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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.
Dordaviprone hydrochloride has the following chemical structure:
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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).
The following potential clinically significant adverse reactions are described elsewhere in the labelling:
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 | ||
| Fatiguea | 34 | 3.2 |
| Gait disturbance | 16 | 3.7 |
| Nervous System Disorders | ||
| Headacheb | 32 | 4.3 |
| Cranial nerve disordersc | 16 | 1.3 |
| Hemiparesis | 15 | 4.5 |
| Dysarthria | 13 | 2.7 |
| Dizziness | 13 | 0.5 |
| Ataxia | 10 | 1.3 |
| Gastrointestinal Disorders | ||
| Vomiting | 24 | 2.7 |
| Nausea | 24 | 0.8 |
| Dysphagia | 13 | 2.1 |
| Constipation | 11 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Musculoskeletal paind | 20 | 2.9 |
| Muscular weakness | 13 | 4.5 |
| Metabolism and Nutrition Disorders | ||
| Hyperglycemia | 12 | 0.8 |
| Infections and Infestations | ||
| Rashe | 11 | 0.8 |
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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 Abnormalitya | MODEYSOb | |||
| All Grades (%) | Grade 3 or 4 (%) | |||
| Chemistry | ||||
| Alanine aminotransferase increased | 28 | 2.4 | ||
| Aspartate aminotransferase increased | 22 | 0.9 | ||
| Calcium decreased | 20 | 2.7 | ||
| Sodium decreased | 14 | 0.3 | ||
| Potassium decreased | 13 | 0.3 | ||
| Glucose decreased | 11 | 0 | ||
| Alkaline phosphatase increased | 11 | 0.3 | ||
| Hematology | ||||
| Hemoglobin decreased | 25 | 0.6 | ||
| Neutrophils decreased | 24 | 1.5 | ||
| Lymphocytes decreased | 19 | 7 | ||
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Table 6 describes drug interactions where concomitant use of another drug affects MODEYSO.
Table 6: Effect of Other Drugs on MODEYSO
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Strong and Moderate CYP3A4 Inhibitors |
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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)]. |
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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)]. |
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Strong or Moderate CYP3A4 Inducers |
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Prevention or Management |
• Avoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO. |
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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. |
Table 7 describes drug interactions associated with QTc interval prolongation when used concomitantly with MODEYSO.
Table 7: Products that Prolong QTc Interval
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Products that Prolong QTc Interval |
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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)]. |
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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)]. |
Included as part of the PRECAUTIONS section.
MODEYSO can cause severe hypersensitivity reactions.
In the pooled safety population [see Adverse Reactions (6.1)], 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 [see Dosage and Administration (2.4)].
MODEYSO causes a 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 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 [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 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 [see Dosage and Administration (2.4)].
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 [see Use in Specific Populations (8.1, 8.3)].
Carcinogenicity studies with dordaviprone were not conducted.
Dordaviprone was not genotoxic in in vitro (Ames and micronucleus assay) and in vivo (mouse micronucleus) assays.
Dedicated fertility studies were not conducted with dordaviprone.
The nonclinical safety profile of dordaviprone reflects the on-target pharmacology and dopamine receptor inhibition. In repeat-dose toxicology studies of up 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.
Advise the patient and caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
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 [see Warnings and Precautions (5.1)].
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 [see Warnings and Precautions (5.2)].
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 [see Drug Interactions (7)].
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 (no food intake at least hour prior to or 3 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].
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 [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 1 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 1 month after the last dose [see Use in Specific Populations (8.3)].
Advise women not to breastfeed during treatment with MODEYSO and for 1 week after the last dose [see Use in Specific Populations (8.2)].
No information provided
No information provided
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.
At 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)].
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of dordaviprone have not been fully characterized.
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.
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).
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.
Dordaviprone is primarily metabolized by CYP3A4 with minor contribution from CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A5.
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.
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).
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.
INSTRUCTIONS FOR USE
MODEYSO [moh-DAY-soh]
(dordaviprone)
capsules, for oral use
This Instructions for Use contains information on how to prepare and take or give MODEYSO capsules as a liquid.
Read this Instructions for Use carefully before you prepare and take or give a dose of MODEYSO for the first time and each time you or your child gets a prescription refill. There may be new information. This information does not take the place of talking with your healthcare provider about your or your child’s medical condition or treatment.
Important Information You Need to Know Before Preparing and Taking or Giving MODEYSO Capsules as a Liquid.
Supplies needed to prepare and dissolve MODEYSO capsules to take or give as a liquid.
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Section A: Preparing and dissolving MODEYSO capsules to take or give as a liquid |
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Preparing to dissolve the capsules Step 1: Wash and dry your hands. Place the MODEYSO bottle on a clean, flat surface. Gather the rest of the supplies you will need so they are ready to use. |
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Step 2: Check the prescribed dose. Count out the number of MODEYSO capsules needed for the dose. |
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Opening the capsules Step 3: Hold the capsule over a 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. |
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Step 4: Repeat Step 3 for each additional capsule needed for the prescribed dose. |
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Dissolving the capsules in liquid Step 5: Use a tablespoon (15 mL) to measure the liquid. Add 1 to 2 tablespoons (about 15 mL to 30 mL) of your chosen liquid (sports drink, apple juice, lemonade, or water) to the cup. |
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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. |
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Section B: Taking or giving a dose of MODEYSO as a liquid |
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Step 7: Take or give all of the mixture as soon as possible. Always take or give the mixture within 2 hours of preparing it. An oral dosing syringe may be used to take or give the mixture by mouth. Refer to Section D for detailed instructions. The mixture may be taken or given through a feeding tube. Refer to Section E for detailed instructions. Throw away the mixture if it is not taken within 2 hours of preparing it and go back to Section A to prepare a 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. |
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Step 8: After taking or giving the dose, add 1 to 2 more tablespoons (about 15 mL to 30 mL) of your chosen liquid to the cup. |
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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. |
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Step 10: Repeat Step 7. |
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Step 11: After taking or giving the dose, throw empty capsule shells in the trash. Do not save or reuse empty capsules. |
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Step 12: After taking or giving the dose, rinse the cup with warm running water to remove all remaining medicine. |
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Step 13: Wash your hands with soap and water. |
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Section D: Taking or giving a dose of MODEYSO as a liquid using an oral dosing syringe |
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If you are using an oral dosing syringe to take or give MODEYSO by mouth:
Refer to Section C: Disposing of (throwing away) empty MODEYSO capsule shells and cleaning the cup. |
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Section E: Taking or giving a dose of MODEYSO as a liquid using a feeding tube |
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MODEYSO may be given through a naso-gastric (“ng”) or gastrostomy (“g”) feeding tube, as directed by your healthcare provider.
Refer to Section C: Disposing of (throwing away) empty MODEYSO capsule shells and cleaning the cup. |
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Storing MODEYSO
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.
