ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following potential clinically significant adverse reactions are described elsewhere in the labelling:oHypersensitivity [see Warnings and Precautions (5.1)].oQTc Interval Prolongation [see Warnings and Precautions (5.2)].. oHypersensitivity [see Warnings and Precautions (5.1)].. oQTc 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 or 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. 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 months, and 17% were exposed for year. The median age was 23 years (range: to 80): 30% were 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 or 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 ONC018Adverse ReactionMODEYSO(N=376)All Grades (%)Grade or (%)General Disorders Fatiguea 343.2 Gait disturbance163.7Nervous System Disorders Headacheb 324.3 Cranial nerve disordersc 161.3 Hemiparesis154.5 Dysarthria132.7 Dizziness130.5 Ataxia101.3Gastrointestinal Disorders Vomiting242.7 Nausea240.8 Dysphagia132.1 Constipation110Musculoskeletal and Connective Tissue Disorders Musculoskeletal paind 202.9 Muscular weakness134.5Metabolism and Nutrition Disorders Hyperglycemia120.8Infections and Infestations Rashe 110.8a. 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 ONC018Laboratory Abnormalitya MODEYSOb All Grades (%)Grade or (%)Chemistry Alanine aminotransferase increased282.4 Aspartate aminotransferase increased220.9 Calcium decreased202.7 Sodium decreased140.3 Potassium decreased130.3 Glucose decreased110 Alkaline phosphatase increased110.3Hematology Hemoglobin decreased250.6 Neutrophils decreased241.5 Lymphocytes decreased197a. 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 baseline and post-treatment laboratory value available, which ranged from 325 to 330 patients.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Dordaviprone is protease activator of the mitochondrial caseinolytic protease (ClpP). Dordaviprone also inhibits the dopamine D2 receptor. Diffuse midline gliomas harboring an H3 K27M mutation are associated with the loss of H3 K27 trimethylation. In-vitro, dordaviprone activated the integrated stress response, induced apoptosis, and altered mitochondrial metabolism leading to restored histone H3 K27 trimethylation in H3 K27M-mutant diffuse glioma models.Dordaviprone exhibited antitumor activity in cell-based assays and in vivo models of H3 K27M-mutant diffuse glioma.. 12.2 Pharmacodynamics Cardiac ElectrophysiologyAt 1.2 times the maximum recommended dose, the estimated mean QTcF change was 11.8 msec (90% CI: 9.8, 13.7) [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].PharmacodynamicsThe exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of dordaviprone have not been fully characterized.. 12.3 Pharmacokinetics Dordaviprone pharmacokinetics were predicted following single dose in patients at the approved recommended dosage and are presented as mean (CV%) unless otherwise specified. Dordaviprone maximum concentration (Cmax) is 2.8 mcg/mL (42%), and total systemic exposure (AUC) is 23 hr.mcg/mL (48%). Dordaviprone Cmax and AUC increased in dose proportional manner over the dose range of 125 to 625 mg. No accumulation is observed following once weekly dosing.AbsorptionDordaviprone median (min, max) time to maximum plasma concentration (Tmax) is 1.4 hours (0.5, 5.6 hours).Food EffectDordaviprone Cmax decreased by 40% with no change on AUC following administration with high-fat meal (800 to 1,000 calories, 50% fat).DistributionDordaviprone apparent (oral) volume of distribution is 450 (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.MetabolismDordaviprone is primarily metabolized by CYP3A4 with minor contribution from CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A5.ExcretionDordaviprone mean terminal half-life is 11 hours (30%), and the apparent clearance is approximately 27 L/hr (48%).Following 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 PatientsThe 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 ImpairmentFollowing single oral dose of 375 mg (0.6 times the maximum approved recommended dose), dordaviprone AUC increased by 1.5-fold and Cmax by 1.1-fold in subjects with severe renal impairment (CLcr <30 mL/min, estimated by the Cockcroft-Gault equation). Hepatic ImpairmentFollowing single oral dose of 125 mg (0.2 times the maximum approved recommended dose) dordaviprone AUC increased by 1.5-fold and Cmax by 1.2-fold in subjects with moderate hepatic impairment (Child Pugh class B).Drug Interaction StudiesClinical Studies and Model-Informed ApproachesCYP3A4 Inhibitors: Dordaviprone Cmax increased by 2-fold and AUC increased by 4-fold following concomitant administration of itraconazole (strong CYP3A4 inhibitor) 200 mg once daily for days. Dordaviprone Cmax 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 Cmax is predicted to decrease by 68% and AUC by 83% following concomitant administration of rifampin (strong CYP3A4 inducer) and dordaviprone Cmax 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The efficacy of MODEYSO was evaluated in adult and pediatric patients with glioma across five open-label, non-randomized clinical studies conducted in the U.S. (ONC006 [NCT02525692], ONC013 [NCT03295396], ONC014 [NCT03416530], ONC016 [NCT05392374], and ONC018 [NCT03134131]). Pre-specified criteria were defined to establish an integrated efficacy population; eligible patients were required to have received single-agent MODEYSO, have diffuse midline glioma harboring an H3 K27M mutation with progressive and measurable disease per Response Assessment in Neuro-Oncology-High Grade Glioma (RANO-HGG) criteria, be >=90 days post-radiation therapy, have adequate washout from prior anticancer therapies, have Karnofsky Performance Status/Lansky Performance Status (KPS/LPS) score >=60, and have stable or decreasing corticosteroid use. Patients with diffuse intrinsic pontine glioma (DIPG), primary spinal tumors, atypical histologies, or cerebrospinal fluid dissemination were excluded. Patients received weight-based dosing of MODEYSO until disease progression or unacceptable toxicity. The integrated efficacy population included 50 patients who met these criteria. The major efficacy outcome measure was overall response rate (ORR) assessed by blinded independent central review (BICR) according to RANO 2.0 