Version May 2024
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Gepirone is not approved for use in pediatric patients.
Note: Perform ECG during therapy (baseline and after dose increases), monitoring more frequently in patients with risk factors for QTc prolongation (eg, in patients who develop QT prolongation [QTc >450 msec] during treatment, concurrent use with other drugs that prolong QT interval, significant risk for torsades de pointes). Do not initiate or increase dose if QTc >450 msec. Correct electrolyte abnormalities prior to starting treatment and monitor during dose increases and periodically in patients with risk factors for electrolyte abnormalities (eg, electrolyte abnormalities at baseline, receiving concomitant diuretics or glucocorticoids, history of hypokalemia or hypomagnesemia).
Major depressive disorder, unipolar: Oral: Initial: 18.2 mg once daily; may increase to 36.3 mg once daily on day 4 based on response and tolerability. May further increase to 54.5 mg once daily on day 7 and 72.6 mg once daily on day 14 based on response and tolerability. Maximum dosage: 72.6 mg once daily.
Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). Reasons for a slower taper (eg, over 4 weeks) include prior history of antidepressant withdrawal symptoms or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).
Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from a monoamine oxidase inhibitor (MAOI). A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between 2 selective serotonin reuptake inhibitors), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, pharmacodynamics), and the degree of symptom control desired (Ref).
Switching to or from a monoamine oxidase inhibitor:
Allow 14 days to elapse between discontinuing an MAOI and initiation of gepirone.
Allow 14 days to elapse between discontinuing gepirone and initiation of an MAOI.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥50 mL/minute: No dosage adjustment necessary.
CrCl <50 mL/minute: Oral: Initial: 18.2 mg once daily; may increase to 36.3 mg once daily on day 7 based on response and tolerability. Maximum dosage 36.3 mg once daily.
Child-Turcotte-Pugh class A: No dosage adjustment necessary.
Child-Turcotte-Pugh class B: Oral: Initial: 18.2 mg once daily; may increase to 36.3 mg once daily on day 7 based on response and tolerability. Maximum dosage 36.3 mg once daily.
Child-Turcotte-Pugh class C: Use is contraindicated.
Major depressive disorder, unipolar: Oral: Initial: 18.2 mg once daily; may increase to 36.3 mg once daily on day 7 based on response and tolerability. Maximum dosage 36.3 mg once daily.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Gastrointestinal: Nausea (35%)
Nervous system: Dizziness (49%), drowsiness (≤15%), fatigue (≤15%), headache (31%), insomnia (14%)
1% to 10%:
Cardiovascular: Increased heart rate (2%), palpitations (4%), peripheral edema (<2%)
Dermatologic: Hyperhidrosis (4%)
Endocrine & metabolic: Weight gain (3%)
Gastrointestinal: Abdominal pain (7%), constipation (4%), diarrhea (10%), dyspepsia (6%), increased appetite (5%), vomiting (7%), xerostomia (8%)
Genitourinary: Breast tenderness (<2%)
Nervous system: Agitation (3%), changes in thinking (<2%), confusion (<2%), hypoesthesia (<2%), increased energy (<2%), jitteriness (3%), lethargy (2%), paresthesia (4%), sleep disturbance (<2%)
Respiratory: Dyspnea (<2%), nasal congestion (4%), nasopharyngitis (4%), upper respiratory tract infection (8%)
Frequency not defined:
Cardiovascular: Prolonged QT interval on ECG
Hypersensitivity: Hypersensitivity reaction
Nervous system: Suicidal ideation, suicidal tendencies
Hypersensitivity to gepirone or any component of the formulation; prolonged QTc interval >450 msec at baseline; congenital long QT syndrome; patients receiving concomitant strong CYP34A inhibitors; severe hepatic impairment; taking or within 14 days of stopping monoamine oxidase inhibitors (MAOIs) due to the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome; starting gepirone in a patient treated with reversible MAOIs such as IV methylene blue.
Note: Although gepirone is contraindicated per manufacturer labeling when used in combination with linezolid, new evidence suggests that the combination is unlikely to cause serotonin syndrome (0.06% to 3% risk), and therefore, these agents can be administered concomitantly when necessary. Monitor patients on this combination; average duration of serotonin toxicity is ~4 days; however, risks may be greater with longer durations of concurrent therapy. Educate them on the signs and symptoms of serotonin syndrome (Bai 2022; Butterfield 2012; Karkow 2017; Kufel 2023; Narita 2007; Taylor 2006).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Major psychiatric warnings:
• Suicidal thinking/behavior: Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years of age. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases). A medication guide concerning the use of antidepressants should be dispensed with each prescription. Gepirone is FDA approved for the treatment of depression in adolescents.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression or psychosis occur.
Concerns related to adverse effects:
• Heart rhythm abnormalities: Gepirone prolongs the QTc interval.
• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors), particularly when used in combination with other serotonergic agents (eg, triptans, tricyclic antidepressants [TCAs], fentanyl, lithium, tramadol, buspirone, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, monoamine oxidase inhibitors [MAOIs], other MAOIs [IV methylene blue]). Monitor patients closely for signs of SS, such as mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, diaphoresis), neuromuscular changes (eg, tremor, rigidity, myoclonus), GI symptoms (eg, nausea, vomiting, diarrhea), and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Kidney impairment: Use with caution in patients with kidney impairment.
• Mania/Hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer should also be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder. Gepirone is not FDA approved for the treatment of bipolar depression.
Other warnings/precautions:
• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant, however, commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with TCAs), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).
Exxua: FDA approved September 2023; anticipated availability is currently unknown.
