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2 DOSAGE AND ADMINISTRATION • Select patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens. ( 2.1 ) • Monitor ECG and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated. ( 2.2 ) • The recommended dose in adult patients is 625 mg orally once weekly. ( 2.3 ) • The recommended dose in pediatric patients weighing ≥10 kg is based on body weight (see Table 1). ( 2.3 ) • Take MODEYSO orally once weekly on an empty stomach, at least 1 hour before or 3 hours after food intake. ( 2.3 ) • Continue MODEYSO until disease progression or unacceptable toxicity. ( 2.3 ) 2.1 Patient Selection Select patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens [see Clinical Studies ( 14 )] . An FDA-approved test for the detection of this mutation is not currently available. 2.2 Recommended Testing Before Starting MODEYSO Monitor electrocardiograms (ECG) and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.2 )] . 2.3 Recommended Dosage and Administration Take MODEYSO on an empty stomach, at least 1 hour before or 3 hours after food intake [see Clinical Pharmacology ( 12.3 )] . Adults The recommended dosage of MODEYSO is 625 mg orally once weekly. Pediatrics The recommended dosage of MODEYSO in pediatric patients aged 1 to <17 years who weigh at least 10 kg is based on body weight (Table 1). A recommended dosage of MODEYSO has not been established in pediatric patients who weigh less than 10 kg. Table 1: Recommended Body Weight-Based Dosage for Pediatric Patients Body Weight (kg) Recommended Dosage 10 kg to <12.5 kg 125 mg Once Weekly 12.5 kg to <27.5 kg 250 mg Once Weekly 27.5 kg to <42.5 kg 375 mg Once Weekly 42.5 kg to <52.5 kg 500 mg Once Weekly ≥52.5 kg 625 mg Once Weekly Continue MODEYSO until disease progression or unacceptable toxicity. Swallow capsules whole. For patients unable to swallow capsules whole, open each capsule, mix contents with approximately 15 to 30 mL of liquid (sports drink, apple juice, lemonade, or water) before administration, and administer orally as a liquid [see Patient Counseling Information ( 17 )] . Once mixed, administer within 2 hours of preparation, or discard and mix a new dose. Vomiting If vomiting occurs after taking a dose, do not take an additional dose and take the next dose at the regularly scheduled time. Missed Dose If a dose is missed within 2 days, take the missed dose as soon as possible. If a dose is missed by more than 2 days, skip the missed dose and take the next dose at the scheduled time. 2.4 Dosage Modifications for Adverse Reactions The recommended dosage reductions for adverse reactions for MODEYSO are provided in Table 2. Table 2: Recommended Dosage Reductions for Adverse Reactions Patient’s Weight (kg) First Dosage Reduction Second Dosage Reduction Pediatric patients 10 kg to <12.5 kg Permanently discontinue N/A Pediatric patients 12.5 kg to <27.5 kg 125 mg once weekly Permanently discontinue Pediatric patients 27.5 kg to <42.5 kg 250 mg once weekly 125 mg once weekly Pediatric patients 42.5 kg to <52.5 kg 375 mg once weekly 250 mg once weekly Pediatric patients ≥52.5 kg and adult patients 500 mg once weekly 375 mg once weekly The recommended dosage modifications for adverse reactions are provided in Table 3. Table 3: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity a Dosage Modification b Hypersensitivity [see Warnings and Precautions ( 5.1 )] Any grade If hypersensitivity is suspected based on clinical judgement, interrupt MODEYSO until resolution of the event. Permanently discontinue MODEYSO in patients who develop serious hypersensitivity reactions. QTc Interval Prolongation [see Warnings and Precautions ( 5.2 )] QTc absolute value >500 ms or An increase of >60 ms from baseline Interrupt MODEYSO until QTc interval ≤480 ms or return to baseline. Resume MODEYSO at the next lower dose level. Torsades de pointes, polymorphic ventricular tachycardia or signs or symptoms of serious or life-threatening arrhythmia Permanently discontinue MODEYSO. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 or 4 Interrupt MODEYSO until ≤Grade 1 or return to baseline. Resume MODEYSO at the next lower dose level. Recurrent Grade 4 Permanently discontinue MODEYSO. a. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. b. See Table 2 for recommended dosage reductions. 2.5 Dosage Modifications for CYP3A4 Inhibitors Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. • If concomitant use of a strong CYP3A4 inhibitor cannot be avoided for adult and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO from 625 mg to 375 mg once weekly. • If concomitant use of a moderate CYP3A4 inhibitor cannot be avoided for adult and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO from 625 mg to 500 mg once weekly. • The recommended dosage for pediatric patients weighing less than 52.5 kg who are receiving strong or moderate CYP3A4 inhibitors has not been established. Upon discontinuation of the CYP3A4 inhibitor, wait for 3 to 5 plasma half-lives of the CYP3A4 inhibitor, then increase MODEYSO to the dose that was taken before starting the CYP3A4 inhibitor [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )].
