, smooth fruit sauce, smooth fruit puree, or smooth fruit jam) twice daily in pediatric patients (> 1 year old to < 7 years old), the AUC 0-24h following the first dose of KOSELUGO oral granules was within the range of that in patients administered KOSELUGO capsules. No clinically relevant differences in the pharmacokinetics of selumetinib were observed following administration of a single-dose of either the granule or capsule dosage forms of KOSELUGO at equivalent dosages, under fasted and fed conditions, in healthy adults. Absorption Selumetinib absolute oral bioavailability is 62%. Selumetinib median (min, max) time to maximum plasma concentrations (Tmax) is 1.5 (0.22, 6.0) hours. Effect of Food No clinically significant differences in selumetinib pharmacokinetics were observed following administration of low fat (400-500 calories) or high-fat (800-1000 calories) meal. Distribution Selumetinib apparent volume of distribution across a dose range of 20 mg/m 2 to 30 mg/m 2 (0.8 to 1.2 times the recommended dosage) ranges from 40 L-3710 L (66). The plasma protein binding is 98.4% (primarily albumin). Elimination Selumetinib elimination half-life is 9 (28) hours with an apparent (oral) clearance of 16 (44) L/hr/m 2 . 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 can be attributed to CYP metabolism and about 29% to direct glucuronidation by UGT enzymes. The active metabolite, N desmethyl selumetinib, is generated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6, and it is metabolized through the same routes as selumetinib. N-desmethyl selumetinib represents < 10% of selumetinib levels in human plasma, but is approximately 3- to 5- 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 (< 1% as parent). Specific Populations No clinically significant differences in the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed based on age (1-79 years) race [White (56%), Asian (22%), Black (19%)]. Pediatric Patients No clinically significant differences in the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed between the pediatric (aged 1 to < 17 years) and adult patients. Patients with Renal Impairment No clinically significant differences in selumetinib exposures were observed in patients with end stage renal disease (CLcr < 15 mL/min) who required dialysis. CLcr was estimated using the Cockroft-Gault formula. Patients with Hepatic Impairment Dose normalized total AUC increased by 1.6-fold in patients with moderate hepatic impairment (Child-Pugh B) and in patients with severe hepatic impairment (Child-Pugh class C). Selumetinib unbound AUC increased by 1.4-fold in patients with moderate hepatic impairment (Child-Pugh B), and 3.2-fold in patients with severe hepatic impairment (Child-Pugh C). Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong or Moderate CYP3A4 Inhibitors: Selumetinib AUC increased by 1.5-fold and C max by 1.2-fold following concomitant administration of itraconazole (strong CYP3A4 inhibitor). Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 1.4-fold and C max by 1.2-fold. Fluconazole: Selumetinib AUC increased by 1.5 fold and C max by 1.3 fold following concomitant administration of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor). Strong or Moderate CYP3A4 Inducers: Selumetinib AUC decreased by 51% and C max by 26% following concomitant administration of rifampicin (strong CYP3A4 inducer). 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 BCRP, P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K. Selumetinib is a substrate of BCRP and P-gp." ], "mechanism_of_action": [ "12.1 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 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." ], "pharmacodynamics": [ "12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KOSELUGO have not been fully characterized. Cardiac Electrophysiology At a dose 1.5-times the maximum recommended dose, clinically significant QTc interval prolongation was not observed." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Selumetinib pharmacokinetics were observed at steady state in adult and pediatric patients with NF1 and are presented as mean (CV%) unless otherwise indicated. The maximum plasma concentration (C max ) is 792 (49) ng/mL and systemic exposure (AUC) is 2141 (55) ng•h/mL following KOSELUGO 25 mg/m 2 twice daily. Selumetinib AUC and C max increases in a dose proportional manner over a dose range from 20 mg/m 2 to 30 mg/m 2 (0.8 to 1.2 times the recommended dose). Selumetinib accumulation range is 1.2-1.5 fold following administration of KOSELUGO at 25 mg/m 2 . At the recommended dosage of 25 mg/m 2 of KOSELUGO oral granules (sprinkled on smooth yogurt, smooth fruit sauce, smooth fruit puree, or smooth fruit jam) twice daily in pediatric patients (> 1 year old to < 7 years old), the AUC 0-24h following the first dose of KOSELUGO oral granules was within the range of that in patients administered KOSELUGO capsules. No clinically relevant differences in the pharmacokinetics of selumetinib were observed following administration of a single-dose of either the granule or capsule dosage forms of KOSELUGO at equivalent dosages, under fasted and fed conditions, in healthy adults. Absorption Selumetinib absolute oral bioavailability is 62%. Selumetinib median (min, max) time to maximum plasma concentrations (Tmax) is 1.5 (0.22, 6.0) hours. Effect of Food No clinically significant differences in selumetinib pharmacokinetics were observed following administration of low fat (400-500 calories) or high-fat (800-1000 calories) meal. Distribution Selumetinib apparent volume of distribution across a dose range of 20 mg/m 2 to 30 mg/m 2 (0.8 to 1.2 times the recommended dosage) ranges from 40 L-3710 L (66). The plasma protein binding is 98.4% (primarily albumin). Elimination Selumetinib elimination half-life is 9 (28) hours with an apparent (oral) clearance of 16 (44) L/hr/m 2 . 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 can be attributed to CYP metabolism and about 29% to direct glucuronidation by UGT enzymes. The active metabolite, N desmethyl selumetinib, is generated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6, and it is metabolized through the same routes as selumetinib. N-desmethyl selumetinib represents < 10% of selumetinib levels in human plasma, but is approximately 3- to 5- 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 (< 1% as parent). Specific Populations No clinically significant differences in the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed based on age (1-79 years) race [White (56%), Asian (22%), Black (19%)]. Pediatric Patients No clinically significant differences in the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed between the pediatric (aged 1 to < 17 years) and adult patients. Patients with Renal Impairment No clinically significant differences in selumetinib exposures were observed in patients with end stage renal disease (CLcr < 15 mL/min) who required dialysis. CLcr was estimated using the Cockroft-Gault formula. Patients with Hepatic Impairment Dose normalized total AUC increased by 1.6-fold in patients with moderate hepatic impairment (Child-Pugh B) and in patients with severe hepatic impairment (Child-Pugh class C). Selumetinib unbound AUC increased by 1.4-fold in patients with moderate hepatic impairment (Child-Pugh B), and 3.2-fold in patients with severe hepatic impairment (Child-Pugh C). Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong or Moderate CYP3A4 Inhibitors: Selumetinib AUC increased by 1.5-fold and C max by 1.2-fold following concomitant administration of itraconazole (strong CYP3A4 inhibitor). Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 1.4-fold and C max by 1.2-fold. Fluconazole: Selumetinib AUC increased by 1.5 fold and C max by 1.3 fold following concomitant administration of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor). Strong or Moderate CYP3A4 Inducers: Selumetinib AUC decreased by 51% and C max by 26% following concomitant administration of rifampicin (strong CYP3A4 inducer). 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 BCRP, P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K. Selumetinib is a substrate of BCRP and P-gp." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 . 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 > 160 mg/kg (~38-times the human C max at the clinical dose of 25 mg/m 2 ). 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/m 2 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 5-times the human exposure based on AUC at the clinical dose of 25 mg/m 2 twice daily). 13.2 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/m 2 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." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 . 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 > 160 mg/kg (~38-times the human C max at the clinical dose of 25 mg/m 2 ). 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/m 2 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 5-times the human exposure based on AUC at the clinical dose of 25 mg/m 2 twice daily)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 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/m 2 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": [ "14 CLINICAL STUDIES 14.1 Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN) Pediatrics 2 18 years of Age (SPRINT Phase II Stratum 1) The efficacy of KOSELUGO was evaluated in SPRINT Phase II Stratum 1, an-open label, multicenter, single arm trial (NCT01362803). Eligible patients were required to have NF1 with inoperable PN, defined as a PN that could not be completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. Patients were also required to have significant morbidity related to the target PN. Morbidities that were present in > 20% of patients included disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction. Patients received KOSELUGO 25 mg/m 2 orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR), defined as the percentage of patients with complete response (defined as disappearance of the target PN) or confirmed partial response (defined as ≥ 20% reduction in PN volume confirmed at a subsequent tumor assessment within 3-6 months). The target PN, defined as the PN that caused relevant clinical symptoms or complications (PN-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 while on treatment after every 4 cycles for 2 years, and then every 6 cycles. An additional efficacy outcome measure was duration of response (DoR). A total of 50 pediatric patients received KOSELUGO. 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 14. The median time to onset of response was 7.2 months (range: 3.3 months to 1.6 years). Table 14 Efficacy Results from SPRINT Phase II Stratum 1 Efficacy Parameter SPRINT N = 50 Overall Response Rate Responses required confirmation at least 3 months after the criteria for first response were met. The ORR assessment (data cut-off date [DCO]: June 2018) was conducted by a single National Cancer Institute reviewer who was a SPRINT investigator and who evaluated all PN imaging from patients enrolled at all trial sites. Overall Response Rate, n (%) 33 (66%) 95% CI (51, 79) Complete Response Complete response: disappearance of the target lesion; Partial response: decrease in target PN volume by ≥ 20% compared to baseline. 0 Confirmed Partial Response, n (%) 33 (66%) Duration of Response DCO: March 2021. Median (95% CI) months NR (41.2 – NE) DoR ≥ 24 months, n (%) 26 (79%) DoR ≥ 36 months, n (%) 21 (64%) CI – confidence interval, DoR – duration of response, NE – not evaluable, NR – not reached. An independent centralized review of tumor response per REiNS criteria (data cut-off June 2018) resulted in an ORR of 44% (95% CI: 30, 59). Adults ≥ 18 years of Age (KOMET) The efficacy of KOSELUGO in adult patients was evaluated in KOMET, a randomized, multicenter, double-blind, placebo-controlled trial (NCT04924608). Eligible patients were required to be 18 years of age or older with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibroma (PN). Inoperable plexiform neurofibroma (PN) is defined as a PN that could not be completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. A total of 145 patients were randomized (1:1) to KOSELUGO 25 mg/m 2 (BSA) or placebo twice daily for 12 cycles (28-day cycles). After the end of Cycle 12, or earlier if disease progression was confirmed by the Independent Central Review (ICR), patients initially randomized to placebo crossed over to receive KOSELUGO in the open-label treatment phase. Treatment was discontinued if a patient was no longer deriving clinical benefit, experienced unacceptable toxicity, patient decision, PN progression, or at the discretion of the investigator. One target and when applicable one non-target PN was assessed by using volumetric MRI analysis and REiNS criteria. The major efficacy outcome measure was overall response rate (ORR) by the end of Cycle 16, as determined by ICR per REiNS criteria. Duration of response was an additional efficacy outcome measure. The study demographics were 52% male, 56% White, 31% Asian, 6% Black or African American, 10% Hispanic or Latino ethnicity, and the median age was 29 years (range: 18 to 60 years). PN-related morbidities that were present in > 20% of patients included pain, motor dysfunction, and disfigurement. The trial demonstrated statistically significant ORR in patients randomized to KOSELUGO compared to placebo by the end of Cycle 16. The median time to response was 3.7 months (range: 3.6 months to 11.2 months). Efficacy results are shown in Table 15. Table 15 Efficacy Results from KOMET Efficacy Parameters KOSELUGO (N = 71) Placebo (N = 74) Overall Response Rate by the end of Cycle 16 (ORR) Patients with confirmed complete response or partial response by independent central review (ICR) per REiNS criteria. Response confirmation was by a consecutive scan within 3 to 6 months after the first response as determined by ICR per REiNS criteria. ORR % (95% CI) All.Partial responders. 20 (11, 31) 5 (2, 13) p value 2-sided p-value calculated using Fisher’s exact method. 0.011 Duration of Response Calculated using Kaplan-Meier method. Median (95% CI) months NR (11.5, NE) ND ≥ 6 months, n (%) 12 (86%) ND CI – confidence interval, ND – Not determined for placebo arm, NE – not estimable, NR - not reached." ], "clinical_studies_table": [ "
Table 14 Efficacy Results from SPRINT Phase II Stratum 1
Efficacy Parameter SPRINT N = 50
Overall Response Rate Responses required confirmation at least 3 months after the criteria for first response were met.The ORR assessment (data cut-off date [DCO]: June 2018) was conducted by a single National Cancer Institute reviewer who was a SPRINT investigator and who evaluated all PN imaging from patients enrolled at all trial sites.
