用法用量
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
Side Effects Overview
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. • Gastrointestinal Disorders: dry mouth. • General Disorders: facial edema, including periorbital edema and face edema. • Metabolism and Nutrition: increased weigh.t • 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.
警告与注意事项
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 occurrence of 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 occurrence of 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 KOSELUGO can cause ocular toxicity, including retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), 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 76% of these patients. 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. 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 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 diarrhea was approximately 1 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) ] .
药代动力学
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.