Oral: Administer with food at approximately the same time every day. Swallow tablets whole; do not split, crush, or chew.
Major depressive disorder, unipolar: Treatment of unipolar major depressive disorder in adults.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Gepirone. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Gepirone. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Gepirone. Management: Reduce the gepirone dose by 50% if combined with moderate CYP3A4 inhibitors. Monitor for QTc interval prolongation with combined use. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Gepirone. Risk X: Avoid combination
Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Linezolid: Gepirone may enhance the serotonergic effect of Linezolid. This could result in serotonin syndrome. Risk X: Avoid combination
Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Methylene Blue: Gepirone may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Monoamine Oxidase Inhibitors (Antidepressant): Gepirone may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Risk X: Avoid combination
Monoamine Oxidase Inhibitors (Type B): Gepirone may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Type B). This could result in serotonin syndrome. Risk X: Avoid combination
Oxitriptan: May enhance the serotonergic effect of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Antidepressants (Moderate Risk): Gepirone may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Gepirone may enhance the serotonergic effect of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Serotonergic Agents (High Risk): Gepirone may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Serotonergic Agents (Moderate Risk, Miscellaneous): Gepirone may enhance the serotonergic effect of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Risk C: Monitor therapy
St John's Wort: Gepirone may enhance the serotonergic effect of St John's Wort. This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Gepirone. Risk C: Monitor therapy
High fat meals (~850 calories) increase peak plasma concentration and, to a lesser extent, the total exposure to gepirone.
Evaluate pregnancy status prior to initiating treatment for depression in patients who could become pregnant; pharmacologic management may vary by reproductive status (WFSBP [Dodd 2018]). Management of mental health conditions in patients who could become pregnant should be made as part of a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]).
Based on data from animal reproduction studies, in utero exposure to gepirone may cause fetal harm.
Adverse effects in the newborn following exposure to other serotonergic antidepressants late in the third trimester can include apnea, constant crying, cyanosis, feeding difficulty, hyperreflexia, hypo- or hypertonia, hypoglycemia, irritability, jitteriness, respiratory distress, seizures, temperature instability, tremor, and vomiting. Prolonged hospitalization, respiratory support, or tube feedings may be required. Symptoms may be due to the direct toxicity or a discontinuation syndrome. Persistent pulmonary hypertension of the newborn has also been reported.
Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Discontinuing effective medications during pregnancy increases the risk of relapse (ACOG 2023). Management should be made as part of a shared decision-making process. When medications are used, the lowest effective dose without underdosing is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Monthly monitoring during pregnancy is recommended (ACOG 2023; BAP [McAllister-Williams 2017]).
Patients effectively treated for depression in the past may use that medication during pregnancy unless contraindications exist (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]). Treatment should not be withheld or discontinued based only on pregnancy status (ACOG 2023). Agents other than gepirone are preferred for use in pregnant patients who are treatment naive or who have not been effectively treated for depression in the past (ACOG 2023).
Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Health care providers are encouraged to enroll patients exposed to gepirone during pregnancy in the National Pregnancy Registry for Antidepressants (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/).
It is not known if gepirone is present in breast milk.
Adverse events reported in infants exposed to other serotonergic antidepressants via breast milk include irritability, restlessness, excessive somnolence, decreased feeding, and weight loss. Monitor breastfed infants for adverse events.
According to the manufacturer, the decision to breastfeed during gepirone therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Patients effectively treated for depression during pregnancy may continue their medication postpartum unless contraindications to breastfeeding exist. The presence and concentration of the drug in breast milk, efficacy of maternal treatment, and infant age should be considered when initiating a medication for the first-time postpartum (ABM [Sriraman 2015]; ACOG 2023). When first initiating an antidepressant in a patient who is breastfeeding, agents other than gepirone are preferred (ABM [Sriraman 2015]; CANMAT [MacQueen 2016). Treatment should not be withheld or discontinued based only on breastfeeding status (ACOG 2023).
ECG (baseline, after dose increases, and more frequently in patients with risk factors for QTc prolongation [eg, preexisting QT prolongation {QTc >450 msec}, concurrent use with other drugs that prolong QT interval, significant risk for torsades de pointes]); electrolytes (baseline, after dose increases, and more frequently in patients with risk factors for electrolyte abnormalities [eg, electrolyte abnormalities at baseline, receiving concomitant diuretics or glucocorticoids, history of hypokalemia or hypomagnesemia]).
The mechanism of the antidepressant effect of gepirone is not fully understood but is thought to be related to parent drug modulation of serotonergic activity in the CNS through selective agonist activity at 5-HT1A receptors and major metabolite activity at the alpha2 receptor.
Absorption: Compared to the fasted state, after intake of low-fat (~200 calories) breakfast Cmax was 27% higher and AUC 14% higher; after medium-fat (~500 calories) breakfast, Cmax was 55% higher and AUC 22% higher; and after a high-fat (~850 calories) breakfast Cmax was 62% higher and AUC 32% to 37% higher.
Distribution: Vd: 94.5 L.
Protein binding: 72%.
Metabolism: Extensively metabolized via CYP3A4 and both major active metabolites 1-PP and 3’-OH-gepirone are present in plasma in higher concentrations than the parent compound.
Bioavailability: 14% to 17%.
Half-life elimination: ~5 hours.
Time to peak: 6 hours (3 hours after a high-fat [~850 calories] meal).
Excretion: Urine: ~81% recovered as metabolites; feces: ~13% recovered as metabolites.
Older adults: Older adults have a higher AUC and Cmax compared to younger adult patients (18 to 40 years of age).
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