criteria. Additional efficacy outcome measures were BICR-assessed ORR according to RANO-HGG criteria and Response Assessment in Neuro-Oncology-Low Grade Glioma (RANO-LGG) criteria, duration of response, and time to response.Baseline demographics were: median age 31 years (range: to 70) with 6% younger than 17 years of age; 46% female; 80% White, 6% Black or African American, 2% Asian, 10% other races, and 2% race unknown; 8% were of Hispanic or Latino ethnicity; 72% had KPS/LPS 80 to 100. Relevant disease characteristics included 72% treated at first recurrence, 28% had or more recurrences; primary tumor location was thalamic in 52% and non-thalamic midline region in 48%; 88% received prior temozolomide; 62% were receiving corticosteroids at baseline; median time from end of prior radiation was 7.4 months (range: 3.0 to 102.1).Efficacy results are shown in Table 8.Table 8: Efficacy Results for Patients with Diffuse Midline Glioma Harboring an H3 K27M Mutation in Studies ONC006, ONC013, ONC014, ONC016, and ONC018 per RANO 2.0Efficacy ParameterMODEYSON=50Overall Response Rate (95% CI)a 22% (12, 36) Partial response (PR)16% Minor response (MR)6%Duration of ResponseN=11 Median (95% CI)b, months10.3 (7.3, 15.2) with observed DOR >=6 monthsc 73% with observed DOR >=12 monthsc 27%Abbreviations: BICR=blinded independent central review; CI=confidence interval; RANO=Response Assessment in Neuro-Oncology.a. Confirmed overall response rate assessed by BICR; CI based on Clopper-Pearson method.b. Based on Kaplan-Meier estimate.c. Based on observed time.Among responders, the median time to response was 3.6 months (range 1.6, 15.6).Using BICR-assessed RANO 2.0 criteria, there was one additional responder based on the integrated response assessment, which takes into account corticosteroid use and performance status. Based on BICR-assessed RANO-HGG criteria (n=50), the ORR was 20% (95% CI: 10, 34), with complete and partial responses. Based on BICR-assessed RANO-LGG criteria (n=50), the ORR was 20% (95% CI: 10, 34), with partial and minor responses.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oSelect patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens. (2.1)oMonitor ECG and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated. (2.2)oThe recommended dose in adult patients is 625 mg orally once weekly. (2.3)oThe recommended dose in pediatric patients weighing >=10 kg is based on body weight (see Table 1). (2.3)oTake MODEYSO orally once weekly on an empty stomach (at least hour before or hours after food intake). (2.3)oContinue MODEYSO until disease progression or unacceptable toxicity. (2.3). oSelect patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens. (2.1). oMonitor ECG and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated. (2.2). oThe recommended dose in adult patients is 625 mg orally once weekly. (2.3). oThe recommended dose in pediatric patients weighing >=10 kg is based on body weight (see Table 1). (2.3). oTake MODEYSO orally once weekly on an empty stomach (at least hour before or hours after food intake). (2.3). oContinue MODEYSO until disease progression or unacceptable toxicity. (2.3). 2.1Patient 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.. 2.2Recommended 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 )].. 2.3Recommended Dosage and Administration Take MODEYSO on an empty stomach (at least hour before or hours after food intake) [see Clinical Pharmacology (12.3)].AdultsThe recommended dosage of MODEYSO is 625 mg orally once weekly.PediatricsThe recommended dosage of MODEYSO in pediatric patients aged to <17 years who weigh at least 10 kg is based on body weight (Table 1). 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 PatientsBody Weight (kg)Recommended Dosage10 kg to <12.5 kg125 mg Once Weekly12.5 kg to <27.5 kg250 mg Once Weekly27.5 kg to <42.5 kg375 mg Once Weekly42.5 kg to <52.5 kg500 mg Once Weekly>=52.5 kg625 mg Once WeeklyContinue 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 liquid [see Patient Counseling Information (17)]. Once mixed, administer within hours of preparation, or discard and mix new dose.VomitingIf vomiting occurs after taking dose, do not take an additional dose and take the next dose at the regularly scheduled time.Missed DoseIf dose is missed within days, take the missed dose as soon as possible. If dose is missed by more than days, skip the missed dose and take the next dose at the scheduled time.. 2.4Dosage 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 ReactionsPatients Weight (kg)First Dosage ReductionSecond Dosage ReductionPediatric patients 10 kg to <12.5 kgPermanently discontinueN/APediatric patients 12.5 kg to <27.5 kg125 mg once weeklyPermanently discontinuePediatric patients 27.5 kg to <42.5 kg250 mg once weekly125 mg once weeklyPediatric patients 42.5 kg to <52.5 kg375 mg once weekly250 mg once weeklyPediatric patients >=52.5 kg and adult patients500 mg once weekly375 mg once weeklyThe recommended dosage modifications for adverse reactions are provided in Table 3.Table 3: Recommended Dosage Modifications for Adverse ReactionsAdverse ReactionSeveritya Dosage Modificationb Hypersensitivity [see Warnings and Precautions (5.1)] Any gradeIf 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 msorAn increase of >60 ms from baselineInterrupt 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 arrhythmiaPermanently discontinue MODEYSO.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade or 4Interrupt MODEYSO until <=Grade or return to baseline.Resume MODEYSO at the next lower dose level.Recurrent Grade 4Permanently discontinue MODEYSO.a. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.b. See Table for recommended dosage reductions.. 2.5Dosage Modifications for CYP3A4 Inhibitors Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. oIf concomitant use of 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. oIf concomitant use of 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. oThe 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 to 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)]. oIf concomitant use of 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. oIf concomitant use of 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. oThe recommended dosage for pediatric patients weighing less than 52.5 kg who are receiving strong or moderate CYP3A4 inhibitors has not been established.