Exxua Drug Information

is indicated for the treatment of major depressive disorder (MDD) in adults. EXXUA is indicated for the treatment of major depressive disorder (MDD) in adults.

Important Recommendations

Prior to Initiating and During Treatment with EXXUA Electrocardiogram and Electrolyte Monitoring Correct electrolyte abnormalities prior to initiating EXXUA. In patients with electrolyte abnormalities, or who are receiving diuretics or glucocorticoids, or who have a history of hypokalemia or hypomagnesemia, also monitor electrolytes during dose titration and periodically during treatment with EXXUA. Perform an electrocardiogram (ECG) prior to initiating EXXUA, during dosage titration, and periodically during treatment. Do not initiate EXXUA if QTc is > 450 msec at baseline. Monitor ECGs more frequently if EXXUA is used: concomitantly with drugs known to prolong the QT interval in patients who develop QTc ≥ 450 msec during treatment in patients with a significant risk of developing torsade de pointes.

Do not escalate the EXXUA dosage if the QTcF is > 450 msec. Bipolar Disorder, Mania, and Hypomania Screening Screen patients for a personal or family history of bipolar disorder, mania, or hypomania prior to initiating treatment with EXXUA .

Important

Administration Instructions Take EXXUA orally with food at approximately the same time each day . Swallow tablets whole. Do not split, crush, or chew EXXUA.

Recommended Dosage

The recommended starting dosage of EXXUA is 18.2 mg once daily. Based on clinical response and tolerability, the dosage may be increased to 36.3 mg orally once daily on Day 4 and further titrated to 54.5 mg orally once daily after Day 7 and to 72.6 mg orally once daily after an additional week. The maximum recommended daily dosage of EXXUA is 72.6 mg once daily.

Dosage Recommendations in Geriatric Patients

The recommended starting dosage of EXXUA in geriatric patients is 18.2 mg orally once daily. Based on clinical response and tolerability, the dosage may be increased to maximum recommended dosage of 36.3 mg orally once daily after Day 7.

Recommended Dosage in Patients with Renal Impairment

The recommended starting dosage of EXXUA in patients with creatinine clearance < 50 mL/min is 18.2 mg orally once daily. Based on clinical response and tolerability, the dosage may be increased to the maximum recommended dosage of 36.3 mg orally once daily after Day 7. The recommended dosage in patients with creatinine clearance ≥ 50 mL/min is the same as in patients with normal renal function .

Recommended Dosage in Patients with Hepatic Impairment

The recommended starting dose of EXXUA in patients with moderate (Child-Pugh B) hepatic impairment is 18.2 mg once daily. Based on clinical response and tolerability, the dosage may be increased to the maximum recommended dosage of 36.3 mg orally once daily after Day 7 . EXXUA is contraindicated in patients with severe (Child-Pugh C) hepatic impairment . The recommended dosage in patients with mild (Child-Pugh A) hepatic impairment is the same as patients with normal hepatic function.

Dosage Modifications for

Concomitant Use with CYP3A4 Inhibitors Reduce the EXXUA dose by 50% when used concomitantly with a moderate CYP3A4 inhibitor . EXXUA is contraindicated in patients receiving strong CYP3A4 inhibitors .

Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

At least 14 days must elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with EXXUA. Conversely, at least 14 days must be allowed after stopping EXXUA before starting an MAOI antidepressant .

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. During premarketing assessment, multiple doses of EXXUA were administered to 1,976 adult patients with major depressive disorder (MDD) in controlled phase 2 and 3 clinical studies, including 1,639 patients in placebo-controlled phase 2 and 3 trials in MDD, with 237 patients exposed for over six months. The population treated with EXXUA in the pooled placebo-controlled studies ranged from 15 to 78 years of age, was 34% male and 66% female, and was 80% Caucasian, 11% Black, and 9% other race.

The adverse reaction data below are based on two placebo-controlled, flexible-dose, clinical studies (Study 1, Study 2) in which either EXXUA 18.2 mg to 72.6 mg (n=226) or placebo (n=230) was administered to adult patients with MDD during an 8-week double-blind treatment period . Study 1 had a median age of 39 years and were 61% female, 73% Caucasian, 9% Black, 2% Asian, and 16% Other (Hispanic or Native American). Study 2 had a median age of 39 years and were 69% female, 65% Caucasian, 23% Black, 1% Asian, and 11% Hispanic. In Study 1 and Study 2, 7% (15/226) of patients treated with EXXUA and 3% (6/230) of patients receiving placebo discontinued treatment due to an adverse reaction. The most common reactions leading to discontinuation for patients taking EXXUA were dizziness and nausea.

