gepirone (Rx)

>10%

Dizziness (49%)

Nausea (35%)

Headache (31%)

Feeling sleepy or tired (15%)

Insomnia (14%)

1-10%

Diarrhea (10%)

Upper respiratory tract infection (8%)

Dry mouth (8%)

Vomiting (7%)

Abdominal pain (7%)

Dyspepsia (6%)

Increased appetite (5%)

Constipation (4%)

Nasopharyngitis (4%)

Nasal congestion (4%)

Paresthesia (4%)

Hyperhidrosis (4%)

Palpitations (4%)

Weight increased (3%)

Agitation (3%)

Feeling jittery (3%)

Heart rate increased (2%)

Lethargy (2%)

Breast tenderness (<2%)

Confusional state (<2%)

Dyspnea(<2%)

Edema peripheral (<2%)

Energy increased (<2%)

Feeling abnormal (<2%)

Hypoesthesia (<2%)

Poor quality sleep (<2%)

Thinking abnormal (<2%)

Frequency not defined

Hypersensitivity reactions

Contraindications

Known hypersensitivity to gepirone or components

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; do not use within 14 days of discontinuing an MAOI

Cautions

Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode; risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder, before initiating treatment, screen for history of bipolar disorder and the presence of risk factors for bipolar disorder (eg, family history of bipolar disorder, suicide, or depression)

Not approved for use in treating bipolar depression

Suicidal thoughts and behaviors in adolescents and young adults

• Incidence of suicidal thoughts and behaviors in antidepressant-treated patients aged ≤24 years was greater than in placebo-treated patients
• Risk of suicidal thoughts and behaviors varies among drugs, but there was an increased risk identified in young patients for most drugs studied
• Monitor for clinical worsening and emergence of suicidal thoughts and behaviors, especially during initial few months of drug therapy, and when dose is adjusted
• Counsel family members or caregivers of patients to monitor for changes in behavior and to alert healthcare provider
• Consider changing therapeutic regimen, including possibly discontinuing, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors

QT prolongation

• May prolongs QTc interval
• Contraindicated in patients with congenital long QT syndrome
• Do not initiate if QTc is >450 msec at baseline
• Correct electrolyte abnormalities before initiating
• In patients with electrolyte abnormalities, who are receiving diuretics or glucocorticoids, or have a history of hypokalemia or hypomagnesemia, monitor electrolytes during dose titration and periodically during treatment
• Perform an ECG before initiation, during dosage titration, and periodically during treatment.

• Monitor ECGs more frequently

  • Coadministration with drugs known to prolong the QT interval
  • Patients who develop QTc ≥450 msec during treatment;do not escalate dosage if QTcF is >450 msec
  • 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

Serotonin syndrome

• Coadministration of gepirone with selective serotonin reuptake inhibitors (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

Drug interaction overview

CYP3A4 inhibitors

• Strong CYP3A4 inhibitor: Contraindicated
• Moderate CYP3A4 inhibitor: Reduce gepirone dose
• A strong and moderate CYP3A4 inhibitor increases gepirone exposure by ~ 5-fold and ~2.4 fold

CYP3A4 inducers

• Strong CYP3A4 inducers: Avoid coadministration
• Strong CYP3A4 inducers reduce gepirone exposure by 20- to 29-fold

MAOIs

• Coadministration with MAOIs is contraindicated; do not initiate gepirone in patient with MAOIs (eg, linezolid, IV methylene blue)
• If MAOI (eg, linezolid, IV methylene blue) is necessary in a gepirone-treated patient, discontinue gepirone before initiating a MAOI

Serotonergic drugs

• Monitor for symptoms of serotonin syndrome
• 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
• Immediately discontinue gepirone and/or concomitant serotonergic drugs if symptoms occur and initiate supportive symptomatic treatment

QT prolonging drugs

• Monitor patients with ECGs more frequently
• Drugs that prolong the QTc interval may potentiate to the QTc prolonging effects of gepirone and increase the risk of cardiac arrhythmias

Pregnancy

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 third trimester of pregnancy

Pregnancy exposure registry

• Registry monitors pregnancy outcomes in women exposed to antidepressants during pregnancy
• Encourage patients 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/

Animal data

• Gepirone has been shown to have adverse effects on embryofetal 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 no observed adverse effect level (NOAEL) at 3 times the maximum recommended human dose (MRHD) on a mg/m² 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 12x the MRHD on a mg/m² basis, respectively

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
• 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 include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying

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

Present in rat milk; when a drug is present in animal milk, it is likely that drug will be present in human milk

There are reports of breastfed infants exposed to other serotonergic antidepressants experiencing irritability, restlessness, excessive somnolence, decreased feeding, and weight loss

Monitor breastfeeding infants for adverse reactions (eg, irritability, restlessness, excessive somnolence, decreased feeding, weight loss)

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Serotonin (5HT)-1a agonist

Mechanism of the antidepressant effect is not fully understood

May be related to its modulation of serotonergic activity in the CNS through selective agonist activity at 5HT1A receptors

Absorption

Bioavailability: 14-17%

Steady-state achieved within 2-4 days

Effects of food

• High-fat meal: Peak plasma time reached 3 hr
• Systemic gepirone exposure and major metabolites were consistently higher under fed conditions as compared to the fasted state
• Gepirone peak plasma concentration after intake of low-fat (~ 200 calories) breakfast was 27% higher, after medium-fat (~500 calories) breakfast 55% higher and after a high-fat (~ 850 calories) breakfast 62% higher as compared to the fasted state

Distribution

Vd: 94.5 L

Protein-bound

• Gepirone: 72% and is not concentration dependent
• Metabolite: 59% (3’-OH gepirone) and 42% (1-PP)

Metabolism

Primarily metabolized by CYP3A4 to its major pharmacologically active metabolites

Both major metabolites 1-PP and 3’-OH-gepirone are present in plasma in higher concentrations than parent compound

Elimination

Half-life: 5 hr

Excretion

• Feces: 13%
• Urine: 81%

Oral Administration

Take with food

Swallow tablets whole; do not cut, crush, or chew

Storage

Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

Protect from high humidity and moisture