MODEYSO Capsule Ref.[115554] Active ingredients: Dordaviprone

5.1 Hypersensitivity

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)].

5.2 QTc Interval Prolongation

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)].

5.3 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 [see Use in Specific Populations (8.1, 8.3)].

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)].

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:

^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:

^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.

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:

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:

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).

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.

MODEYSO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating MODEYSO [see Use in Specific Populations (8.1)].

Contraception

Females

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 (8.1)].

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.

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 [see Adverse Reactions (6.1) and Clinical Studies (14)].

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 [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 1 year of age.

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.