The most common adverse reactions (≥ 5% and twice the incidence of placebo) in EXXUA-treated patients were dizziness, nausea, insomnia, abdominal pain, and dyspepsia. Table 2 presents the adverse reactions that occurred at an incidence of ≥ 2% of patients treated with EXXUA and at a higher incidence than in the placebo-treated patients. Table 2 Adverse Reactions that Occurred in ≥ 2% of Patients Treated with EXXUA and Greater than the Incidence in Placebo-Treated Patients in Pooled MDD Studies (Study 1 and Study 2) Adverse Reaction Placebo (N=230) (%) EXXUA (18.2 mg to 76.2 mg) (N=226) (%) Dizziness The following terms were combined:Dizziness=Lightheadedness, Dizziness, Dizziness Postural.Headache=Headache, Sinus Headache, Tension Headache.Feeling Sleepy or Tired=Fatigue, Sedation, Somnolence.Insomnia=Initial Insomnia, Insomnia, Middle Insomnia, Terminal Insomnia.Abdominal Pain=Abdominal Discomfort, Abdominal Pain, Abdominal Pain Upper. 10 49 Nausea 13 35 Headache 20 31 Feeling Sleepy or Tired 14 15 Insomnia 5 14 Diarrhea 9 10 Upper Respiratory Tract Infection 7 8 Dry Mouth 5 8 Vomiting 4 7 Abdominal Pain 3 7 Dyspepsia 2 6 Increased Appetite 3 5 Constipation 3 4 Nasopharyngitis 3 4 Nasal Congestion 2 4 Paresthesia 1 4 Hyperhidrosis 0 4 Palpitations 0 4 Weight Increased 1 3 Agitation 0 3 Feeling Jittery 0 3 Heart Rate Increased 0 2 Lethargy 0 2 Other Adverse Reactions Observed in Clinical Studies The following is a list of adverse reactions that occurred at an incidence of < 2% in MDD patients treated with EXXUA andat least greater than placebo in Study 1 and Study 2: breast tenderness, confusional state, dyspnea, edema peripheral energy increased, feeling abnormal, hypoesthesia, poor quality sleep, and thinking abnormal.

Additional Adverse Reactions Observed in Clinical Studies Hypersensitivity reactions including rash, pruritus, and urticaria were reported in clinical studies with EXXUA.

Table 3 displays clinically important drug interactions with EXXUA. Table 3 Clinically Important Drug Interactions with EXXUA CYP3A4 Inhibitors Clinical Impact Strong CYP3A4 Inhibitors Concomitant use of EXXUA with a strong CYP3A4 inhibitor increases EXXUA exposure by ~ 5-fold . Moderate CYP3A4 Inhibitors Concomitant use with a moderate CYP3A4 inhibitor increases EXXUA exposure by ~ 2.6-fold . Intervention Strong CYP3A4 Inhibitors EXXUA is contraindicated in patients taking strong CYP3A4 inhibitors . Moderate CYP3A4 Inhibitors If EXXUA is used with a moderate CYP3A4 inhibitor, reduce the dosage of EXXUA. Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of EXXUA with MAOIs increases the risk of serotonin syndrome. Intervention EXXUA is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue or in patients who have taken MAOIs within the preceding 14 days. Allow at least 14 days after stopping EXXUA before starting an MAOI. Drugs that Prolong the QTc Interval Clinical Impact Concomitant use of drugs that prolong the QTc interval may add to the QTc prolonging effects of EXXUA and increase the risk of cardiac arrhythmias.

Intervention Monitor patients with ECGs more frequently if EXXUA is administered with other drugs known to prolong QT interval . CYP3A4 Inducers Clinical Impact Concomitant use of EXXUA with a strong CYP3A4 inducer reduces EXXUA exposure by 20- to 29-fold . Intervention Avoid concomitant use of EXXUA in patients taking strong CYP3A4 inducers. Other Serotonergic Drugs Clinical Impact Concomitant use of EXXUA and serotonergic drugs increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when EXXUA is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems.

If serotonin syndrome occurs, consider discontinuation of EXXUA and/or concomitant serotonergic drug . Strong CYP3A4 inducers: Reduces EXXUA exposure. Avoid concomitant use.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including EXXUA, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/. Risk Summary Based on animal reproduction studies, gepirone has been shown to have adverse effects on embryo/fetal and postnatal development. In rats, increased mortality during the first 4 days after birth and persistent reduction in body weight through lactation and weaning were observed at all doses and increased still births were seen with a no observed adverse effect level (NOAEL) at 3 times the maximum recommended human dose (MRHD) on a mg/m 2 basis.

In embryofetal development studies in rats and rabbits, decreased embryofetal growth, body weights and lengths, with accompanying skeletal variations were seen with a NOAEL at 9 and 12 times the MRHD on a mg/m 2 basis, respectively (see Data). There are insufficient clinical data on gepirone use during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are clinical considerations regarding neonates exposed to serotonergic antidepressants during the third trimester of pregnancy (see Clinical Considerations and Data). There are risks associated with untreated depression during pregnancy (see Clinical Considerations). Consider if the risks outweigh the benefits of treatment with gepirone during pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown.