Overall Response Rate, n (%)33 (66%)
95% CI(51, 79)
Complete ResponseComplete response: disappearance of the target lesion; Partial response: decrease in target PN volume by ≥ 20% compared to baseline.0
Confirmed Partial Response, n (%)33 (66%)
Duration of ResponseDCO: March 2021.
Median (95% CI) monthsNR (41.2 – NE)
DoR ≥ 24 months, n (%)26 (79%)
DoR ≥ 36 months, n (%)21 (64%)
CI – confidence interval, DoR – duration of response, NE – not evaluable, NR – not reached.
", "
Table 15 Efficacy Results from KOMET
Efficacy ParametersKOSELUGO(N = 71)Placebo(N = 74)
Overall Response Rate by the end of Cycle 16 (ORR)Patients with confirmed complete response or partial response by independent central review (ICR) per REiNS criteria. Response confirmation was by a consecutive scan within 3 to 6 months after the first response as determined by ICR per REiNS criteria.
ORR % (95% CI)All.Partial responders.20 (11, 31)5 (2, 13)
p value2-sided p-value calculated using Fisher’s exact method.0.011
Duration of ResponseCalculated using Kaplan-Meier method.
Median (95% CI) monthsNR (11.5, NE)ND
≥ 6 months, n (%)12 (86%)ND
CI – confidence interval, ND – Not determined for placebo arm, NE – not estimable, NR - not reached.
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Selumetinib Capsules Strength Description Capsules per Bottle NDC Number 10 mg White to off-white, opaque, hard capsule sealed with a clear band and marked with “SEL 10” in black ink. 60 0310-0610-60 28 0310-0610-28 25 mg Blue, opaque, hard capsule sealed with a clear band and marked with “SEL 25” in black ink. 60 0310-0625-60 28 0310-0625-28 Selumetinib Oral Granules Strength Description Capsules per Bottle NDC Number 5 mg Off‑white to light‑yellow free‑flowing oral granules contained within capsules. The capsules have a yellow cap and white body. The cap is printed with “sel 5” in black ink, and body is printed with a sprinkle capsule image indicating opening. 60 0310‑0635‑60 7.5 mg Off‑white to light‑yellow free‑flowing oral granules contained within capsules. The capsules have a pink cap and white body where the cap is printed with “sel 7.5” in black ink, and body is printed with a sprinkle capsule image indicating opening. 60 0310‑0640‑60 Storage KOSELUGO Capsules Store KOSELUGO capsules 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) [see USP Controlled Room Temperature]. Dispense and store in the original bottle to protect from light and moisture. Do not remove desiccant. Keep the bottle tightly closed after first opening. KOSELUGO Oral Granules Store and transport KOSELUGO oral granules refrigerated at 2°C to 8°C (36°F to 46°F). After receipt, patients may store at room temperature 20°C to 25°C (68°F to 77°F). Do NOT exceed 30°C (86°F). KOSELUGO oral granules may clump together or stick to the capsule shell if exposed to high temperatures, which may lead to underdose. Dispense and store in the original bottle to protect from light and moisture. Do not remove desiccant. Keep the bottle tightly closed after first opening." ], "how_supplied_table": [ "
StrengthDescriptionCapsules per BottleNDC Number
10 mgWhite to off-white, opaque, hard capsule sealed with a clear band and marked with “SEL 10” in black ink.600310-0610-60
280310-0610-28
25 mgBlue, opaque, hard capsule sealed with a clear band and marked with “SEL 25” in black ink.600310-0625-60
280310-0625-28
", "
StrengthDescriptionCapsules per BottleNDC Number
5 mgOff‑white to light‑yellow free‑flowing oral granules contained within capsules. The capsules have a yellow cap and white body. The cap is printed with “sel 5” in black ink, and body is printed with a sprinkle capsule image indicating opening.600310‑0635‑60
7.5 mgOff‑white to light‑yellow free‑flowing oral granules contained within capsules. The capsules have a pink cap and white body where the cap is printed with “sel 7.5” in black ink, and body is printed with a sprinkle capsule image indicating opening.600310‑0640‑60
" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Left Ventricular Dysfunction Advise patients and caregivers that KOSELUGO can cause a reduction in LVEF and to immediately report any signs or symptoms of cardiomyopathy to their healthcare provider [see Warnings and Precautions (5.1) ] . Ocular Toxicity Advise patients and caregivers that KOSELUGO can cause ocular toxicity that can lead to blindness and to contact their healthcare provider if the patient experiences any changes in their vision [see Warnings and Precautions (5.2) ] . Gastrointestinal Toxicity Advise patients and caregivers that KOSELUGO can cause diarrhea, nausea, vomiting, and stomatitis and to contact their healthcare provider at the first sign of gastrointestinal toxicity [see Warnings and Precautions (5.3) ] . Skin Toxicity Advise patients and caregivers that KOSELUGO can cause serious skin toxicities and to contact their healthcare provider for severe skin changes [see Warnings and Precautions (5.4) ] . Increased Creatine Phosphokinase Advise patients and caregivers that KOSELUGO can cause increased CPK and rhabsomyolysis to report any signs and symptoms of muscle pain or weakness to their healthcare provider [see Warnings and Precautions (5.5) ] . Increased Vitamin E Levels and Increased Risk of Bleeding (KOSELUGO Capsules) 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 [see Warnings and Precautions (5.6) ] . 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 [see Warnings and Precautions (5.7) , Use in Specific Populations (8.1) ]. • Advise females of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose [see Use in Specific Populations (8.3) ] . • Advise males with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] . Lactation Advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose [see Use in Specific Populations (8.2) ] . 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, and Seville orange while taking KOSELUGO [see Drug Interactions (7) ] . Dosing and Administration Inform patients and caregivers on how to take KOSELUGO and what to do for missed or vomited doses [see Dosage and Administration (2.1) ] . Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 © AstraZeneca 20XX" ], "spl_patient_package_insert": [ "Patient Information KOSELUGO ® (ko-SEL-u-go) (selumetinib) capsules, for oral use KOSELUGO ® (ko-SEL-u-go) (selumetinib) oral granules What is KOSELUGO? KOSELUGO is a prescription medicine that is used to treat adults and children 1 year of age and older with neurofibromatosis type 1 (NF1) who have plexiform neurofibromas that cause symptoms and cannot be completely removed by surgery. It is not known if KOSELUGO is safe and effective in children under 1 year of age. Before taking KOSELUGO, tell your healthcare provider about all of your medical conditions, including if you: • have heart problems. • have eye problems. • have liver problems. • are pregnant or plan to become pregnant. KOSELUGO can harm your unborn baby. Females who are able to become pregnant: ∘ Your healthcare provider should check to see if you are pregnant before you begin treatment with KOSELUGO. ∘ You should use effective birth control (contraception) during treatment with KOSELUGO and for 1 week after your last dose. ∘ Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with KOSELUGO. Males with female partners who are able to become pregnant: ∘ You should use effective birth control (contraception) during treatment with KOSELUGO and for 1 week after your last dose. • are breastfeeding or plan to breastfeed. It is not known if KOSELUGO passes into your breast milk. ∘ Do not breastfeed during treatment with KOSELUGO and for 1 week after your last dose. ∘ Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, or herbal supplements. Certain medicines may affect the way KOSELUGO works. Especially tell your healthcare provider if you are taking a supplement containing vitamin E, aspirin, blood thinners, or other medicines to treat blood clots. KOSELUGO capsules contain vitamin E, which may increase your risk of bleeding. How should I take KOSELUGO? • Take or give KOSELUGO exactly as your healthcare provider tells you to. • Do not change your dose or stop taking KOSELUGO unless your healthcare provider tells you to. • Your healthcare provider will decide on the right dose of KOSELUGO based on your or your child’s weight or size (body surface area). • Take or give KOSELUGO 2 times a day. • If you or your child miss a dose of KOSELUGO capsules or KOSELUGO oral granules, take or give the dose as soon as you remember, unless the next dose is due within 6 hours. If your scheduled dose is due within 6 hours, skip the dose and take or give the next dose at the regular time. • If you or your child vomit after taking a dose of KOSELUGO capsules or KOSELUGO oral granules, do not take an additional dose. Take the next dose at the regular scheduled time. KOSELUGO comes in capsules and oral granules. • If your healthcare provider prescribes KOSELUGO capsules: ∘ Take KOSELUGO capsules with or without food. ∘ Swallow KOSELUGO capsules whole. Do not open, chew, or crush the capsules. ∘ Tell your healthcare provider if you or your child has trouble swallowing capsules. • If your healthcare provider prescribes KOSELUGO oral granules: ∘ See the Instructions for Use for the instructions on how to prepare and take or give KOSELUGO oral granules. ∘ Prepare KOSELUGO oral granules by carefully opening the capsule and sprinkling all of the oral granules on a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry. ∘ Take or give the KOSELUGO oral granules and food mixture within 30 minutes of preparing the dose. ∘ If the prepared dose of KOSELUGO oral granules and food mixture is not taken or given within 30 minutes, do not take or give the prepared dose. Throw away the mixture and prepare a new dose. ∘ If part of a dose is taken or given within 30 minutes of preparing, throw away the remainder of the mixture and do not prepare a new dose. Take or give the full dose within 30 minutes next time. ∘ The KOSELUGO oral granules should flow freely. Do not use if the oral granules are clumped or stuck inside the capsule shell. Contact your pharmacy if this happens. ∘ Throw away the empty capsule shells after use. ∘ Do not swallow, chew, or dissolve the capsule shells of KOSELUGO oral granules. ∘ Do not chew or crush the KOSELUGO oral granules. Do not add oral granules to liquids. ∘ Do not mix KOSELUGO oral granules in grapefruit or any juice, fruit puree or jam containing Seville orange. What should I avoid while taking KOSELUGO? Avoid St John’s wort, grapefruit or grapefruit juice, and Seville orange during treatment with KOSELUGO. What are the possible side effects of KOSELUGO? KOSELUGO can cause serious side effects, including: • Heart problems. KOSELUGO can lower the amount of blood pumped by your heart, which can be severe. Your healthcare provider will do tests before and during treatment with KOSELUGO to check how well your heart is working. Tell your healthcare provider right away if you get any of the following signs or symptoms: ∘ persistent coughing or wheezing ∘ shortness of breath ∘ swelling of your ankles and feet ∘ tiredness ∘ increased heart rate • Eye problems. KOSELUGO can cause eye problems that can lead to blindness. Your healthcare provider will check your vision before and during treatment with KOSELUGO. Tell your healthcare provider right away if you get new or worsening vision changes, including: ∘ blurred vision ∘ loss of vision ∘ dark spots in your vision (floaters) ∘ other changes to your vision • Stomach, intestine, and mouth (gastrointestinal) problems. KOSELUGO can cause diarrhea, vomiting, nausea, and mouth sores. Diarrhea can be severe with KOSELUGO. Tell your healthcare provider right away the first time that you get diarrhea during treatment with KOSELUGO. Your healthcare provider may give you medicine to help control your diarrhea and may tell you to drink more fluids. • Skin problems. Koselugo can cause severe skin rashes. Tell your healthcare provider if you get any of the following signs of skin problems: ∘ rash that covers a large area of your body ∘ flat skin rash ∘ raised bumps on your skin ∘ skin bumps that look like acne ∘ blisters ∘ peeling skin ∘ itchy rash ∘ hair thinning or hair loss (alopecia) Increased level of an enzyme called creatine phosphokinase (CPK) in your blood and muscle problems. Koselugo can cause severe muscle problems. Treatment with KOSELUGO may increase the level of enzyme in your blood called creatine phosphokinase (CPK), which may be a sign of muscle damage. Increased level of CPK in the blood are common during treatment with KOSELUGO and can also be severe. Your healthcare provider should do a blood test to check your blood levels of CPK before and during treatment with KOSELUGO. Tell your healthcare provider right away if you get any of the following signs or symptoms: ∘ muscle aches or pain ∘ muscle spasms and weakness ∘ dark, reddish urine Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with KOSELUGO if you have any of these side effects. The most common side effects of KOSELUGO in children include: • vomiting • diarrhea • increased level of an enzyme