MODEYSO- dordaviprone capsule

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MODEYSO- dordaviprone capsule
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]

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Overview

MODEYSO- dordaviprone capsule is a protease activator that is FDA approved for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy.. Common adverse reactions include fatigue, headache, vomiting, nausea, and musculoskeletal pain..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Diffuse Midline Glioma Harboring an H3 K27M Mutation

FDA-Labeled Indication

  • MODEYSO is indicated for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy.
  • This indication is approved under accelerated approval based on overall response rate and duration of response.
  • Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Patient Selection

  • Select patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens.
  • An FDA-approved test for the detection of this mutation is not currently available.
  • Monitor electrocardiograms (ECG) and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated.

Dosing Information

  • Take MODEYSO on an empty stomach, at least 1 hour before or 3 hours after food intake.

Adults

  • The recommended dosage of MODEYSO is 625 mg orally 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.
  • 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.
Dosage Modifications for Adverse Reactions
  • The recommended dosage reductions for adverse reactions for MODEYSO are provided in Table below.

Recommended Dosage Reductions for Adverse Reactions

Patient's Weight (kg)First Dosage ReductionSecond Dosage Reduction
Pediatric patients 10 kg to <12.5 kgPermanently discontinueN/A
Pediatric patients 12.5 kg to <27.5 kg125 mg once weeklyPermanently discontinue
Pediatric patients 27.5 kg to <42.5 kg250 mg once weekly125 mg once weekly
Pediatric patients 42.5 kg to <52.5 kg375 mg once weekly250 mg once weekly
Pediatric patients ≥52.5 kg and adult patients500 mg once weekly375 mg once weekly
  • The recommended dosage modifications for adverse reactions are provided in Table below.

Recommended Dosage Modifications for Adverse Reactions

Adverse ReactionSeverityaDosage Modificationb
HypersensitivityAny 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 ProlongationQTc 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 arrhythmiaPermanently discontinue MODEYSO.
Other Adverse ReactionsGrade 3 or 4Interrupt MODEYSO until ≤Grade 1 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 2 for recommended dosage reductions.
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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of MODEYSO- dordaviprone capsule in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of MODEYSO- dordaviprone capsule in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Diffuse Midline Glioma Harboring an H3 K27M Mutation

FDA-Labeled Indication

  • MODEYSO is indicated for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy.
  • This indication is approved under accelerated approval based on overall response rate and duration of response.
  • Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Patient Selection

  • Select patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens.
  • An FDA-approved test for the detection of this mutation is not currently available.
  • Monitor electrocardiograms (ECG) and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated.

Dosing Information

  • Take MODEYSO on an empty stomach, at least 1 hour before or 3 hours after food intake.

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.

Recommended Body Weight-Based Dosage for Pediatric Patients

Body Weight (kg)Recommended Dosage
10 kg to <12.5 kg125 mg Once Weekly
12.5 kg to <27.5 kg250 mg Once Weekly
27.5 kg to <42.5 kg375 mg Once Weekly
42.5 kg to <52.5 kg500 mg Once Weekly
≥52.5 kg625 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.
  • 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.
Dosage Modifications for Adverse Reactions
  • The recommended dosage reductions for adverse reactions for MODEYSO are provided in Table 2.

Recommended Dosage Reductions for Adverse Reactions

Patient's Weight (kg)First Dosage ReductionSecond Dosage Reduction
Pediatric patients 10 kg to <12.5 kgPermanently discontinueN/A
Pediatric patients 12.5 kg to <27.5 kg125 mg once weeklyPermanently discontinue
Pediatric patients 27.5 kg to <42.5 kg250 mg once weekly125 mg once weekly
Pediatric patients 42.5 kg to <52.5 kg375 mg once weekly250 mg once weekly
Pediatric patients ≥52.5 kg and adult patients500 mg once weekly375 mg once weekly
Dosage Modifications for CYP3A4 Inhibitors
  • Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO.
  • The recommended dosage for pediatric patients weighing less than 52.5 kg who are receiving strong or moderate CYP3A4 inhibitors has not been established.
Pediatric Use
  • The safety and effectiveness of MODEYSO has been established in pediatric patients aged 1 year and older for the treatment of diffuse midline glioma harboring an H3 K27M mutation.
  • The safety and effectiveness of MODEYSO have not been established in pediatric patients less than 1 year of age.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of MODEYSO- dordaviprone capsule in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of MODEYSO- dordaviprone capsule in pediatric patients.