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. Clinical Considerations Disease-associated Maternal and/or Embryofetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy.

Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal Adverse Reactions Neonates exposed to other serotonergic antidepressants in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Complications can arise immediately upon delivery.

Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs or possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

Data Human Data Exposure during late pregnancy to serotonergic antidepressants may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1- 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data In embryofetal development studies, oral administration of gepirone to pregnant rats (75, 150, and 300 mg/kg) or pregnant rabbits (50, 100, and 200 mg/kg) during the period of organogenesis resulted in decreased embryofetal growth, body weights and lengths, with accompanying skeletal variations at mid and high doses; the mid doses are 18 and 24 times the MRHD on a mg/m 2 basis in rats and rabbits, respectively. No malformations were seen in these studies.

The developmental NOAEL was 9 and 12 times the MRHD on a mg/m 2 basis in rats and rabbits, respectively. When pregnant rats were treated with gepirone (10, 20, and 40 mg/kg) from late gestation through weaning, decreased birth weights were seen at mid and high doses; the mid dose is twice the MRHD. Increased offspring mortality during the first 4 days after birth and persistent reduction in body weight were observed at all doses; the lowest dose is approximately equal to the MRHD on a mg/m 2 basis. The no-effect dose for fetal effects was not determined in this study.

When gepirone was administered orally to male and female rats prior to and throughout mating, gestation, and lactation at doses of 5, 27, 64, and 150 mg/kg/day, increased still births were seen at ≥ 64 mg/kg. Early postnatal mortality was increased at 150 mg/kg (18 times the MRHD on a mg/m 2 basis). The NOAEL (27 mg/kg) for still births was associated with a maternal dose 3 times the MRHD on a mg/m 2 basis. Fetal weights were decreased at 27 mg/kg (3 times the MRHD on a mg/m 2 basis) and fetal lengths were decreased at 64 mg/kg (8 times the MRHD on a mg/m 2 basis) and above.

Pup weights were decreased at birth, throughout lactation and weaning, and until at least 14 weeks of age, with delays of some developmental landmarks, at 64 mg/kg and above. The NOAEL for growth and development (5 mg/kg) was associated with a maternal dose below the MRHD on a mg/m 2 basis.

Pediatric Use The safety and effectiveness of EXXUA in pediatric patients have not been established for the treatment of MDD. Efficacy was not demonstrated in two 8-week, randomized, placebo-controlled trials in 426 pediatric patients 7 to 17 years of age with MDD. The primary efficacy endpoint was change from double-blind baseline to Week 8 on the Children’s Depression Rating Scale-Revised (CDRS-R) measure. The effect of treatment with EXXUA was not significantly different from placebo. In the pediatric trial patients, there was a higher occurrence of vomiting in pediatric patients (13%) compared to adults (6.6%). Antidepressants, such as EXXUA, increase the risk of suicidal thoughts and behaviors in pediatric patients . Juvenile Animal Toxicity Data In a juvenile animal study, male and female rats were treated with gepirone once daily with oral doses of 0, 10, 40, and 70 mg/kg, from postnatal day 14 to 42. Increased motor activity and impaired performance in the Morris water maze were observed at 40 and 70 mg/kg after a two-week recovery period.

The no observed adverse effect level (NOAEL) for the neurobehavioral development effect was 10 mg/kg. When the animals were mated after a 3-week recovery period, increased pre-implantation loss was observed for mated pairs treated with 70 mg/kg. The NOAEL for this finding was 40 mg/kg/day.

is contraindicated in patients: with known hypersensitivity to gepirone or components of EXXUA . with prolonged QTc interval > 450 msec at baseline. with congenital long QT syndrome. receiving concomitant strong CYP3A4 inhibitors. with severe hepatic impairment. taking, or within 14 days of stopping, MAOIs due to the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome . Starting EXXUA in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is also contraindicated. Known hypersensitivity to gepirone or components of EXXUA. Prolonged QTc interval > 450 msec at baseline. Congenital long QT syndrome.

Concomitant use of strong CYP3A4 inhibitors. Severe hepatic impairment. Use with an MAOI or within 14 days of stopping treatment with EXXUA. Do not use EXXUA within 14 days of discontinuing an MAOI.

In clinical studies, cases of acute ingestions up to 454 mg (6.25 times the maximum recommended dose) of EXXUA alone or in combination with other drugs, were reported. Signs and symptoms reported with overdose of EXXUA at doses up to 454 mg included vomiting and transient incomplete bundle branch block; an unknown dose of EXXUA produced altered level of consciousness and a 60-second convulsion. No specific antidotes for EXXUA are known.

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.