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oCYP3A4 Inhibitors: Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. If concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO as recommended. (2.5, 7.1)oCYP3A4 Inducers: Avoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO. (7.1)oDrugs Known to Prolong QTc Interval: Avoid concomitant use of MODEYSO with products known to prolong the QTc interval. If concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product. (5.2, 7.2, 12.2). oCYP3A4 Inhibitors: Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. If concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO as recommended. (2.5, 7.1). oCYP3A4 Inducers: Avoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO. (7.1). oDrugs Known to Prolong QTc Interval: Avoid concomitant use of MODEYSO with products known to prolong the QTc interval. If concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product. (5.2, 7.2, 12.2). 7.1Effect of Other Drugs on MODEYSO Table describes drug interactions where concomitant use of another drug affects MODEYSO.Table 6: Effect of Other Drugs on MODEYSOStrong and Moderate CYP3A4 InhibitorsPrevention or ManagementoAvoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO.oIf concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the MODEYSO dose as recommended [see Dosage and Administration (2.5)].Mechanism and Clinical EffectsoDordaviprone is CYP3A4 substrate.oStrong and moderate CYP3A4 inhibitors increase dordaviprone exposure [see Clinical Pharmacology (12.3)], which may increase the risk of MODEYSO-related adverse reactions [see Warnings and Precautions (5.2)].Strong or Moderate CYP3A4 InducersPrevention or ManagementoAvoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO.Mechanism and Clinical EffectsoDordaviprone is CYP3A4 substrate.oStrong and moderate CYP3A4 inducers decrease dordaviprone exposure [see Clinical Pharmacology (12.3)], which may reduce the anti-tumor activity of MODEYSO.. oAvoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO.. oIf concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the MODEYSO dose as recommended [see Dosage and Administration (2.5)].. oDordaviprone is CYP3A4 substrate.. oStrong and moderate CYP3A4 inhibitors increase dordaviprone exposure [see Clinical Pharmacology (12.3)], which may increase the risk of MODEYSO-related adverse reactions [see Warnings and Precautions (5.2)].. oAvoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO.. oDordaviprone is CYP3A4 substrate.. oStrong and moderate CYP3A4 inducers decrease dordaviprone exposure [see Clinical Pharmacology (12.3)], which may reduce the anti-tumor activity of MODEYSO.. 7.2Drugs Known to Prolong QTc Interval Table describes drug interactions associated with QTc interval prolongation when used concomitantly with MODEYSO.Table 7: Products that Prolong QTc IntervalProducts that Prolong QTc IntervalPrevention or ManagementoAvoid concomitant use of MODEYSO with products known to prolong the QTc interval. oIf concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].Clinical ImpactoMODEYSO causes concentration dependent QTc interval prolongation [see Clinical Pharmacology (12.2)]. oConcomitant use of MODEYSO with other QT-prolonging products may increase the risk of QTc-associated arrhythmias [see Warnings and Precautions (5.2)].. oAvoid concomitant use of MODEYSO with products known to prolong the QTc interval. oIf concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].. oMODEYSO causes concentration dependent QTc interval prolongation [see Clinical Pharmacology (12.2)]. oConcomitant use of MODEYSO with other QT-prolonging products may increase the risk of QTc-associated arrhythmias [see Warnings and Precautions (5.2)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient and caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).HypersensitivityAdvise patients that MODEYSO can cause hypersensitivity. Inform patients about the signs and symptoms of hypersensitivity reactions and instruct patients or caregivers to seek immediate medical attention if symptoms occur [see Warnings and Precautions (5.1)].QTc Interval ProlongationAdvise patients that MODEYSO can cause QTc interval prolongation. Inform patients of the signs and symptoms of QTc prolongation and instruct patients or caregivers to seek immediate medical attention if symptoms occur [see Warnings and Precautions 5.2 )].Drug InteractionsInform patients that MODEYSO may interact with some drugs. Advise patients to inform their healthcare provider about all medications they are taking, including prescription and over-the-counter drugs, vitamins, and herbal products. Additionally, patients should consult their healthcare provider before starting or stopping any prescription drug, nonprescription drug, or supplement [see Drug Interactions 7)].Administration Instruct patients and caregivers to read the Instructions for Use before taking MODEYSO, and each time the patient gets refill as there may be new information they need to know.Patients should take MODEYSO orally once weekly on an empty stomach (no food intake at least hour prior to or hours after taking MODEYSO). Take the prescribed dose at the same time on the same day of the week [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].Instruct patients to swallow capsules whole. For patients unable to swallow capsules whole, instruct patients to open capsules and mix contents with approximately 15 to 30 mL of liquid (sports drink, apple juice, lemonade, or water). Instruct patients to drink the mixture. After drinking the mixture, instruct patients to add another 15 to 30 mL of the liquid to the container, swirl to dissolve any remaining medication, and then drink the remaining contents [see Dosage and Administration 2.3) and Instructions for Use].Embryo-fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus.Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].Advise females of reproductive potential to use effective contraception during treatment with MODEYSO and for month after the last dose [see Use in Specific Populations (8.3)].Advise male patients with female partners of reproductive potential to use effective contraception during treatment with MODEYSO and for month after the last dose [see Use in Specific Populations (8.3)].LactationAdvise women not to breastfeed during treatment with MODEYSO and for week after the last dose [see Use in Specific Populations (8.2)].Distributed by:Jazz Pharmaceuticals, Inc.Palo Alto, CA 94306.