Dordaviprone
FDA Drug Information • Also known as: Modeyso
- Brand Names
- Modeyso
- Route
- ORAL
- Dosage Form
- CAPSULE
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION Dordaviprone is a protease activator. Dordaviprone is present as dordaviprone hydrochloride with the molecular formula C 24 H 26 N 4 O
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(4 H )-one dihydrochloride. Dordaviprone hydrochloride has the following chemical structure: Dordaviprone hydrochloride is a white to off-white solid that is freely soluble in water. The 1% solution of dordaviprone hydrochloride is measured as pH 3.3. MODEYSO (dordaviprone) capsules are supplied as 125 mg strength capsules in an immediate‑release oral formulation. 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). chem structureWhat Is Dordaviprone Used For?
1 INDICATIONS AND USAGE 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 [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). MODEYSO is a protease activator 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. ( 1 ) This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Dosage and Administration
2 DOSAGE AND ADMINISTRATION
Select patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens. ( 2.1 ) Monitor ECG and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated. ( 2.2 ) The recommended dose in adult patients is 625 mg orally once weekly. ( 2.3 ) The recommended dose in pediatric patients weighing ≥10 kg is based on body weight (see Table 1). ( 2.3 ) Take MODEYSO orally once weekly on an empty stomach, at least 1 hour before or 3 hours after food intake. ( 2.3 ) Continue MODEYSO until disease progression or unacceptable toxicity. ( 2.3 ) 2.1 Patient Selection Select patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens [see Clinical Studies ( 14 )] . An FDA-approved test for the detection of this mutation is not currently available. 2.2 Recommended Testing Before Starting MODEYSO Monitor electrocardiograms (ECG) and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.2 )] . 2.3 Recommended Dosage and Administration Take MODEYSO on an empty stomach, at least 1 hour before or 3 hours after food intake [see Clinical Pharmacology ( 12.3 )] . Adults The recommended dosage of MODEYSO is 625 mg orally once weekly. Pediatrics The recommended dosage of MODEYSO in pediatric patients aged 1 to <17 years who weigh at least 10 kg is based on body weight (Table 1). A recommended dosage of MODEYSO has not been established in pediatric patients who weigh less than 10 kg. Table 1: Recommended Body Weight-Based Dosage for Pediatric Patients Body Weight (kg) Recommended Dosage 10 kg to <12.5 kg 125 mg Once Weekly 12.5 kg to <27.5 kg 250 mg Once Weekly 27.5 kg to <42.5 kg 375 mg Once Weekly 42.5 kg to <52.5 kg 500 mg Once Weekly ≥52.5 kg 625 mg Once Weekly Continue MODEYSO until disease progression or unacceptable toxicity. Swallow capsules whole. For patients unable to swallow capsules whole, open each capsule, mix contents with approximately 15 to 30 mL of liquid (sports drink, apple juice, lemonade, or water) before administration, and administer orally as a liquid [see Patient Counseling Information ( 17 )] . Once mixed, administer within 2 hours of preparation, or discard and mix a new dose. Vomiting If vomiting occurs after taking a dose, do not take an additional dose and take the next dose at the regularly scheduled time. Missed Dose If a dose is missed within 2 days, take the missed dose as soon as possible. If a dose is missed by more than 2 days, skip the missed dose and take the next dose at the scheduled time. 2.4 Dosage Modifications for Adverse Reactions The recommended dosage reductions for adverse reactions for MODEYSO are provided in Table 2. Table 2: Recommended Dosage Reductions for Adverse Reactions Patient’s Weight (kg) First Dosage Reduction Second Dosage Reduction Pediatric patients...Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following potential clinically significant adverse reactions are described elsewhere in the labelling:
Hypersensitivity [see Warnings and Precautions ( 5.1 )] . QTc Interval Prolongation [see Warnings and Precautions ( 5.2 )] . The most common (≥20%) adverse reactions are fatigue, headache, vomiting, nausea, and musculoskeletal pain. The most common (≥2%) Grade 3 or 4 laboratory abnormalities are decreased lymphocytes, decreased calcium, and increased alanine aminotransferase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chimerix at toll-free phone # 1-866-662-2679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in WARNINGS AND PRECAUTIONS and below reflects exposure to MODEYSO at the recommended weight-based dose taken until disease progression or unacceptable toxicity in 376 adult and pediatric patients with