gepirone (Rx)

Brand and Other Names:Exxua

Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet

  • 18.2mg
  • 36.3mg
  • 54.5mg
  • 72.6mg

Major Depressive Disorder

Indicated for the treatment of major depressive disorder (MDD)

18.2 mg PO qDay

Based on clinical response and tolerability

  • May increase to 36.3 mg qDay on Day 4
  • Further titrate to 54.5 mg qDay after Day 7
  • Then, 72.6 mg qDay after an additional week; maximum recommended daily dosage 72.6 mg qDay

Dosage Modifications

Coadministration of CYP3A4 Inhibitors

  • Moderate CYP3A4 inhibitors: Reduce gepirone dose by 50%
  • Strong CYP3A4 inhibitors: Contraindicated

Switching to or from a monoamine oxidase inhibitor (MAOI) antidepressant

  • At least 14 days must elapse between discontinuation of an MAOI and initiating gepirone
  • Allow at least 14 days after stopping gepirone before starting an MAOI antidepressant

Renal impairment

  • CrCl ≥50 mL/min: No dosage adjustment necessary
  • CrCl <50 mL/min: Start at 18.2 mg qDay; may increase to maximum recommended dosage of 36.3 mg qDay after Day 7 based on clinical response and tolerability

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment necessary
  • Moderate (Child-Pugh B): Start at 18.2 mg qDay; may increase to maximum recommended dosage of 36.3 mg qDay after Day 7 based on clinical response and tolerability
  • Severe (Child-Pugh C): Contraindicated

Dosing Considerations

Screen for a personal or family history of bipolar disorder, mania, or hypomania before initiating treatment

Advise patients to inform healthcare provider if taking, or plan to take, any prescription or over-the-counter medications due to an increased risk for drug interactions with this medication

Electrolyte abnormalities and electrocardiogram (ECG)

  • Correct electrolyte abnormalities before initiating for patients with electrolyte abnormalities, or who are receiving diuretics or glucocorticoids, or who have a history of hypokalemia or hypomagnesemia
  • Monitor electrolytes during dose titration and periodically during treatment
  • Perform an ECG before initiating, during dosage titration, and periodically during treatment
  • Do not initiate if QTc is >450 msec at baseline
  • Monitor ECGs more frequently if used with:
    • Drugs known to prolong the QT interval
    • Patients who develop QTc ≥450 msec during treatment
    • Patients with a significant risk of developing torsade de pointes
  • Do not escalate dosage if QTcF is 450 msec

Safety and efficacy not established

Major Depressive Disorder

Indicated for the treatment of major depressive disorder (MDD)

18.2 mg PO qDay

Based on clinical response and tolerability, may increase dosage to maximum recommended dosage of 36.3 mg qDay after Day 7

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Interactions

Interaction Checker

and gepirone

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

            All Interactions Sort By:
             activity indicator 

            Contraindicated (0)

              Serious - Use Alternative (1)

              • olopatadine intranasal

                gepirone and olopatadine intranasal both increase sedation. Avoid or Use Alternate Drug. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

              Monitor Closely (10)

              • daridorexant

                gepirone and daridorexant both increase sedation. Modify Therapy/Monitor Closely. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

              • diazepam intranasal

                diazepam intranasal, gepirone. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration may potentiate the CNS-depressant effects of each drug.

              • difelikefalin

                difelikefalin and gepirone both increase sedation. Use Caution/Monitor.

              • fenfluramine

                fenfluramine, gepirone. Either increases effects of the other by serotonin levels. Use Caution/Monitor. Coadministration with drugs that increase serotoninergic effects may increase the risk of serotonin syndrome.

              • gabapentin

                gabapentin, gepirone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

              • gabapentin enacarbil

                gabapentin enacarbil, gepirone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

              • ganaxolone

                gepirone and ganaxolone both increase sedation. Use Caution/Monitor.

              • lasmiditan

                lasmiditan, gepirone. Either increases effects of the other by sedation. Use Caution/Monitor. Coadministration of lasmiditan and other CNS depressant drugs, including alcohol have not been evaluated in clinical studies. Lasmiditan may cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions.

              • pregabalin

                pregabalin, gepirone. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

              • remimazolam

                remimazolam, gepirone. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.

              Minor (0)

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                Adverse Effects

                >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

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                Warnings

                Black Box Warnings

                Suicidal thoughts and behaviors

                • Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adults in short-term studies
                • Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors
                • Not approved for use in pediatric patients

                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
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                Pregnancy & Lactation

                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

                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.

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                Pharmacology

                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%
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                Administration

                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

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                Patient Handout

                A Patient Handout is not currently available for this monograph.
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                Formulary

                FormularyPatient Discounts

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                Tier Description
                1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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                NC NOT COVERED – Drugs that are not covered by the plan.
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                Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.