Side Effects Overview
6 ADVERSE REACTIONS The following potential clinically significant adverse reactions are described elsewhere in the labelling: • Hypersensitivity [see Warnings and Precautions ( 5.1 )] . • QTc Interval Prolongation [see Warnings and Precautions ( 5.2 )] . The most common (≥20%) adverse reactions are fatigue, headache, vomiting, nausea, and musculoskeletal pain. The most common (≥2%) Grade 3 or 4 laboratory abnormalities are decreased lymphocytes, decreased calcium, and increased alanine aminotransferase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chimerix at toll-free phone # 1-866-662-2679 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 WARNINGS AND PRECAUTIONS and below reflects exposure to MODEYSO at the recommended weight-based dose taken until disease progression or unacceptable toxicity in 376 adult and pediatric patients with glioma across four open-label clinical studies (ONC006, ONC013, ONC014, and ONC018) [see Clinical Studies ( 14 )] . Of the 376 patients who received MODEYSO, 35% were exposed for 6 months, and 17% were exposed for 1 year. The median age was 23 years (range: 3 to 80): 30% were 2 to 11 years old, 11% were 12 to 17 years old, 55% were 18 to 64 years old, and 3.7% were 65 years or older. Fifty-two percent (52%) were female; 74% White, 10% unknown race or race not reported, 9% Black or African American, 4% Asian, 2.9% other or multiple races; and 13% were of Hispanic or Latino ethnicity. Karnofsky/Lansky Performance Status (KPS/LPS) score was 80 to 100 in 66% of patients, 60 to 70 in 27%, and <60 in 7%. Relevant disease characteristics included primary tumor locations in the midline (91%) and non‑midline regions (9%); 33% had diffuse intrinsic pontine glioma (DIPG); 30% had multifocal disease; 79% had an H3 K27M mutation; 75% had recurrent disease. Serious adverse reactions occurred in 33% of patients who received MODEYSO. Serious adverse reactions in >2% of patients included hydrocephalus (5%), vomiting (4.3%), headache (3.2%), seizure (2.4%), and muscular weakness (2.1%). Fatal adverse reactions occurred in 1% of patients who received MODEYSO, including cardiac arrest (0.5%), intracranial hemorrhage (0.3%), and encephalopathy (0.3%). Permanent discontinuation of MODEYSO due to an adverse reaction occurred in 2.1% of patients. Adverse reactions which resulted in permanent discontinuation of MODEYSO in >1 patient included confusional state. Dosage interruptions of MODEYSO due to an adverse reaction occurred in 6% of patients. Adverse reactions which required dosage interruption in >1 patient included increased alanine aminotransferase, increased aspartate aminotransferase, decreased lymphocyte count, muscular weakness, and aspiration pneumonia. Dose reductions of MODEYSO due to an adverse reaction occurred in 2.7% of patients. Adverse reactions which required dose reductions in >1 patient included decreased neutrophil count and increased alanine aminotransferase. The most common adverse reactions (≥20%) were fatigue, headache, vomiting, nausea, and musculoskeletal pain. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased calcium, and increased alanine aminotransferase. Adverse reactions that occurred in at least 10% of patients treated with MODEYSO are presented in Table 4. Table 4: Adverse Reactions (≥10%) in Patients with Glioma Who Received MODEYSO in ONC006, ONC013, ONC014, and ONC018 Adverse Reaction MODEYSO (N=376) All Grades (%) Grade 3 or 4 (%) General Disorders Fatigue a 34 3.2 Gait disturbance 16 3.7 Nervous System Disorders Headache b 32 4.3 Cranial nerve disorders c 16 1.3 Hemiparesis 15 4.5 Dysarthria 13 2.7 Dizziness 13 0.5 Ataxia 10 1.3 Gastrointestinal Disorders Vomiting 24 2.7 Nausea 24 0.8 Dysphagia 13 2.1 Constipation 11 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain d 20 2.9 Muscular weakness 13 4.5 Metabolism and Nutrition Disorders Hyperglycemia 12 0.8 Skin and Subcutaneous Tissue Disorders Rash e 11 0.8 a. Includes asthenia. b. Includes head discomfort and sinus headache. c. Includes accessory nerve disorder, auditory nerve disorder, facial nerve disorder, facial paralysis, facial paresis, glossopharyngeal nerve disorder, hypoglossal nerve disorder, IIIrd nerve disorder, IIIrd nerve paralysis, IVth nerve disorder, IVth nerve paralysis, tongue paralysis, trigeminal nerve disorder, trigeminal neuralgia, VIth nerve disorder, VIth nerve paralysis, and VIth nerve paresis. d. Includes back pain, pain in extremity, arthralgia, neck pain, non-cardiac chest pain, myalgia, bone pain, musculoskeletal chest pain, musculoskeletal stiffness, and spinal pain. e. Includes dermatitis, dermatitis acneiform, dermatitis bullous, eczema, erythema multiforme, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. Other clinically important adverse reactions observed in less than 10% of patients treated with MODEYSO were peripheral neuropathy, seizure, diarrhea, tremor, and venous thromboembolic events. Selected laboratory abnormalities that occurred in at least 10% of patients treated with MODEYSO are presented in Table 5. Table 5: Select Laboratory Abnormalities (≥10%) that Worsened from Baseline in Patients with Glioma Receiving MODEYSO in ONC006, ONC013, ONC014, and ONC018 Laboratory Abnormality a MODEYSO b All Grades (%) Grade 3 or 4 (%) Chemistry Alanine aminotransferase increased 28 2.4 Aspartate aminotransferase increased 22 0.9 Calcium decreased 20 2.7 Sodium decreased 14 0.3 Potassium decreased 13 0.3 Glucose decreased 11 0 Alkaline phosphatase increased 11 0.3 Hematology Hemoglobin decreased 25 0.6 Neutrophils decreased 24 1.5 Lymphocytes decreased 19 7 a. Severity as defined by the National Cancer Institute CTCAE Version 5.0. b. The denominator for each laboratory parameter is based on the number of patients with a baseline and post‑treatment laboratory value available, which ranged from 325 to 330 patients.