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use INSTRUCTIONS FOR USEMODEYSO [moh-DAY-soh](dordaviprone)capsules, for oral useThis Instructions for Use contains information on how to prepare and take or give MODEYSO capsules as liquid. Read this Instructions for Use carefully before you prepare and take or give dose of MODEYSO for the first time and each time you or your child gets prescription refill. There may be new information. This information does not take the place of talking with your healthcare provider about your or your childs medical condition or treatment.Important Information You Need to Know Before Preparing and Taking or Giving MODEYSO Capsules as Liquid.oFor oral use only (take by mouth). oTake or give MODEYSO exactly as your healthcare provider tells you. Do not change the dose or stop taking MODEYSO without talking to your healthcare provider. oTake or give MODEYSO time each week on the same day of the week. Take or give all of the capsules prescribed for your dose at the same time.oTake or give MODEYSO on an empty stomach, at least hour before or hours after eating food.oIf you or your child cannot swallow the capsules whole, the capsules can be dissolved in sports drink, apple juice, lemonade, or water and taken as liquid.oCheck the expiration date on the MODEYSO bottle. Do not take or give MODEYSO if the expiration date has passed. Contact your pharmacist if the medicine is expired. oDo not take or give MODEYSO if the bottle or the capsules are broken or damaged. Contact your healthcare provider or pharmacist for replacement.Supplies needed to prepare and dissolve MODEYSO capsules to take or give as liquid.Section A: Preparing and dissolving MODEYSO capsules to take or give as liquidPreparing to dissolve the capsulesStep 1: Wash and dry your hands.Place the MODEYSO bottle on clean, flat surface. Gather the rest of the supplies you will need so they are ready to use.Step 2:Check the prescribed dose. Count out the number of MODEYSO capsules needed for the dose.Opening the capsulesStep 3:Hold the capsule over clean, empty cup.Carefully open the capsule by gently pulling and twisting both ends. Slowly empty the contents (powder) into the cup. If any powder remains inside the capsule shell, gently tap the shell over the cup to remove any remaining powder.Step 4:Repeat Step for each additional capsule needed for the prescribed dose.Dissolving the capsules in liquidStep 5: Use tablespoon (15 mL) to measure the liquid. Add to tablespoons (about 15 mL to 30 mL) of your chosen liquid (sports drink, apple juice, lemonade, or water) to the cup. Step 6:Gently swirl the liquid around the cup before taking or giving the mixture until no large chunks of powder remain. The mixture may look cloudy. This is normal and okay. Section B: Taking or giving dose of MODEYSO as liquidStep 7:Take or give all of the mixture as soon as possible. Always take or give the mixture within hours of preparing it. An oral dosing syringe may be used to take or give the mixture by mouth. Refer to Section for detailed instructions.The mixture may be taken or given through feeding tube. Refer to Section for detailed instructions.Throw away the mixture if it is not taken within hours of preparing it and go back to Section to prepare new dose.If vomiting happens after taking or giving the dose, or not all of the liquid is swallowed, do not take or give another dose. Take the next dose of MODEYSO on the next regularly scheduled day of the week.Step 8:After taking or giving the dose, add to more tablespoons (about 15 mL to 30 mL) of your chosen liquid to the cup.Step 9: Swirl the liquid around the cup to make sure any remaining medicine is mixed with the liquid.This helps make sure that no medicine is left behind.Step 10:Repeat Step 7.Section C: Disposing of (throwing away) empty MODEYSO capsule shells and cleaning the cupStep 11:After taking or giving the dose, throw empty capsule shells in the trash. Do not save or reuse empty capsules.Step 12:After taking or giving the dose, rinse the cup with warm running water to remove all remaining medicine. Step 13:Wash your hands with soap and water.Section D: Taking or giving dose of MODEYSO as liquid using an oral dosing syringeIf you are using an oral dosing syringe to take or give MODEYSO by mouth:1.Follow Steps through in Section to prepare the MODEYSO liquid mixture in cup. 2.If there is cap, remove the cap of the oral dosing syringe.3.Push the plunger down into the oral dosing syringe as far as it will go. 4.Place the oral dosing syringe tip in the mixture in the cup. Pull up on the plunger to draw all the mixture into the oral dosing syringe.5.You or your child should sit upright to take or give dose of MODEYSO. Place the tip of the oral dosing syringe towards the inside of the cheek in your or your childs mouth.6.Slowly push the medicine into the mouth by pressing down on the plunger, allowing time for swallowing. Do not forcefully push the plunger. This may cause choking.7.You or your child may drink other liquids right away after swallowing the mixture.8.Steps through in this section may be repeated until all the mixture has been taken or given. 9.After taking or giving the dose, add to more tablespoons (about 15 mL to 30 mL) of your chosen liquid to the cup. 10.Swirl the liquid around the cup to make sure any remaining medicine is mixed with the liquid. This helps make sure that no medicine is left behind.11.Using the oral dosing syringe, repeat Steps through in this section until all of the mixture in the cup has been taken or given.12.After completing Step 11 in this section, remove the plunger from the oral dosing syringe and rinse each part with warm running water to remove all remaining medicine. Allow the parts to air dry completely before putting the syringe back together.Refer to Section C: Disposing of (throwing away) empty MODEYSO capsule shells and cleaning the cup. Section E: Taking or giving dose of MODEYSO as liquid using feeding tubeMODEYSO may be given through naso-gastric (ng) or gastrostomy (g) feeding tube, as directed by your healthcare provider. 