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 )
Contraindications
None. None. ( 4 )
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 ).
5.1Left 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.
5.2Ocular 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) ].
5.3Gastrointestinal 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) ].
5.4Skin 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 macu
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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 )
7.1Effect 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.
Pregnancy and breastfeeding
8.1Pregnancy 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).
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.
6.1Clinical 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 receiv
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
SELUMETINIB SULFATE EQ 5MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
