New Drug
Lauren Howell, PharmD
In September 2023, FDA approved Exxua (gepirone), a new extended-release antidepressant. When Exxua comes to the market in early 2024, it will mark a new treatment option for the estimated 21 million Americans who are affected by major depressive disorder (MDD) each year. Unlike most other antidepressants, Exxua doesn’t carry a warning of weight gain or sexual dysfunction, suggesting that it may increase compliance for patients who experience these common adverse effects from other treatment options for depression.
Recommended dosage and administration
While the exact mechanism of action is not fully understood, it’s thought that Exxua works by modulating the serotonergic activity in the central nervous system through selective agonist activity at the 5HT1A receptors. The recommended starting dose is 18.2 mg administered orally once daily with food at approximately the same time each day. Based on clinical response and tolerability, the dosage may be increased to 36.3 mg once daily on day 4, 54.5 once daily after day 7, and 72.6 mg after an additional week. Exxua is available in 18.2 mg, 36.3 mg, 54.5 mg, and 72.6 mg extended-release tablets.
In geriatric patients, patients with renal impairment (CrCl <50 mL/min), or patients with moderate hepatic impairment (Child-Pugh Class B), the recommended starting dosage is 18.2 mg once daily and can be increased to 36.3 mg after 7 days. The Exxua dose should be adjusted by 50% when a moderate CYP3A4 inhibitor is administered concomitantly.
Before treatment with Exxua is initiated, electrolyte abnormalities should be corrected. An ECG should be performed prior to initiating treatment, during dosage titration, and periodically during treatment. Exxua should not be started in individuals with a QTc interval of greater than 450 msec.
Adverse effects
Like many other antidepressants, Exxua carries a boxed warning for thoughts of suicide and suicidal behaviors. There is an increased risk of suicidal thinking and behavior in pediatric and young adult patients taking antidepressants. Patients should be closely monitored for worsening and emergence of suicidal thoughts and behaviors. Exxua is not approved for use in pediatric patients.
Exxua is contraindicated in known hypersensitivity to gepirone or components of Exxua, prolonged QTc interval of greater than 450 msec at baseline, congenital long QT syndrome, concomitant use of strong CYP3A4 inhibitors, severe hepatic impairment, or use with an MAOI or within 14 days of discontinuing one. The most common adverse reactions in patients taking Exxua include dizziness, nausea, insomnia, abdominal pain, and dyspepsia.
Exxua prolongs the QTc interval. Monitor ECGs more frequently when Exxua is used concomitantly with drugs known to prolong the QT interval, in patients who develop a QTc of greater than or equal to 450 msec during treatment, or patients who are at significant risk of developing torsade de pointes.
Do not escalate dosage if QTc is greater than 450 msec. There is an increased risk of serotonin syndrome when Exxua is coadministered with other serotonergic agents. If serotonin syndrome occurs, discontinue Exxua and initiate supportive measures. Patients should be screened for bipolar disorder as activation of mania or hypomania can occur. Avoid concomitant use with strong CYP3A4 inhibitors as they reduce Exxua exposure. Use during the third trimester of pregnancy may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation, such as respiratory distress, temperature instability, feeding difficulty, hypotonia, and irritability in the neonate.
Clinical trials
The efficacy of Exxua for the treatment of MDD in adults was evaluated in two 8-week randomized, double-blind, placebo-controlled, flexible-dose studies in adults between the ages of 18 years and 69 years that met the Diagnostic and Statistical Manual of Mental Disorders’ criteria for MDD. In both studies, after an initial dosage of 18.2 mg daily, dosage was titrated based on clinical response.
The primary efficacy measure was the change from baseline in the Hamilton Depression Rating Scale total score at week 8. Patients in the Exxua groups experienced statistically significantly greater improvement on the primary endpoint compared to patients in the placebo groups in both studies. ■