Contraindications

None.

Warnings

Hypersensitivity

  • MODEYSO can cause severe hypersensitivity reactions.
  • In the pooled safety population, Grade 3 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.

QTc Interval Prolongation

  • MODEYSO causes a concentration-dependent QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death.
  • In the pooled safety population, 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 a 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.
  • Increase the frequency of monitoring when administering MODEYSO to patients taking other products that have a known potential to prolong the QT interval and in patients with congenital long QT syndrome, existing QTc prolongation, a 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.

Embryo-fetal Toxicity

  • Based on findings from animal studies and its mechanism of action, MODEYSO can cause fetal harm when administered to a 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 a fetus.
  • Advise females of reproductive potential to use effective contraception during treatment with MODEYSO and for 1 month after the last dose.
  • Advise male patients with female partners of reproductive potential to use effective contraception during treatment with MODEYSO and for 1 month after the last dose.

Adverse Reactions

Clinical Trials Experience

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).
  • 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 ReactionMODEYSO (N=376)
All Grades (%)Grade 3 or 4 (%)
General Disorders
Fatiguea343.2
Gait disturbance163.7
Nervous System Disorders
Headacheb324.3
Cranial nerve disordersc161.3
Hemiparesis154.5
Dysarthria132.7
Dizziness130.5
Ataxia101.3
Gastrointestinal Disorders
Vomiting242.7
Nausea240.8
Dysphagia132.1
Constipation110
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paind202.9
Muscular weakness134.5
Metabolism and Nutrition Disorders
Hyperglycemia120.8
Skin and Subcutaneous Tissue Disorders
Rashe110.8
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 AbnormalityaMODEYSOb
All Grades (%)Grade 3 or 4 (%)
Chemistry
Alanine aminotransferase increased282.4
Aspartate aminotransferase increased220.9
Calcium decreased202.7
Sodium decreased140.3
Potassium decreased130.3
Glucose decreased110
Alkaline phosphatase increased110.3
Hematology
Hemoglobin decreased250.6
Neutrophils decreased241.5
Lymphocytes decreased197
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.

Postmarketing Experience

There is limited information regarding MODEYSO- dordaviprone capsule Postmarketing Experience in the drug label.

Drug Interactions

Effect of Other Drugs on MODEYSO

Effect of Other Drugs on MODEYSO

Strong and Moderate CYP3A4 Inhibitors
Prevention or ManagementAvoid 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 MODEYSO dose as recommended.
Mechanism and Clinical EffectsDordaviprone is a CYP3A4 substrate.
Strong and moderate CYP3A4 inhibitors increase dordaviprone exposure, which may increase the risk of MODEYSO-related adverse reactions.
Strong or Moderate CYP3A4 Inducers
Prevention or ManagementAvoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO.
Mechanism and Clinical EffectsDordaviprone is a CYP3A4 substrate.
Strong and moderate CYP3A4 inducers decrease dordaviprone exposure, which may reduce the anti-tumor activity of MODEYSO.

Drugs Known to Prolong QTc Interval

Products that Prolong QTc Interval

Products that Prolong QTc Interval
Prevention or ManagementAvoid 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.
Clinical ImpactMODEYSO causes concentration dependent QTc interval prolongation.
Concomitant use of MODEYSO with other QT-prolonging products may increase the risk of QTc-associated arrhythmias.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Risk Summary

  • Based on findings from animal studies and its mechanism of action, MODEYSO can cause fetal harm when administered to a pregnant woman.
  • There are no available data on MODEYSO use in pregnant women to inform a 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 a fetus.
  • In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

  • In an embryo-fetal development study, dordaviprone was administered orally to pregnant rats during the period of organogenesis from gestation day 7 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 7 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).