called creatine phosphokinase (CPK) in your blood • dry skin • redness around the fingernails • nausea • skin bumps that look like acne • fever The most common side effects of KOSELUGO in adults include: • rash • diarrhea • skin bumps that look like acne These are not all of the possible side effects of KOSELUGO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store KOSELUGO? • Store KOSELUGO capsules and KOSELUGO oral granules at room temperature between 68°F to 77°F (20°C to 25°C). • Do not store KOSELUGO oral granules above 86°F (30°C). Store KOSELUGO oral granules in the refrigerator between 36°F to 46°F (2°C to 8°C) if the temperature is above 86°F (30°C). KOSELUGO oral granules may clump together or stick to the capsule shell if the medicine gets too hot, and you may not get your full dose. • Keep KOSELUGO oral granules cold in a cooler bag with a cold pack if you need to take it anywhere. • The bottle of KOSELUGO capsules and KOSELUGO oral granules contain a desiccant packet to reduce moisture. Do not throw away the desiccant packet. • Keep KOSELUGO capsules and KOSELUGO oral granules in its original bottle to protect from light and moisture. Keep the bottle tightly closed. Keep KOSELUGO and all medicines out of the reach of children . General information about the safe and effective use of KOSELUGO. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use KOSELUGO for a condition for which it was not prescribed. Do not give KOSELUGO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about KOSELUGO that is written for a healthcare professional. What are the ingredients in KOSELUGO? Active ingredient: selumetinib. KOSELUGO capsule inactive ingredients: • The 10 mg and 25 mg capsules contain: vitamin E polyethylene glycol succinate. • The 10 mg capsule shell contains: carnauba wax, carrageenan, hypromellose, potassium chloride, purified water, and titanium dioxide. • The 10 mg capsule printing ink contains: ammonium hydroxide, iron oxide black, propylene glycol, and shellac. • The 25 mg capsule shell contains: carnauba wax and/or corn starch, carrageenan, FD&C blue 2, ferric oxide yellow, hypromellose, potassium chloride, purified water, and titanium dioxide. • The 25 mg capsule printing ink contains: carnauba wax, FD&C Blue 2 aluminum lake, ferric oxide red, ferric oxide yellow, glyceryl monooleate, and shellac. KOSELUGO oral granule inactive ingredients: • The 5 mg and 7.5 mg uncoated cores contain: glyceryl dibehenate and stearoyl polyoxylglycerides. • The 5 mg and 7.5 mg granule coatings contain: acetone, hypromellose acetate succinate, and stearic acid. • The 5 mg shell contains: ferric oxide yellow, hypromellose, and titanium dioxide. • The 5 mg printing ink contains: butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution. • The 7.5 mg shell contains: ferric oxide red, hypromellose, and titanium dioxide. • The 7.5 mg printing ink contains: butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 ©AstraZeneca 2025 For more information, go to website www.KOSELUGO.com or call 1-800-236-9933 This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2025" ], "spl_patient_package_insert_table": [ "have heart problems.have eye problems.have liver problems.are pregnant or plan to become pregnant. KOSELUGO can harm your unborn baby.Females who are able to become pregnant:Your healthcare provider should check to see if you are pregnant before you begin treatment with KOSELUGO.You should use effective birth control (contraception) during treatment with KOSELUGO and for 1 week after your last dose.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with KOSELUGO.Males with female partners who are able to become pregnant:You should use effective birth control (contraception) during treatment with KOSELUGO and for 1 week after your last dose.are breastfeeding or plan to breastfeed. It is not known if KOSELUGO passes into your breast milk.Do not breastfeed during treatment with KOSELUGO and for 1 week after your last dose. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements. Certain medicines may affect the way KOSELUGO works.Especially tell your healthcare provider if you are taking a supplement containing vitamin E, aspirin, blood thinners, or other medicines to treat blood clots. KOSELUGO capsules contain vitamin E, which may increase your risk of bleeding.Take or give KOSELUGO exactly as your healthcare provider tells you to.Do not change your dose or stop taking KOSELUGO unless your healthcare provider tells you to.Your healthcare provider will decide on the right dose of KOSELUGO based on your or your child’s weight or size (body surface area).Take or give KOSELUGO 2 times a day. If you or your child miss a dose of KOSELUGO capsules or KOSELUGO oral granules, take or give the dose as soon as you remember, unless the next dose is due within 6 hours. If your scheduled dose is due within 6 hours, skip the dose and take or give the next dose at the regular time.If you or your child vomit after taking a dose of KOSELUGO capsules or KOSELUGO oral granules, do not take an additional dose. Take the next dose at the regular scheduled time.KOSELUGO comes in capsules and oral granules.If your healthcare provider prescribes KOSELUGO capsules:Take KOSELUGO capsules with or without food.Swallow KOSELUGO capsules whole. Do not open, chew, or crush the capsules.Tell your healthcare provider if you or your child has trouble swallowing capsules.If your healthcare provider prescribes KOSELUGO oral granules:See the Instructions for Use for the instructions on how to prepare and take or give KOSELUGO oral granules.Prepare KOSELUGO oral granules by carefully opening the capsule and sprinkling all of the oral granules on a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry.Take or give the KOSELUGO oral granules and food mixture within 30 minutes of preparing the dose.If the prepared dose of KOSELUGO oral granules and food mixture is not taken or given within 30 minutes, do not take or give the prepared dose. Throw away the mixture and prepare a new dose.If part of a dose is taken or given within 30 minutes of preparing, throw away the remainder of the mixture and do not prepare a new dose. Take or give the full dose within 30 minutes next time.The KOSELUGO oral granules should flow freely. Do not use if the oral granules are clumped or stuck inside the capsule shell. Contact your pharmacy if this happens.Throw away the empty capsule shells after use.Do not swallow, chew, or dissolve the capsule shells of KOSELUGO oral granules.Do not chew or crush the KOSELUGO oral granules. Do