glioma across four open-label clinical studies (ONC006, ONC013, ONC014, and ONC018) [see Clinical Studies ( 14 )] . Of the 376 patients who received MODEYSO, 35% were exposed for 6 months, and 17% were exposed for 1 year. The median age was 23 years (range: 3 to 80): 30% were 2 to 11 years old, 11% were 12 to 17 years old, 55% were 18 to 64 years old, and 3.7% were 65 years or older. Fifty-two percent (52%) were female; 74% White, 10% unknown race or race not reported, 9% Black or African American, 4% Asian, 2.9% other or multiple races; and 13% were of Hispanic or Latino ethnicity. Karnofsky/Lansky Performance Status (KPS/LPS) score was 80 to 100 in 66% of patients, 60 to 70 in 27%, and <60 in 7%. Relevant disease characteristics included primary tumor locations in the midline (91%) and non‑midline regions (9%); 33% had diffuse intrinsic pontine glioma (DIPG); 30% had multifocal disease; 79% had an H3 K27M mutation; 75% had recurrent disease. Serious adverse reactions occurred in 33% of patients who received MODEYSO. Serious adverse reactions in >2% of patients included hydrocephalus (5%), vomiting (4.3%), headache (3.2%), seizure (2.4%), and muscular weakness (2.1%). Fatal adverse reactions occurred in 1% of patients who received MODEYSO, including cardiac arrest (0.5%), intracranial hemorrhage (0.3%), and encephalopathy (0.3%). Permanent discontinuation of MODEYSO due to an adverse reaction occurred in 2.1% of patients. Adverse reactions which resulted in permanent discontinuation of MODEYSO in >1 patient included confusional state. Dosage interruptions of MODEYSO due to an adverse reaction occurred in 6% of patients. Adverse reactions which required dosage interruption in >1 patient included increased alanine aminotransferase, increased aspartate aminotransferase, decreased lymphocyte count, muscular weakness, and aspiration pneumonia. Dose reductions of MODEYSO due to an adverse reaction occurred in 2.7% of patients. Adverse reactions which required dose reductions in >1 patient included decreased neutrophil count and increased alanine aminotransferase. The most common adverse reactions (≥20%) were fatigue, headache, vomiting, nausea, and musculoskeletal pain. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased calcium, and increased alanine aminotransferase. Adverse reactions that occurred in at least 10% of patients treated with MODEYSO are presented in Table 4. Table 4: Adverse Reactions (≥10%) in Patients with Glioma Who Received MODEYSO in ONC006, ONC013, ONC014, and ONC018 Adverse Reaction MODEYSO (N=376) All Grades (%) Grade 3 or 4 (%) General Disorders Fatigue a 34 3.2 Gait disturbance 16 3.7 Nervous System Disorders Headache b 32 4.3 Cranial nerve disorders c 16 1.3 Hemiparesis 15 4.5...Drug Interactions
7 DRUG INTERACTIONS
CYP3A4 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 ) CYP3A4 Inducers: Avoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO. ( 7.1 ) Drugs 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 ) 7.1 Effect of Other Drugs on MODEYSO Table 6 describes drug interactions where concomitant use of another drug affects MODEYSO. Table 6: Effect of Other Drugs on MODEYSO Strong and Moderate CYP3A4 Inhibitors Prevention or Management 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 MODEYSO dose as recommended [see Dosage and Administration ( 2.5 )] . Mechanism and Clinical Effects Dordaviprone is a CYP3A4 substrate. Strong 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 Inducers Prevention or Management Avoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO . Mechanism and Clinical Effects Dordaviprone is a CYP3A4 substrate. Strong and moderate CYP3A4 inducers decrease dordaviprone exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the anti-tumor activity of MODEYSO. 7.2 Drugs Known to Prolong QTc Interval Table 7 describes drug interactions associated with QTc interval prolongation when used concomitantly with MODEYSO. Table 7: Products that Prolong QTc Interval Products that Prolong QTc Interval Prevention or Management 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 [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.2 )] . Clinical Impact MODEYSO causes concentration dependent QTc interval prolongation [see Clinical Pharmacology ( 12.2 )] . Concomitant use of MODEYSO with other QT-prolonging products may increase the risk of QTc-associated arrhythmias [see Warnings and Precautions ( 5.2 )] .Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , 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 C max ).
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Strength Description Package Configuration NDC Number 125 mg White, 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].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.