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of MODEYSO- dordaviprone capsule in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of MODEYSO- dordaviprone capsule during labor and delivery.

Nursing Mothers

Risk Summary

  • There are no data on the presence of dordaviprone or its metabolites in human milk, their effects on a 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 1 week after the last dose.

Pediatric Use

  • The safety and effectiveness of MODEYSO has been established in pediatric patients aged 1 year and older for the treatment of diffuse midline glioma harboring an H3 K27M mutation.
  • The efficacy of MODEYSO was evaluated in 4 pediatric patients aged 9 to 17 years with diffuse midline glioma harboring an H3 K27M mutation.
  • Safety was evaluated in 154 pediatric patients with glioma aged 3 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 3 to 11 years of age and 27% were 12 to 17 years of age.
  • No additional safety signals were observed in pediatric patients.
  • 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.
  • The safety and effectiveness of MODEYSO have not been established in pediatric patients less than 1 year of age.

Geriatic 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.

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).

Gender

There is no FDA guidance on the use of MODEYSO- dordaviprone capsule with respect to specific gender populations.

Race

There is no FDA guidance on the use of MODEYSO- dordaviprone capsule with respect to specific racial populations.

Renal Impairment

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 Cmax by 1.1-fold in subjects with severe renal impairment (CLcr <30 mL/min, estimated by the Cockcroft-Gault equation).

Hepatic Impairment

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.

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 Cmax by 1.2-fold in subjects with moderate hepatic impairment (Child Pugh class B).

Females of Reproductive Potential and Males

  • MODEYSO can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

  • Verify pregnancy status of females of reproductive potential prior to initiating MODEYSO.

Contraception

Females

  • Advise females of reproductive potential to use effective contraception during treatment with MODEYSO and for 1 month after the last dose.

Males

  • Advise male patients with female partners of reproductive potential to use effective contraception during treatment with MODEYSO and for 1 month after the last dose.

Infertility

  • Based 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.

Immunocompromised Patients

There is no FDA guidance one the use of MODEYSO- dordaviprone capsule in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Take MODEYSO on an empty stomach, at least 1 hour before or 3 hours after food intake.
  • 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.
  • 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.

Administration

  • Instruct patients and caregivers to read the Instructions for Use before taking MODEYSO, and each time the patient gets a refill as there may be new information they need to know.
  • Patients should take MODEYSO orally once weekly on an empty stomach, at least 1 hour before or 3 hours after food intake.
  • Take the prescribed dose at the same time on the same day of the week.
  • 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.

Monitoring

  • Monitor electrocardiograms (ECG) and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated.

QTc Interval Prolongation

  • Monitor ECGs and electrolytes prior to starting MODEYSO and then periodically during treatment as clinically indicated.
  • Increase the frequency of monitoring when administering MODEYSO to patients taking other products that have a known potential to prolong the QT interval and in patients with congenital long QT syndrome, existing QTc prolongation, a history of ventricular arrhythmias, electrolyte abnormalities, heart failure, or who are taking strong or moderate CYP3A4 inhibitors.

Pregnancy Testing

  • Verify pregnancy status of females of reproductive potential prior to initiating MODEYSO.

IV Compatibility

There is limited information regarding the compatibility of MODEYSO- dordaviprone capsule and IV administrations.

Overdosage

There is limited information regarding MODEYSO- dordaviprone capsule overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding MODEYSO- dordaviprone capsule Pharmacology in the drug label.

Mechanism of Action

  • Dordaviprone is a protease activator of the mitochondrial caseinolytic protease P (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.

Structure

  • Dordaviprone is a protease activator.
  • Dordaviprone is present as dordaviprone hydrochloride with the molecular formula C24H26N4O•2HCl.
  • The molecular weight is 459.41.
  • The full chemical name for dordaviprone hydrochloride is 7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one dihydrochloride.

  • Each MODEYSO capsule contains 125 mg of dordaviprone (equivalent to 148.8 mg of dordaviprone hydrochloride).
  • The inactive ingredients in the capsule include magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.
  • The capsule shell consists of 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).