not add oral granules to liquids.Do not mix KOSELUGO oral granules in grapefruit or any juice, fruit puree or jam containing Seville orange.Heart problems. KOSELUGO can lower the amount of blood pumped by your heart, which can be severe. Your healthcare provider will do tests before and during treatment with KOSELUGO to check how well your heart is working. Tell your healthcare provider right away if you get any of the following signs or symptoms:persistent coughing or wheezingshortness of breathswelling of your ankles and feettirednessincreased heart rateEye problems. KOSELUGO can cause eye problems that can lead to blindness. Your healthcare provider will check your vision before and during treatment with KOSELUGO. Tell your healthcare provider right away if you get new or worsening vision changes, including:blurred visionloss of visiondark spots in your vision (floaters)other changes to your visionStomach, intestine, and mouth (gastrointestinal) problems. KOSELUGO can cause diarrhea, vomiting, nausea, and mouth sores. Diarrhea can be severe with KOSELUGO. Tell your healthcare provider right away the first time that you get diarrhea during treatment with KOSELUGO. Your healthcare provider may give you medicine to help control your diarrhea and may tell you to drink more fluids.Skin problems. Koselugo can cause severe skin rashes. Tell your healthcare provider if you get any of the following signs of skin problems:rash that covers a large area of your bodyflat skin rashraised bumps on your skinskin bumps that look like acneblisterspeeling skinitchy rashhair thinning or hair loss (alopecia)muscle aches or painmuscle spasms and weaknessdark, reddish urinevomitingdiarrheaincreased level of an enzyme called creatine phosphokinase (CPK) in your blooddry skinredness around the fingernailsnauseaskin bumps that look like acnefeverrashdiarrheaskin bumps that look like acneStore KOSELUGO capsules and KOSELUGO oral granules at room temperature between 68°F to 77°F (20°C to 25°C).Do not store KOSELUGO oral granules above 86°F (30°C). Store KOSELUGO oral granules in the refrigerator between 36°F to 46°F (2°C to 8°C) if the temperature is above 86°F (30°C). KOSELUGO oral granules may clump together or stick to the capsule shell if the medicine gets too hot, and you may not get your full dose.Keep KOSELUGO oral granules cold in a cooler bag with a cold pack if you need to take it anywhere.The bottle of KOSELUGO capsules and KOSELUGO oral granules contain a desiccant packet to reduce moisture. Do not throw away the desiccant packet.Keep KOSELUGO capsules and KOSELUGO oral granules in its original bottle to protect from light and moisture. Keep the bottle tightly closed.Keep KOSELUGO and all medicines out of the reach of children.The 10 mg and 25 mg capsules contain: vitamin E polyethylene glycol succinate.The 10 mg capsule shell contains: carnauba wax, carrageenan, hypromellose, potassium chloride, purified water, and titanium dioxide.The 10 mg capsule printing ink contains: ammonium hydroxide, iron oxide black, propylene glycol, and shellac.The 25 mg capsule shell contains: carnauba wax and/or corn starch, carrageenan, FD&C blue 2, ferric oxide yellow, hypromellose, potassium chloride, purified water, and titanium dioxide.The 25 mg capsule printing ink contains: carnauba wax, FD&C Blue 2 aluminum lake, ferric oxide red, ferric oxide yellow, glyceryl monooleate, and shellac.KOSELUGO oral granule inactive ingredients:The 5 mg and 7.5 mg uncoated cores contain: glyceryl dibehenate and stearoyl polyoxylglycerides.The 5 mg and 7.5 mg granule coatings contain: acetone, hypromellose acetate succinate, and stearic acid.The 5 mg shell contains: ferric oxide yellow, hypromellose, and titanium dioxide.The 5 mg printing ink contains: butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.The 7.5 mg shell contains: ferric oxide red, hypromellose, and titanium dioxide.The 7.5 mg printing ink contains: butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850©AstraZeneca 2025For more information, go to website www.KOSELUGO.com or call 1-800-236-9933
Patient Information
KOSELUGO® (ko-SEL-u-go)(selumetinib)capsules, for oral useKOSELUGO® (ko-SEL-u-go)(selumetinib)oral granules
What is KOSELUGO?KOSELUGO is a prescription medicine that is used to treat adults and children 1 year of age and older with neurofibromatosis type 1 (NF1) who have plexiform neurofibromas that cause symptoms and cannot be completely removed by surgery.It is not known if KOSELUGO is safe and effective in children under 1 year of age.
Before taking KOSELUGO, tell your healthcare provider about all of your medical conditions, including if you:
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How should I take KOSELUGO?
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What should I avoid while taking KOSELUGO?Avoid St John’s wort, grapefruit or grapefruit juice, and Seville orange during treatment with KOSELUGO.
What are the possible side effects of KOSELUGO?KOSELUGO can cause serious side effects, including:
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Increased level of an enzyme called creatine phosphokinase (CPK) in your blood and muscle problems. Koselugo can cause severe muscle problems. Treatment with KOSELUGO may increase the level of enzyme in your blood called creatine phosphokinase (CPK), which may be a sign of muscle damage. Increased level of CPK in the blood are common during treatment with KOSELUGO and can also be severe. Your healthcare provider should do a blood test to check your blood levels of CPK before and during treatment with KOSELUGO. Tell your healthcare provider right away if you get any of the following signs or symptoms:
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Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with KOSELUGO if you have any of these side effects.The most common side effects of KOSELUGO in children include:
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The most common side effects of KOSELUGO in adults include:
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These are not all of the possible side effects of KOSELUGO.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store KOSELUGO?
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General information about the safe and effective use of KOSELUGO.Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use KOSELUGO for a condition for which it was not prescribed. Do not give KOSELUGO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about KOSELUGO that is written for a healthcare professional.