1.Follow Steps through in Section to prepare the MODEYSO liquid mixture in cup. 2.Flush the feeding tube according to the manufacturers instructions before each dose. 3.Draw up the mixture into catheter tip syringe. 4.Connect the syringe containing the mixture to the feeding tube.5.Apply slow, steady pressure to the plunger to give all the contents of the syringe through the feeding tube.6.After giving the dose, add to more tablespoons (about 15 mL to 30 mL) of your chosen liquid to the cup. 7.Swirl the liquid around the cup to make sure any remaining medicine is mixed with the liquid. This helps make sure that no medicine is left behind. 8.Using the syringe, repeat Steps through in this section until all the mixture in the cup has been given.9.After completing Step in this section, flush the feeding tube according to the manufacturers instructions.10.After completing Step in this section, remove the plunger from the syringe and rinse each part with warm running water to remove all remaining medicine. Allow the parts to air dry completely before putting the syringe back together.Refer to Section C: Disposing of (throwing away) empty MODEYSO capsule shells and cleaning the cup. Storing MODEYSOoStore MODEYSO at room temperature between 68F to 77F (20C to 25C). oThe MODEYSO bottle has child-resistant closure.Keep MODEYSO and all medicines out of the reach of children.Distributed by:Jazz Pharmaceuticals, Inc.Palo Alto, CA 94306 For more information, contact Chimerix, Inc. at 1-866-662-2679.This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 08/2025. oFor oral use only (take by mouth). oTake or give MODEYSO exactly as your healthcare provider tells you. Do not change the dose or stop taking MODEYSO without talking to your healthcare provider. oTake or give MODEYSO time each week on the same day of the week. Take or give all of the capsules prescribed for your dose at the same time.. oTake or give MODEYSO on an empty stomach, at least hour before or hours after eating food.. oIf you or your child cannot swallow the capsules whole, the capsules can be dissolved in sports drink, apple juice, lemonade, or water and taken as liquid.. oCheck the expiration date on the MODEYSO bottle. Do not take or give MODEYSO if the expiration date has passed. Contact your pharmacist if the medicine is expired. oDo not take or give MODEYSO if the bottle or the capsules are broken or damaged. Contact your healthcare provider or pharmacist for replacement.. 1.Follow Steps through in Section to prepare the MODEYSO liquid mixture in cup. 2.If there is cap, remove the cap of the oral dosing syringe.. 3.Push the plunger down into the oral dosing syringe as far as it will go. 4.Place the oral dosing syringe tip in the mixture in the cup. Pull up on the plunger to draw all the mixture into the oral dosing syringe.. 5.You or your child should sit upright to take or give dose of MODEYSO. Place the tip of the oral dosing syringe towards the inside of the cheek in your or your childs mouth.. 6.Slowly push the medicine into the mouth by pressing down on the plunger, allowing time for swallowing. Do not forcefully push the plunger. This may cause choking.. 7.You or your child may drink other liquids right away after swallowing the mixture.. 8.Steps through in this section may be repeated until all the mixture has been taken or given. 9.After taking or giving the dose, add to more tablespoons (about 15 mL to 30 mL) of your chosen liquid to the cup. 10.Swirl the liquid around the cup to make sure any remaining medicine is mixed with the liquid. This helps make sure that no medicine is left behind.. 11.Using the oral dosing syringe, repeat Steps through in this section until all of the mixture in the cup has been taken or given.. 12.After completing Step 11 in this section, remove the plunger from the oral dosing syringe and rinse each part with warm running water to remove all remaining medicine. Allow the parts to air dry completely before putting the syringe back together.. 1.Follow Steps through in Section to prepare the MODEYSO liquid mixture in cup. 2.Flush the feeding tube according to the manufacturers instructions before each dose. 3.Draw up the mixture into catheter tip syringe. 4.Connect the syringe containing the mixture to the feeding tube.. 5.Apply slow, steady pressure to the plunger to give all the contents of the syringe through the feeding tube.. 6.After giving the dose, add to more tablespoons (about 15 mL to 30 mL) of your chosen liquid to the cup. 7.Swirl the liquid around the cup to make sure any remaining medicine is mixed with the liquid. This helps make sure that no medicine is left behind. 8.Using the syringe, repeat Steps through in this section until all the mixture in the cup has been given.. 9.After completing Step in this section, flush the feeding tube according to the manufacturers instructions.. 10.After completing Step in this section, remove the plunger from the syringe and rinse each part with warm running water to remove all remaining medicine. Allow the parts to air dry completely before putting the syringe back together.. oStore MODEYSO at room temperature between 68F to 77F (20C to 25C). oThe MODEYSO bottle has child-resistant closure.. image-02. image-03. image-04. image-05. image-06. image-07. image-08. image-09. image-10. image-11. image-12. image-13. image-14. image-15.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Dordaviprone pharmacokinetics were predicted following single dose in patients at the approved recommended dosage and are presented as mean (CV%) unless otherwise specified. Dordaviprone maximum concentration (Cmax) is 2.8 mcg/mL (42%), and total systemic exposure (AUC) is 23 hr.mcg/mL (48%). Dordaviprone Cmax and AUC increased in dose proportional manner over the dose range of 125 to 625 mg. No accumulation is observed following once weekly dosing.AbsorptionDordaviprone median (min, max) time to maximum plasma concentration (Tmax) is 1.4 hours (0.5, 5.6 hours).Food EffectDordaviprone Cmax decreased by 40% with no change on AUC following administration with high-fat meal (800 to 1,000 calories, 50% fat).DistributionDordaviprone apparent (oral) volume of distribution is 450 (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.MetabolismDordaviprone is primarily metabolized by CYP3A4 with minor contribution from CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A5.ExcretionDordaviprone