Pharmacodynamics

Cardiac Electrophysiology

  • At 1.2 times the maximum recommended dose, the estimated mean QTcF change was 11.8 msec (90% CI: 9.8, 13.7).

Pharmacodynamics

  • The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of dordaviprone have not been fully characterized.

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 (Cmax) is 2.8 mcg/mL (42%), and total systemic exposure (AUC) is 23 hr·mcg/mL (48%).
  • Dordaviprone Cmax 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 (Tmax) is 1.4 hours (0.5, 5.6 hours).

Food Effect

  • Dordaviprone Cmax 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 Cmax 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 Cmax 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 Cmax 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 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 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

  • Carcinogenicity studies with dordaviprone were not conducted.

Mutagenesis

  • Dordaviprone was not genotoxic in in vitro (Ames and micronucleus assay) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

  • Dedicated fertility studies were not conducted with dordaviprone.

Animal Toxicology and/or Pharmacology

  • The nonclinical safety profile of dordaviprone reflects the on-target pharmacology and dopamine receptor inhibition.
  • In repeat-dose toxicology studies of up to 13 weeks in duration, weekly oral administration of dordaviprone to dogs caused central nervous system-related toxicities including whole body tremors, cranial tremors, seizures, excessive salivation, lateral recumbency, rigidity, paddling of limbs, overall rigid body, salivation, abnormal gait/stance, and twitching at doses resulting in less than or equal to 0.7 times the human exposure at the highest recommended dose based on AUC.
  • In a 13-week repeat-dose toxicology study in rats, mammary gland hyperplasia occurred at doses resulting in 0.11 times the human exposure at the highest recommended dose based on AUC.

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 a 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: 9 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 2 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 for Patients with Diffuse Midline Glioma Harboring an H3 K27M Mutation in Studies ONC006, ONC013, ONC014, ONC016, and ONC018 per RANO 2.0

Efficacy ParameterMODEYSO
N=50
Overall Response Rate (95% CI)a22% (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 monthsc73%
% with observed DOR ≥12 monthsc27%
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 1 complete and 9 partial responses.
  • Based on BICR-assessed RANO-LGG criteria (n=50), the ORR was 20% (95% CI: 10, 34), with 5 partial and 5 minor responses.

How Supplied

Dosage Forms and Strengths

  • Capsules: 125 mg, white, opaque, hard capsules printed with "DDP" and "125" on the body and "CMRX" on the cap of the capsule.
  • Each capsule contains 125 mg dordaviprone.

How Supplied

StrengthDescriptionPackage ConfigurationNDC Number
125 mgWhite, opaque, hard capsules printed with "DDP" and "125" on the body and "CMRX" on the cap of the capsule.Each bottle contains 10 capsules and desiccant with a child-resistant closure.68727-250-01

Storage

  • Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Images

Drug Images

Package and Label Display Panel

Principal Display Panel

Patient Counseling Information

Patient Counseling Information

  • Advise the patient and caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Hypersensitivity

  • Advise 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.

QTc Interval Prolongation

  • Advise 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.

Drug Interactions

  • Inform 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.

Administration

  • Instruct patients and caregivers to read the Instructions for Use before taking MODEYSO, and each time the patient gets a refill as there may be new information they need to know.
  • Patients should take MODEYSO orally once weekly on an empty stomach, at least 1 hour before or 3 hours after food intake.
  • Take the prescribed dose at the same time on the same day of the week.
  • 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.

Embryo-fetal Toxicity

  • Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
  • Advise females to inform their healthcare provider of a known or suspected pregnancy.
  • Advise females of reproductive potential to use effective contraception during treatment with MODEYSO and for 1 month after the last dose.
  • Advise male patients with female partners of reproductive potential to use effective contraception during treatment with MODEYSO and for 1 month after the last dose.

Lactation

  • Advise women not to breastfeed during treatment with MODEYSO and for 1 week after the last dose.

Precautions with Alcohol

Alcohol-MODEYSO- dordaviprone capsule interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding MODEYSO- dordaviprone capsule Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding MODEYSO- dordaviprone capsule Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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