What are the ingredients in KOSELUGO?Active ingredient: selumetinib.KOSELUGO capsule inactive ingredients:
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" ], "instructions_for_use": [ "Instructions for Use INSTRUCTIONS FOR USE KOSELUGO ® (ko-SEL-u-go) (selumetinib) oral granules This Instructions for Use contains information on how to take or give KOSELUGO oral granules. Read this Instructions for Use before taking or giving KOSELUGO oral granules and each time you get a refill. There may be new information . This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment. Talk to your healthcare provider or pharmacist if you have any questions about how to take or give KOSELUGO oral granules. Important Information You Need to Know Before Taking or Giving KOSELUGO oral granules • KOSELUGO oral granules come in capsules that must be opened before use. Do not swallow, chew, or dissolve the capsule shells. Do not chew or crush the oral granules. Do not add oral granules to liquids. • Take or give KOSELUGO oral granules exactly as your healthcare provider tells you to. • Do not change your dose or stop taking KOSELUGO oral granules unless your healthcare provider tells you to. • Your healthcare provider will decide on the right dose of KOSELUGO based on your or your child’s weight or size (body surface area). • KOSELUGO oral granules come in 2 different strengths: 5 mg and 7.5 mg. Each strength is a different color. Your healthcare provider may prescribe more than 1 strength of KOSELUGO oral granules for your or your child’s dose. Make sure that you understand how many capsules of KOSELUGO oral granules you need and what strengths to take. • Your healthcare provider may change the dose, temporarily stop, or permanently stop treatment with KOSELUGO oral granules if you or your child has side effects. • Take or give KOSELUGO oral granules 2 times a day. • If you or your child miss a dose of KOSELUGO oral granules, take or give the dose as soon as you remember, unless the next dose is due within 6 hours. If your scheduled dose is due within 6 hours, skip the dose and take or give the next dose at the regular time. • If you or your child vomits after taking a dose of KOSELUGO oral granules, do not take an additional dose. Take the next dose at the regular scheduled time. • For more information about KOSELUGO oral granules, see the Patient Information leaflet. Supplies needed to prepare a dose of KOSELUGO oral granules : • The prescribed number of KOSELUGO oral granules. • Smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry. • A spoon or a small cup. • A paper towel or plate. Preparing KOSELUGO oral granules Step 1: Wash and dry your hands thoroughly. Step 2: Open the bottle(s) and take out the number of capsule(s) needed for your prescribed dose of KOSELUGO oral granules. Step 3: Add a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing apple, banana, pear, or strawberry onto the spoon or into a small cup. • Do not mix KOSELUGO oral granules in grapefruit or any juice, fruit puree or jam containing Seville orange. Step 4: Place the spoon or cup on the paper towel or plate. Carefully open the capsule(s) one at a time and sprinkle the entire contents of the capsule (oral granules) onto the food that is on the spoon or in the small cup. • If you are using a spoon to prepare KOSELUGO oral granules, you may find it easier to prepare and take or give 1 capsule at a time. Repeat Steps 3 to 6 for each capsule until the full dose is taken or given. • Do not swallow, chew, or dissolve the capsule shells. Do not chew or crush the oral granules. Do not add oral granules to liquids. Important: The oral granules should flow freely inside the capsule. Do not use the capsule if the oral granules are clumped or stuck inside the capsule shell. Contact your pharmacy if this happens. Taking or giving KOSELUGO oral granules Step 5: Take or give the KOSELUGO oral granules and food mixture within 30 minutes of preparing the dose. Swallow the mixture without chewing while seated upright. Do not save for future use. Note: • If you do not take or give the KOSELUGO oral granules and food mixture within 30 minutes of preparing the dose, do not take or give the mixture. Throw away the mixture and prepare a new dose. • If you take or give part of the mixture within 30 minutes of preparing the dose, throw away the remainder of the mixture and do not prepare a new dose. Take or give the full dose within 30 minutes next time. Step 6: If you used a cup to prepare KOSELUGO oral granules, add more of the same food into the cup and take or give all of the mixture to make sure you get the full dose. Clean up • Throw away empty capsule shells, used paper towel, and any spilled oral granules in your household trash. • Wash your hands and all the supplies used to take or give KOSELUGO oral granules. Storing KOSELUGO oral granules • Store KOSELUGO oral granules at room temperature between 68°F to 77°F (20°C to 25°C). • Do not store KOSELUGO oral granules above 86°F (30°C). Store KOSELUGO oral granules in the refrigerator between 36°F to 46°F (2°C to 8°C) if the temperature is above 86°F (30°C). KOSELUGO oral granules may clump together or stick to the capsule shell if the medicine gets too hot, and you may not get your full dose. • Keep KOSELUGO oral granules cold in a cooler bag with a cold pack if you need to take it anywhere. • The bottle of KOSELUGO oral granules contains a desiccant packet to reduce moisture. Do not throw away the desiccant packet. • Keep KOSELUGO oral granules in its original bottle to protect from light and moisture. Keep the bottle tightly closed. Keep KOSELUGO and all medicines out of the reach of children. Disposing of KOSELUGO oral granules • Ask your pharmacist how to throw away unused doses, expired medicines, or medicines you no longer use. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 ©AstraZeneca 2025 For more information, go to website www.KOSELUGO.com or call 1-800-236-9933. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved: Sep/2025 Step_1 Step_2 Step_3 Step_4 Step_5 Step_6" ], "instructions_for_use_table": [ "KOSELUGO oral granules come in capsules that must be opened before use. Do not swallow, chew, or dissolve the capsule shells. Do not chew or crush the oral granules. Do not add oral granules to liquids.Take or give KOSELUGO oral granules exactly as your healthcare provider tells you to.Do not change your dose or stop taking KOSELUGO oral granules unless your healthcare provider tells you to.Your healthcare provider will decide on the right dose of KOSELUGO based on your or your child’s weight or size (body surface area).KOSELUGO oral granules come in 2 different strengths: 5 mg and 7.5 mg. Each strength is a different color. Your healthcare provider may prescribe more than 1 strength of KOSELUGO oral granules for your or your child’s dose. Make sure that you understand how many capsules of KOSELUGO oral granules you need and what strengths to take.Your healthcare provider may change the dose, temporarily stop, or permanently stop treatment with KOSELUGO oral granules if you or your child has side effects.Take or give KOSELUGO oral granules 2 times a day.If you or your child miss a dose of KOSELUGO oral granules, take or give the dose as soon as you remember, unless the next dose is due within 6 hours. If your scheduled dose is due within 6 hours, skip the dose and take or give the next dose at the regular time.If you or your child vomits after taking a dose of KOSELUGO oral granules, do not take an additional dose. Take the next dose at the regular scheduled time.For more information about KOSELUGO oral granules, see the Patient Information leaflet.Supplies needed to prepare a dose of KOSELUGO oral granules:The prescribed number of KOSELUGO oral granules.Smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry.A spoon or a small cup.A paper towel or plate.Do not mix KOSELUGO oral granules in grapefruit or any juice, fruit puree or jam containing Seville orange.If you are using a spoon to prepare KOSELUGO oral granules, you may find it easier to prepare and take or give 1 capsule at a time. Repeat Steps 3 to 6 for each capsule until the full dose is taken or given.Do not swallow, chew, or dissolve the capsule shells. Do not chew or crush the oral granules. Do not add oral granules to liquids.If you do not take or give the KOSELUGO oral granules and food mixture within 30 minutes of preparing the dose, do not take or give the mixture. Throw away the mixture and prepare a new dose.If you take or give part of the mixture within 30 minutes of preparing the dose, throw away the remainder of the mixture and do not prepare a new dose. Take or give the full dose within 30 minutes next time.Throw away empty capsule shells, used paper towel, and any spilled oral granules in your household trash.Wash your hands and all the supplies used to take or give KOSELUGO oral granules.Store KOSELUGO oral granules at room temperature between 68°F to 77°F (20°C to 25°C).Do not store KOSELUGO oral granules above 86°F (30°C). Store KOSELUGO oral granules in the refrigerator between 36°F to 46°F (2°C to 8°C) if the temperature is above 86°F (30°C). KOSELUGO oral granules may clump together or stick to the capsule shell if the medicine gets too hot, and you may not get your full dose.Keep KOSELUGO oral granules cold in a cooler bag with a cold pack if you need to take it anywhere.The bottle of KOSELUGO oral granules contains a desiccant packet to reduce moisture. Do not throw away the desiccant packet.Keep KOSELUGO oral granules in its original bottle to protect from light and moisture. Keep the bottle tightly closed.Keep KOSELUGO and all medicines out of the reach of children.Ask your pharmacist how to throw away unused doses, expired medicines, or medicines you no longer use.