mean terminal half-life is 11 hours (30%), and the apparent clearance is approximately 27 L/hr (48%).Following 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 PatientsThe 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 ImpairmentFollowing single oral dose of 375 mg (0.6 times the maximum approved recommended dose), dordaviprone AUC increased by 1.5-fold and Cmax by 1.1-fold in subjects with severe renal impairment (CLcr <30 mL/min, estimated by the Cockcroft-Gault equation). Hepatic ImpairmentFollowing single oral dose of 125 mg (0.2 times the maximum approved recommended dose) dordaviprone AUC increased by 1.5-fold and Cmax by 1.2-fold in subjects with moderate hepatic impairment (Child Pugh class B).Drug Interaction StudiesClinical Studies and Model-Informed ApproachesCYP3A4 Inhibitors: Dordaviprone Cmax increased by 2-fold and AUC increased by 4-fold following concomitant administration of itraconazole (strong CYP3A4 inhibitor) 200 mg once daily for days. Dordaviprone Cmax 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 Cmax is predicted to decrease by 68% and AUC by 83% following concomitant administration of rifampin (strong CYP3A4 inducer) and dordaviprone Cmax 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 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.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Package Insert PATIENT INFORMATIONMODEYSO (moh-DAY-soh)(dordaviprone)capsules, for oral useWhat is MODEYSO MODEYSO is prescription medicine used to treat adults and children year of age and older with certain type of brain tumor called diffuse midline glioma that has specific H3 K27M gene mutation and has worsened after other treatments.It is not known if MODEYSO is safe and effective in children less than year of age.Before taking MODEYSO, tell your healthcare provider about all your medical conditions, including if you: ohave heart failure or heart rhythm problems, including QT prolongation and long QT syndrome.oare pregnant or plan to become pregnant. MODEYSO can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with MODEYSO. oYour healthcare provider should check to see if you are pregnant before you begin treatment with MODEYSO.oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with MODEYSO and for month after your last dose. oMales with partners who are able to become pregnant should use effective contraception during treatment with MODEYSO and for month after your last dose. oare breastfeeding or plan to breastfeed. It is not known if MODEYSO passes into breast milk. Do not breastfeed during treatment with MODEYSO and for 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. MODEYSO and other medicines may affect the way each other work and may cause serious side effects. You can ask your healthcare provider or pharmacist for list of medications that interact with MODEYSO.Know the medicines you take. Keep list of your medicines to show your healthcare provider and pharmacist. Do not start or stop taking any new medicines without first talking to your healthcare provider. How should take MODEYSO oTake MODEYSO exactly as your healthcare provider tells you. oDo not change your dose or stop taking MODEYSO without talking to your healthcare provider.oYour healthcare provider may change your dose, temporarily stop, or completely stop treatment with MODEYSO if you develop certain side effects.oTake MODEYSO time each week on the same day of the week. Take all of the capsules prescribed for your dose at the same time.oTake MODEYSO on an empty stomach, at least hour before or hours after eating food. oSwallow MODEYSO capsules whole. If the capsules cannot be swallowed whole, see the detailed Instructions for Use for how to prepare and take or give MODEYSO as liquid.oIf vomiting happens after taking dose of MODEYSO, do not take another dose. Take the next dose of MODEYSO on the next regularly scheduled weekly day of the week. oIf you miss weekly dose of MODEYSO by:o2 days or less, take the missed dose as soon as you remember. Take the next dose of MODEYSO on the next regularly scheduled day of the week.oMore than days, skip the missed dose and take the next dose of MODEYSO on the next regularly scheduled day of the week.What are the possible side effects of MODEYSO MODEYSO may cause serious side effects, including: oAllergic reactions. Allergic reactions may happen during treatment with MODEYSO and can be severe. Stop taking MODEYSO and get immediate emergency medical help right away if you get any signs or symptoms of allergic reactions, including:orashohivesofeverofeeling faint or dizzyowheezing or trouble breathingoswelling of the face or throat oHeart rhythm problems (QTc interval prolongation). MODEYSO can cause changes in the electrical activity of your heart and can increase your chance of getting type of abnormal heart rhythm that can lead to sudden death called torsades de pointes. Before you start treatment and during treatment as needed, your healthcare provider will check your heart using an electrocardiograph (ECG) and check your blood levels of salts called electrolytes. Get emergency medical help right away if you get any signs or symptoms of abnormal heart rhythm, including:ofeeling lightheaded or faintodizzinessofast heartbeatoheart palpitationsoshortness of breath The most common side effects of MODEYSO include: otirednessoheadacheovomitingonauseaomuscle, joint, and bone painThe most common abnormal blood tests include decreased white blood cells, decreased red blood cells, decreased calcium, and increased liver enzymes.MODEYSO may cause fertility problems in males and females, which may affect your ability to have children. Talk to your healthcare provider if this is concern for you.These are not all of the possible side effects of MODEYSO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You may also report side effects to Chimerix, Inc. at 1-866-662-2679.How should store MODEYSO oStore MODEYSO at room temperature between 68F to 77F (20C to 25C). oThe MODEYSO bottle has child-resistant closure. Keep MODEYSO and all medicines out of the reach of children.General information about the safe and effective use of MODEYSO. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use MODEYSO for condition for which it was not prescribed. Do not give MODEYSO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about MODEYSO that is written for health professionals.What are the ingredients in MODEYSO Active ingredient: dordaviproneInactive ingredients: magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The capsule shell contains hypromellose and titanium dioxide. The black printing ink contains alcohol, D&C yellow 10, FD&C blue 1, FD&C blue 2, FD&C red 40, ferrosoferric oxide, methyl alcohol, N-butyl alcohol, propylene glycol, and shellac glaze (20% esterified). Distributed by:Jazz Pharmaceuticals, Inc.Palo Alto, CA 94306For more information, contact Chimerix, Inc. at 1-866-662-2679.This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 08/2025. ohave heart failure or heart rhythm problems, including QT prolongation and long QT syndrome.. oare pregnant or plan to become pregnant. MODEYSO can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with MODEYSO. oYour healthcare provider should check to see if you are pregnant before you begin treatment with MODEYSO.oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with MODEYSO and for month after your last dose. oMales with partners who are able to become pregnant should use effective contraception during treatment with MODEYSO and for month after your last dose. oYour healthcare provider should check to see if you are pregnant before you begin treatment with MODEYSO.. oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with MODEYSO and for month after your last dose. oMales with partners who are able to become pregnant should use effective contraception during treatment with MODEYSO and for month after your last dose. oare breastfeeding or plan to breastfeed. It is not known if MODEYSO passes into breast milk. Do not breastfeed during treatment with MODEYSO and for week after your last dose. Talk to your healthcare provider about the best way to feed your baby during this time.. oTake MODEYSO exactly as your healthcare provider tells you. oDo not change your dose or stop taking MODEYSO without talking to your healthcare provider.. oYour healthcare provider may change your dose, temporarily stop, or completely stop treatment with MODEYSO if you develop certain side effects.. oTake MODEYSO time each week on the same day of the week. Take all of the capsules prescribed for your dose at the same time.. oTake MODEYSO on an empty stomach, at least hour before or hours after eating food. oSwallow MODEYSO capsules whole. If the capsules cannot be swallowed whole, see the detailed Instructions for Use for how to prepare and take or give MODEYSO as liquid.. oIf vomiting happens after taking dose of MODEYSO, do not take another dose. Take the next dose of MODEYSO on the next regularly scheduled weekly day of the week. oIf you miss weekly dose of MODEYSO by:o2 days or less, take the missed dose as soon as you remember. Take the next dose of MODEYSO on the next regularly scheduled day of the week.oMore than days, skip the missed dose and take the next dose of MODEYSO on the next regularly scheduled day of the week.. o2 days or less, take the missed dose as soon as you remember. Take the next dose of MODEYSO on the next regularly scheduled day of the week.. oMore than days, skip the missed dose and take the next dose of MODEYSO on the next regularly scheduled day of the week.. oAllergic reactions. Allergic reactions may happen during treatment with MODEYSO and can be severe. Stop taking MODEYSO and get immediate emergency medical help right away if you get any signs or symptoms of allergic reactions, including:orashohivesofeverofeeling faint or dizzyowheezing or trouble breathingoswelling of the face or throat orash. ohives. ofever. ofeeling faint or dizzy. owheezing or trouble breathing. oswelling of the face or throat. oHeart rhythm problems (QTc interval prolongation). MODEYSO can cause changes in the electrical activity of your heart and can increase your chance of getting type of abnormal heart rhythm that can lead to sudden death called torsades de pointes. Before you start treatment and during treatment as needed, your healthcare provider will check your heart using an electrocardiograph (ECG) and check your blood levels of salts called electrolytes. Get emergency medical help right away if you get any signs or symptoms of abnormal heart rhythm, including:ofeeling lightheaded or faintodizzinessofast heartbeatoheart palpitationsoshortness of breath ofeeling lightheaded or faint. odizziness. ofast heartbeat. oheart palpitations. oshortness of breath. otiredness. oheadache. ovomiting. onausea. omuscle, joint, and bone pain. oStore MODEYSO at room temperature between 68F to 77F (20C to 25C). oThe MODEYSO bottle has child-resistant closure.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Advise not to breastfeed. (8.2). oLactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], MODEYSO can cause fetal harm when administered to pregnant woman. There are no available data on MODEYSO use in pregnant women to inform drug-associated risk. In animal embryo-fetal development studies, oral administration of dordaviprone to pregnant rats and rabbits during the period of organogenesis caused embryofetal mortality, alterations to growth, and structural abnormalities at exposures below the human exposure at the highest recommended dose (see Data). Advise pregnant women of the potential risk to 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. DataAnimal DataIn an embryo-fetal development study, dordaviprone was administered orally to pregnant rats during the period of organogenesis from gestation day to 17 at doses of 25, 62.5, and 125 mg/kg/day. Dordaviprone caused maternal mortality, pre-implantation loss, and embryo-fetal toxicity of absent eye and small renal papillae at the 125 mg/kg/day dose (>=2 times the human recommended doses based on body surface area). In an embryo-fetal development study, dordaviprone was administered orally to pregnant rabbits during the period of organogenesis from gestation days to 19 at doses of 10, 25, 62.5, and 100 mg/kg/day. Dordaviprone caused maternal mortality, embryo-fetal mortality, lower fetal weights, and structural malformations of the face, limbs, vessels, brain, and heart at doses of >=10 mg/kg/day (>=0.4 times the human exposure at the highest recommended dose based on Cmax).. 