Gepirone

Concomitant use of drugs that prolong the QTc interval may add to the QTc prolonging effects of gepirone and increase the risk of cardiac arrhythmias. Monitor patients with ECGs more frequently if gepirone is administered with other drugs known to prolong QT interval.

Concomitant use of gepirone and serotonergic drugs increases the risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome when gepirone is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of gepirone and/or concomitant serotonergic drug.

Concomitant use of gepirone with a strong CYP3A4 inducers reduces gepirone exposure by 20- to 29-fold. Avoid concomitant use of gepirone in patients taking strong CYP3A4 inducers.

Reduce the gepirone dose by 50% when used concomitantly with a moderate CYP3A4 inhibitor.

The recommended starting dosage of gepirone 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 starting dose of gepirone 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.

Correct electrolyte abnormalities prior to gepirone initiation. 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.

Monitor patients with ECGs more frequently.

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.

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/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 12 times the MRHD on a mg/m² 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/m² 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/m² 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/m² 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/m² basis). The NOAEL (27 mg/kg) for still births was associated with a maternal dose 3 times the MRHD on a mg/m² basis. Fetal weights were decreased at 27 mg/kg (3 times the MRHD on a mg/m² basis) and fetal lengths were decreased at 64 mg/kg (8 times the MRHD on a mg/m² 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/m² basis.

Risk Summary

There are no data on the presence of gepirone in human milk, the effects on the breastfed infant, or the effects on milk production. Gepirone is present in rat milk. When a drug is present in animal milk, it is likely that the 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 (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for gepirone and any adverse effects on the breastfed infant from gepirone or from the underlying maternal condition.

Clinical Considerations

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

Carcinogenesis

No evidence of carcinogenic potential was observed in lifetime carcinogenicity studies performed in rats and mice at doses up to 43.6 and 317.8 mg/kg/day, respectively. These doses are approximately 6 and 18 times the maximum recommended human dose (MRHD), respectively, on a mg/m² basis.

Mutagenicity

Gepirone showed no mutagenicity in three different in vitro genotoxicity assays (bacterial gene mutation, mammalian gene mutation, or DNA repair). No clastogenicity was observed in a rat micronucleus assay.

Impairment of Fertility

When gepirone was administered orally to male and female rats prior to and throughout mating at daily doses of 5, 27, 64, and 150 mg/kg, the latency to mating was increased at doses of 64 mg/kg (8 times the MRHD on a mg/m² basis) and above.

• Suicidal Thoughts and Behaviors in Adolescents and Young Adults
• QT Prolongation
• Serotonin Syndrome
• Activation of Mania or Hypomania

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 gepirone 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 gepirone 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 gepirone 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 gepirone 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 gepirone were dizziness and nausea.

The most common adverse reactions (≥ 5% and twice the incidence of placebo) in gepirone-treated patients were dizziness, nausea, insomnia, abdominal pain, and dyspepsia.

Table 1 presents the adverse reactions that occurred at an incidence of ≥ 2% of patients treated with gepirone and at a higher incidence than in the placebo-treated patients.

Table 1. Adverse Reactions that Occurred in ≥ 2% of Patients Treated with gepirone and Greater than the Incidence in Placebo-Treated Patients in Pooled MDD Studies (Study 1 and Study 2):

^* 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.

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 gepirone and at 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 Reaction Observed in Clinical Studies

Hypersensitivity reactions including rash, pruritus, and urticaria were reported in clinical studies with gepirone.