INSTRUCTIONS FOR USEKOSELUGO® (ko-SEL-u-go)(selumetinib)oral granules
This Instructions for Use contains information on how to take or give KOSELUGO oral granules.Read this Instructions for Use before taking or giving KOSELUGO oral granules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment. Talk to your healthcare provider or pharmacist if you have any questions about how to take or give KOSELUGO oral granules.
Important Information You Need to Know Before Taking or Giving KOSELUGO oral granules
••••••••••••••
Preparing KOSELUGO oral granules
Step 1: Wash and dry your hands thoroughly.
Step 2: Open the bottle(s) and take out the number of capsule(s) needed for your prescribed dose of KOSELUGO oral granules.
Step 3: Add a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing apple, banana, pear, or strawberry onto the spoon or into a small cup.
•
Step 4: Place the spoon or cup on the paper towel or plate. Carefully open the capsule(s) one at a time and sprinkle the entire contents of the capsule (oral granules) onto the food that is on the spoon or in the small cup.
••
Important: The oral granules should flow freely inside the capsule. Do not use the capsule if the oral granules are clumped or stuck inside the capsule shell. Contact your pharmacy if this happens.
Taking or giving KOSELUGO oral granules
Step 5: Take or give the KOSELUGO oral granules and food mixture within 30 minutes of preparing the dose. Swallow the mixture without chewing while seated upright. Do not save for future use.Note:
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Step 6: If you used a cup to prepare KOSELUGO oral granules, add more of the same food into the cup and take or give all of the mixture to make sure you get the full dose.
Clean up
••
Storing KOSELUGO oral granules
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Disposing of KOSELUGO oral granules
•
Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850©AstraZeneca 2025For more information, go to website www.KOSELUGO.com or call 1-800-236-9933.
" ], "package_label_principal_display_panel": [ "PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 10mg NDC 0310-0610-28 Koselugo ® (selumetinib) capsules 10 mg Rx only Dispense in original bottle. Do not remove desiccant . Protect from moisture. Keep the bottle tightly closed. 28 Capsules AstraZeneca 10mg 28count", "PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 25mg NDC 0310-0625-28 Koselugo ® (selumetinib) capsules 25 mg Rx only Dispense in original bottle. Do not remove desiccant . Protect from moisture. Keep the bottle tightly closed. 28 Capsules AstraZeneca 25mg 28ct", "Package/Label Display Panel 5 mg NDC 0310-0635-60 Koselugo ® (selumetinib) Oral granules 7.5 mg Sprinkle oral granules on or mix with smooth yogurt or fruit puree. Dispense and store in original bottle below 25° C (77°F) to protect from light and moisture. 60 Capsules Rx only Astrazeneca 5mg_oral_granules", "Package/Label Display Panel 7.5 mg NDC 0310-0640-60 Koselugo ® (selumetinib) Oral granules 7.5 mg Sprinkle oral granules on or mix with smooth yogurt or fruit puree. Dispense and store in original bottle below 25° C (77°F) to protect from light and moisture. 60 Capsules Rx only Astrazeneca 7_5mg_oral_granules" ], "set_id": "7d042c61-f28f-4ab5-ab10-d7558c0d49ff", "id": "bdebc47d-8420-42eb-aaa7-b243dc9e42b2", "effective_time": "20260526", "version": "17", "openfda": { "application_number": [ "NDA213756", "NDA219943" ], "brand_name": [ "KOSELUGO" ], "generic_name": [ "SELUMETINIB" ], "manufacturer_name": [ "AstraZeneca Pharmaceuticals LP" ], "product_ndc": [ "0310-0610", "0310-0625", "0310-0635", "0310-0640" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "SELUMETINIB" ], "rxcui": [ "2289418", "2289424", "2289426", "2289428", "2723653", "2723657", "2723659", "2723661" ], "spl_id": [ "bdebc47d-8420-42eb-aaa7-b243dc9e42b2" ], "spl_set_id": [ "7d042c61-f28f-4ab5-ab10-d7558c0d49ff" ], "package_ndc": [ "0310-0610-60", "0310-0610-28", "0310-0625-60", "0310-0625-28", "0310-0635-60", "0310-0640-60" ], "is_original_packager": [ true ], "nui": [ "N0000175605", "N0000193943", "N0000193944" ], "pharm_class_epc": [ "Kinase Inhibitor [EPC]" ], "pharm_class_moa": [ "Mitogen-Activated Protein Kinase Kinase 1 Inhibitors [MoA]", "Mitogen-Activated Protein Kinase Kinase 2 Inhibitors [MoA]" ], "unii": [ "6UH91I579U" ] } } ] }