AHFS Class:

• Serotonin Modulators 28:16.04.24

Generic Name(s):

• Gepirone Hydrochloride

Gepirone hydrochloride, a selective serotonin (5HT) 1A receptor agonist, is an antidepressant.1

Gepirone has the following uses:

Gepirone is indicated for the treatment of major depressive disorder (MDD) in adults.1

General

Gepirone is available in the following dosage form(s) and strength(s):

Extended-release tablets: 18.2 mg, 36.3 mg, 54.5 mg, and 72.6 mg1

Administration

Correct electrolyte abnormalities and perform electrocardiogram (ECG) prior to initiating treatment with gepirone.1 Do not initiate gepirone if QTc is >450 msec.1

Perform ECGs during dosage titration and periodically during treatment.1

Dosage

Adults

• The recommended starting dose is 18.2 mg administered orally once daily with food at approximately the same time each day.1 Depending on clinical response and tolerability, the dosage may be increased to 36.3 mg once daily on Day 4.1 Dosage may be further titrated to 54.5 mg once daily after Day 7 and to 72.6 mg once daily after an additional week.1 The maximum recommended daily dosage is 72.6 mg once daily.1
• Geriatric patients: Recommended starting dosage is 18.2 mg once daily.1 Dosage may be increased to maximum recommended dosage of 36.3 mg once daily after 7 days.1
• Renal Impairment (creatinine clearance 50 mL/min): Recommended starting dosage is 18.2 mg once daily.1 Dosage may be increased to maximum recommended dosage of 36.3 mg once daily after 7 days.1
• Moderate hepatic Impairment (Child Pugh B) : Recommended starting dosage is 18.2 mg once daily.1 Dosage may be increased to maximum recommended dosage of 36.3 mg once daily after 7 days.1
• Concomitant use with CYP3A4 inhibitors: Reduce gepirone dose by 50% when used concomitantly with a moderate CYP3A4 inhibitor.1 Contraindicated in patients receiving strong CYP3A4 inhibitors.1

Contraindications

• Known hypersensitivity to gepirone or components of the formulation.1
• Prolonged QTc interval >450 msec at baseline.1
• Congenital long QT syndrome.1
• Concomitant use of strong CYP3A4 inhibitors.1
• Severe hepatic impairment.1
• Use with an MAOI or within 14 days of stopping treatment with gepirone.1 Do not use gepirone within 14 days of discontinuing an MAOI.1

Warnings/Precautions

Suicidal Thoughts and Behaviors in Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients aged 24 years and younger was greater than in placebo-treated patients.1

There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.1 There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD.1

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months.1 However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that the use of antidepressants can delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.1

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes.1 Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider.1 Consider changing the therapeutic regimen, including possibly discontinuing gepirone, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.1

QT Prolongation

Gepirone prolongs the QTc interval.1 Gepirone is contraindicated in patients with congenital long QT syndrome and in patients with severe hepatic impairment or in patients receiving concomitant strong CYP3A4 inhibitors as they increase gepirone plasma concentrations.1

Do not initiate gepirone if QTc is >450 msec at baseline.1

Correct electrolyte abnormalities prior to gepirone initiation.1 In patients with electrolyte abnormalities, who are receiving diuretics or glucocorticoids, or have a history or hypokalemia or hypomagnesemia, also monitor electrolytes during dose titration and periodically during treatment with gepirone.1

Perform an ECG prior to gepirone initiation, during dosage titration, and periodically during treatment.1

Monitor patients with ECGs more frequently:

• If gepirone is used concomitantly with drugs known to prolong the QT interval.1
• In patients who develop QTc ≥450 msec during treatment with gepirone.1 Do not escalate the gepirone dosage if QTcF is >450 msec.1
• In patients with a significant risk of developing torsade de pointes, including those with uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism.1

Reduce the gepirone dosage when used concomitantly with moderate CYP3A4 inhibitors, as they may increase gepirone concentrations.1

Serotonin Syndrome

Concomitant use of gepirone with SSRIs or tricyclic antidepressants may cause serotonin syndrome, a potentially life-threatening condition with changes including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.1

The concomitant use of gepirone with MAOIs is contraindicated.1 In addition, do not initiate gepirone in a patient being treated with MAOIs such as linezolid or IV methylene blue.1 If it is necessary to initiate treatment with an MAOI such as linezolid or IV methylene blue in a patient taking gepirone, discontinue gepirone before initiating treatment with the MAOI.1

If concomitant use of gepirone with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.1 Discontinue gepirone and/or concomitant serotonergic drug immediately if the above symptoms occur and initiate supportive symptomatic treatment.1

Activation of Mania or Hypomania

Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode.1 The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder.1 Prior to initiating treatment with gepirone, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression).1 Gepirone is not approved for use in treating bipolar depression.1

Specific Populations

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including gepirone, during pregnancy.1 Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visiting online at [Web].1