8.2 Lactation Risk Summary There are no data on the presence of dordaviprone or its metabolites in human milk, their effects on breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children from MODEYSO, advise women not to breastfeed during treatment with MODEYSO and for week after the last dose.. 8.3 Females and Males of Reproductive Potential MODEYSO can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating MODEYSO [see Use in Specific Populations (8.1)].Contraception FemalesAdvise females of reproductive potential to use effective contraception during treatment with MODEYSO and for month after the last dose [see Use in Specific Populations (8.1)].MalesAdvise male patients with female partners of reproductive potential to use effective contraception during treatment with MODEYSO and for month after the last dose.InfertilityBased on the mechanism of action of dordaviprone (dopamine D2 receptor inhibition and alterations to mitochondrial function), treatment with MODEYSO may adversely impact fertility in males and females.. 8.4 Pediatric Use The safety and effectiveness of MODEYSO has been established in pediatric patients aged year and older for the treatment of diffuse midline glioma harboring an H3 K27M mutation [see Adverse Reactions (6.1) and Clinical Studies (14)]. The efficacy of MODEYSO was evaluated in pediatric patients aged to 17 years with diffuse midline glioma harboring an H3 K27M mutation. Safety was evaluated in 154 pediatric patients with glioma aged to 17 years who received MODEYSO at the recommended dose across four open-label clinical studies (ONC006, ONC013, ONC014, and ONC018). Of these 154 patients, 73% were to 11 years of age and 27% were 12 to 17 years of age. No additional safety signals were observed in pediatric patients [see Adverse Reactions (6.1)]. The exposure of dordaviprone in pediatric patients weighing 10 kg and higher is predicted to be within the range of exposures predicted in adults at the recommended dosage [see Clinical Pharmacology (12.3)]. The safety and effectiveness of MODEYSO have not been established in pediatric patients less than year of age.. 8.5 Geriatric Use Of the 376 patients with glioma who received MODEYSO at the recommended dose across four open-label clinical studies (ONC006, ONC013, ONC014, and ONC018), 3.7% of patients were >=65 years of age and 0.5% were >=75 years of age. Clinical studies of MODEYSO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypersensitivity: If clinically significant hypersensitivity or anaphylaxis occur, immediately discontinue MODEYSO and initiate appropriate medical treatment and supportive care. (5.1)oQTc Interval Prolongation: MODEYSO causes concentration dependent QTc interval prolongation. Interrupt or reduce the dose of MODEYSO in patients who develop QT prolongation, and permanently discontinue MODEYSO in patients with signs of life-threatening arrhythmias. (5.2, 12.2)oEmbryo-fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.3, 8.1, 8.3). oHypersensitivity: If clinically significant hypersensitivity or anaphylaxis occur, immediately discontinue MODEYSO and initiate appropriate medical treatment and supportive care. (5.1). oQTc Interval Prolongation: MODEYSO causes concentration dependent QTc interval prolongation. Interrupt or reduce the dose of MODEYSO in patients who develop QT prolongation, and permanently discontinue MODEYSO in patients with signs of life-threatening arrhythmias. (5.2, 12.2). oEmbryo-fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.3, 8.1, 8.3). 5.1Hypersensitivity MODEYSO can cause severe hypersensitivity reactions.In the pooled safety population [see Adverse Reactions (6.1)], Grade hypersensitivity reactions occurred in 0.3% of patients receiving MODEYSO. Signs and symptoms of hypersensitivity may include rash, hives, fever, low blood pressure, wheezing, or swelling of the face or throat. Inform patients about the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical attention if symptoms occur. If clinically significant hypersensitivity or anaphylaxis occur, immediately interrupt MODEYSO and initiate appropriate medical treatment and supportive care. Based on the severity of the adverse reaction, temporarily interrupt or permanently discontinue MODEYSO [see Dosage and Administration (2.4)].. 5.2QTc Interval Prolongation MODEYSO causes concentration-dependent QTc interval prolongation [see Clinical Pharmacology (12.2)], which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death.In the pooled safety population [see Adverse Reactions (6.1)], of the 82 patients who underwent at least one post-baseline ECG assessment, 6% experienced an increase in QTc of >60 msec compared to baseline after receiving MODEYSO and 1.2% had an increase in QTc to >500 msec. Monitor ECGs and electrolytes prior to starting MODEYSO and then periodically during treatment as clinically indicated.Significant prolongation of the QT interval may occur when MODEYSO is taken concomitantly with other products that have known potential to prolong the QT interval. Avoid concomitant use of MODEYSO with products known to prolong the QT interval. If concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)].Increase the frequency of monitoring when administering MODEYSO to patients taking other products that have known potential to prolong the QT interval and in patients with congenital long QT syndrome, existing QTc prolongation, history of ventricular arrhythmias, electrolyte abnormalities, heart failure, or who are taking strong or moderate CYP3A4 inhibitors. Interrupt or reduce the dose of MODEYSO in patients who develop QT prolongation, and permanently discontinue MODEYSO in patients with signs of life-threatening arrhythmias [see Dosage and Administration (2.4)].. 5.3Embryo-fetal Toxicity Based on findings from animal studies and its mechanism of action, MODEYSO can cause fetal harm when administered to pregnant woman. In embryo-fetal development studies, oral administration of dordaviprone to pregnant rats and rabbits during organogenesis caused embryo-fetal mortality, alterations to growth, and structural abnormalities at exposures below the human exposure at the highest recommended dose.Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with MODEYSO and for month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with MODEYSO and for month after the last dose [see Use in Specific Populations (8.1, 8.3)].