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12.3 Pharmacokinetics Dordaviprone pharmacokinetics were predicted following a single dose in patients at the approved recommended dosage and are presented as mean (CV%) unless otherwise specified. Dordaviprone maximum concentration (C max ) is 2.8 mcg/mL (42%), and total systemic exposure (AUC) is 23 hr·mcg/mL (48%). Dordaviprone C max and AUC increased in a dose proportional manner over the dose range of 125 to 625 mg. No accumulation is observed following once weekly dosing. Absorption Dordaviprone median (min, max) time to maximum plasma concentration (T max ) is 1.4 hours (0.5, 5.6 hours). Food Effect Dordaviprone C max decreased by 40% with no change on AUC following administration with a high-fat meal (800 to 1,000 calories, 50% fat). Distribution Dordaviprone apparent (oral) volume of distribution is 450 L (40%). Dordaviprone plasma protein binding is 95% to 97% and independent of concentrations in vitro. The median blood-to-plasma ratio is 0.67 in vitro. Metabolism Dordaviprone is primarily metabolized by CYP3A4 with minor contribution from CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A5. Excretion Dordaviprone mean terminal half-life is 11 hours (30%), and the apparent clearance is approximately 27 L/hr (48%). Following a single dose of radiolabeled dordaviprone, 70% of the dose was recovered in urine and 20% in feces with no notable unchanged dordaviprone in urine or feces. Specific Populations No clinically significant differences in the pharmacokinetics of dordaviprone were observed based on age (3 to 90 years), sex, race (74% White, 9% Black or African American, or 5% Asian) or mild hepatic impairment (total bilirubin ≤ULN with AST >ULN or total bilirubin >1 to 1.5 times ULN with any AST). The effect of severe hepatic impairment (total bilirubin >3 times ULN with any AST) on dordaviprone pharmacokinetics is unknown. Pediatric Patients The exposure of dordaviprone in pediatrics weighing 10 kg and higher is predicted to be within the range of exposures predicted in adults at the recommended dosage. Renal Impairment Following a single oral dose of 375 mg (0.6 times the maximum approved recommended dose), dordaviprone AUC increased by 1.5-fold and C max by 1.1-fold in subjects with severe renal impairment (CLcr <30 mL/min, estimated by the Cockcroft-Gault equation). Hepatic Impairment Following a single oral dose of 125 mg (0.2 times the maximum approved recommended dose) dordaviprone AUC increased by 1.5-fold and C max by 1.2-fold in subjects with moderate hepatic impairment (Child Pugh class B). Drug Interaction Studies Clinical Studies and Model-Informed Approaches CYP3A4 Inhibitors: Dordaviprone C max increased by 2-fold and AUC increased by 4-fold following concomitant administration of itraconazole (strong CYP3A4 inhibitor) 200 mg once daily for 8 days. Dordaviprone C max is predicted to increase by ~1.5-fold and AUC by 2.5-fold following concomitant administration of fluconazole or erythromycin (moderate CYP3A4 inhibitor). CYP3A4 Inducers : Dordaviprone C max is predicted to decrease by 68% and AUC by 83% following concomitant administration of rifampin (strong CYP3A4 inducer) and dordaviprone C max is predicted to decrease by 44% and AUC by 65% following concomitant administration of efavirenz (moderate CYP3A4 inducer). Other Drugs : No clinically significant difference in dordaviprone pharmacokinetics is predicted when used concomitantly with cimetidine (weak CYP3A4 inhibitor). No clinically significant difference in dordaviprone pharmacokinetics is observed with multiple doses of a rabeprazole (proton-pump inhibitor). No clinically significant differences in the pharmacokinetics of the following drugs are predicted following concomitant use with MODEYSO: dabigatran etixelate (P-gp substrate), rosuvastatin (BCRP substrate), midazolam (CYP3A substrate), desipramine (CYP2D6 substrate) and repaglinide (CYP2C8 substrate). In Vitro Studies CYP Enzymes : Dordaviprone inhibits CYP1A2, CYP2B6, and CYP2C19 and induces CYP2B6. Transporter Systems : Dordaviprone inhibits MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, and OCT1.