Based on animal reproduction studies, gepirone has been shown to have adverse effects on embryo/fetal and postnatal development.1 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/m² basis.1 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/m² basis, respectively.1 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.1 There are clinical considerations regarding neonates exposed to serotonergic antidepressants during the third trimester of pregnancy.1 There are risks associated with untreated depression during pregnancy.1 Consider if the risks outweigh the benefits of treatment with gepirone during pregnancy.1 The background risk of major birth defects and miscarriage for the indicated population is unknown.1 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.1

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.1 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.1 Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.1

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.1 Complications can arise immediately upon delivery.1 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.1 These findings are consistent with either a direct toxic effect of SSRIs or possibly a drug discontinuation syndrome.1 It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.1

Lactation

There are no data on the presence of gepirone in human milk, the effects on the breastfed infant, or the effects on milk production.1 Gepirone is present in rat milk.1 When a drug is present in animal milk, it is likely that the drug will be present in human milk.1 There are reports of breastfed infants exposed to other serotonergic antidepressants experiencing irritability, restlessness, excessive somnolence, decreased feeding, and weight loss.1 The developmental and health benefits of breastfeeding should be considered along with the mother's clincial need for gepirone and any adverse effects on the breastfed infant from gepirone or from the underlying maternal condition.1

Monitor breastfeeding infants for adverse reactions, such as irritability, restlessness, excessive somnolence, decreased feeding, and weight loss.1

Pediatric Use

The safety and effectiveness of gepirone in pediatric patients have not been established for the treatment of MDD.1

Efficacy was not demonstrated in two 8-week, randomized, placebo-controlled trials in 426 pediatric patients 7 to 17 years of age with MDD.1 The primary efficacy endpoint was change from double-blind baseline to Week 8 on the Children's Depression Rating Scale-Revised (CDRS-R) measure.1 The effect of treatment with gepirone was not significantly different from placebo.1 In the pediatric trial patients, there was a higher occurrence of vomiting in pediatric patients (13%) compared adults (6.6%).1

Antidepressants, such as gepirone, increase the risk of suicidal thoughts and behaviors in pediatric patients.1

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 42.1 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.1 The no observed adverse effect level (NOAEL) for the neurobehavioral development effect was 10 mg/kg.1 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.1 The NOAEL for this finding was 40 mg/kg/day.1

Geriatric Use

Of the 1,639 patients exposed to gepirone in placebo-controlled clinical studies of MDD, 0.7% (12 patients) were 65 years of age or older and 0.2% (3 patients) were 75 years of age or older.1

Geriatric patients (65 to 81 years of age) had higher gepirone AUC and Cmax values than younger adult (18 to 40 years of age) patients.1 The maximum recommended daily dosage of gepirone in geriatric patients is lower than in younger adult patients.1

Hepatic Impairment

In patients with mild (Child-Pugh A) hepatic impairment to moderate (Child-Pugh B) hepatic impairment, the metabolism of gepirone and its major metabolites was decreased.1 The maximum recommended dosage of gepirone in patients with moderate hepatic impairment is lower than in patients with normal hepatic function.1 The recommended dosage in patients with mild hepatic impairment is the same as in patients with normal hepatic function.1

Gepirone is contraindicated in patients with severe (Child-Pugh C) hepatic impairment.1

Renal Impairment

In patients with creatinine clearance <50 mL/min, the metabolism and excretion of gepirone and some of its major metabolites were decreased.1 The maximum recommended daily dosage of gepirone in patients with a creatinine clearance <50 mL/min is lower than in patients with normal renal function.1 The recommended dosage in patients with a creatinine clearance ≥50 mL/min is the same as in patients with normal renal function.1

Common Adverse Effects

Most common adverse reactions (incidence of ≥5% and at least twice incidence of placebo) were dizziness, nausea, insomnia, abdominal pain, and dyspepsia.1

Specifc Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Strong CYP3A4 inducers: Reduces geprione exposure.1 Avoid concomitant use.1

Actions

Mechanism of Action

The mechanism of the antidepressant effect of gepirone is not fully understood but is thought to be related to its modulation of serotonergic activity in the CNS through selective agonist activity at 5HT1A receptors. 1

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).1
• Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially during early treatment and when the dose is adjusted up or down and instruct them to report such symptoms to their healthcare provider.1
• Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations.1 Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter medications because there is an increased risk for drug interactions with gepirone.1
• Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of gepirone with SSRIs or tricyclic antidepressants.1 Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.1
• Advise patients to observe for signs of activation of mania or hypomania and instruct them to report such symptoms to their healthcare provider.1
• Advise patients to swallow gepirone whole and not to split, chew, or crush the tablets.1 Advise patients to take gepirone at the approximately the same time every day with food.1
• Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with gepirone.1
• Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to gepirone during pregnancy.1
• Advise patients that gepirone use late in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN).1
• Advise breastfeeding individuals using gepirone to monitor infants for excess sedation, restlessness, agitation, poor feeding and poor weight gain and to see medical care if they notice these signs.1

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Only references cited for selected revisions after 1984 are available electronically.

1. Fabre-Kramer Pharmaceuticals. EXXUA (gepirone) ORAL prescribing information. 2023 Sep.