EXXUA

EXXUA
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kosar Doraghi, M.D.[2]

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Black Box Warning

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete Boxed Warning. SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING. Increased risk of suicidal thinking and behavior in pediatric and young adult patients taking antidepressants. Closely monitor for worsening and emergence of suicidal thoughts and behaviors. EXXUA is not approved for use in pediatric patients

Overview

EXXUA is a extended-release tablets that is FDA approved for the treatment of major depressive disorder (MDD) in adults. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, nausea, insomnia, abdominal pain, and dyspepsia.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Correct electrolyte abnormalities and conduct an electrocardiogram, ECG, before commencing treatment with EXXUA.

• Refrain from initiating EXXUA (gepirone) if QTc exceeds 450 msec. Perform ECGs during dosage titration and regularly throughout treatment.

The recommended initial dose is 18.2 mg orally once daily with food at approximately the same time each day. Depending on clinical response and tolerability, escalate the dosage to 36.3 mg once daily on Day 4. Further titration may increase to 54.5 mg once daily after Day 7 and to 72.6 mg once daily after an additional week. For geriatric patients, the recommended starting dose is 18.2 mg once daily, with the possibility of increasing to 36.3 mg after 7 days. In cases of renal impairment, creatinine clearance < 50 mL/min, start with 18.2 mg once daily, with potential escalation to 36.3 mg once daily after 7 days. In moderate hepatic impairment, Child Pugh B, consider increasing the dosage to 36.3 mg once daily after 7 days. Adjust the EXXUA dose by 50% when administering a moderate CYP3A4 inhibitor.

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

Off-Label Use and Dosage (Adult)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding EXXUA FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Contraindications

• Known hypersensitivity to gepirone or components of EXXUA.
• Prolonged QTc interval exceeding 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 with EXXUA. Avoid EXXUA within 14 days of discontinuing an MAOI.

Warnings

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete Boxed Warning. SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING. Increased risk of suicidal thinking and behavior in pediatric and young adult patients taking antidepressants. Closely monitor for worsening and emergence of suicidal thoughts and behaviors. EXXUA is not approved for use in pediatric patients

R QT Interval Prolongation: EXXUA prolongs the QTc.

• Correct electrolyte abnormalities. Conduct ECGs before starting treatment, during dose titration, and regularly during EXXUA therapy. Monitor ECGs more frequently when EXXUA is used alongside drugs known to lengthen the QT interval, in patients with QTc ≥ 450 msec during treatment, or at significant risk of torsade de pointes. Refrain from increasing the dosage if QTc exceeds 450 msec.
• Serotonin Syndrome: Risk increases when co-administered with other serotonergic agents. In case of serotonin syndrome, discontinue EXXUA and provide supportive measures.
• Activation of Mania/Hypomania: Screen patients for bipolar disorder.

Adverse Reactions

Clinical Trials Experience

• Suicidal thoughts and behaviors, QT prolongation, serotonin syndrome, and activation of mania or hypomania are notable warnings and precautions associated with EXXUA.
• Clinical trials involving 1,976 adult patients with major depressive disorder (MDD) revealed adverse reactions.
• The trials included patients aged 15 to 78, with a majority being Caucasian and female.
• Among patients treated with EXXUA, common adverse reactions included dizziness, nausea, insomnia, abdominal pain, and dyspepsia.
• Approximately 7% of EXXUA-treated patients discontinued treatment due to adverse reactions, with dizziness and nausea being the most common causes.
• These findings provide insight into the safety profile and adverse reactions associated with EXXUA in the treatment of MDD.

Postmarketing Experience

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

Drug Interactions

• CYP3A4 Inhibitors
• Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact: Concomitant use increases the risk of serotonin syndrome. Intervention: Contraindicated with EXXUA. Allow at least 14 days after stopping EXXUA before starting an MAOI.

• Drugs that Prolong the QTc Interval

Clinical Impact: Concomitant use may add to QTc prolonging effects of EXXUA. Intervention: Monitor patients with ECGs more frequently if administered with other QT prolonging drugs.

• CYP3A4 Inducers

Clinical Impact: Concomitant use reduces EXXUA exposure by 20- to 29-fold.

• Intervention: Avoid concomitant use of EXXUA with strong CYP3A4 inducers.Other Serotonergic Drugs

Clinical Impact: Concomitant use increases the risk of serotonin syndrome. Intervention: Monitor for symptoms of serotonin syndrome and consider discontinuation if it occurs.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including EXXUA, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of EXXUA in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of EXXUA during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of EXXUA in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of EXXUA in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of EXXUA in geriatric settings.

Gender

There is no FDA guidance on the use of EXXUA with respect to specific gender populations.

Race

There is no FDA guidance on the use of EXXUA with respect to specific racial populations.

Renal Impairment

In patients with creatinine clearance <50 mL/min, the metabolism and excretion of EXXUA and some of its major metabolites were decreased

Hepatic Impairment

In patients with mild (Child-Pugh A) hepatic impairment to moderate (Child-Pugh B) hepatic impairment, the metabolism of EXXUA and its major metabolites was decreased

Females of Reproductive Potential and Males

There is no FDA guidance on the use of EXXUA in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of EXXUA in patients who are immunocompromised.

Administration and Monitoring

Administration

Take EXXUA orally with food at approximately the same time each day. Swallow tablets whole; do not split, crush, or chew them.

• Recommended Dosage:

Starting dosage: 18.2 mg once daily. Titration:

• Day 4: Increase to 36.3 mg once daily.
• Day 7: Further titration to 54.5 mg once daily.
• Additional week: Increase to 72.6 mg once daily.
• Maximum daily dosage: 72.6 mg once daily.
• Recommended Dosage in Special Populations:

Geriatric patients: Start with 18.2 mg once daily, with potential escalation to 36.3 mg once daily after Day 7.

• Patients with renal impairment (creatinine clearance < 50 mL/min): Start with 18.2 mg once daily, with potential escalation to 36.3 mg once daily after Day 7.
• Patients with hepatic impairment:
• Moderate (Child-Pugh B): Start with 18.2 mg once daily, with potential escalation to 36.3 mg once daily after Day 7. Severe (Child-Pugh C) impairment: Contraindicated.
• Mild (Child-Pugh A): Same dosage as patients with normal hepatic function.

Dosage Modifications for Concomitant Use with CYP3A4 Inhibitors:

• Reduce EXXUA dose by 50% when used with a moderate CYP3A4 inhibitor. Contraindicated with strong CYP3A4 inhibitors.

Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant:

• Allow at least 14 days between discontinuation of an MAOI and initiation of EXXUA therapy, and vice versa.

Monitoring

There is limited information regarding EXXUA Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of EXXUA and IV administrations.

Overdosage

There is limited information regarding EXXUA overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding EXXUA Pharmacology in the drug label.

Mechanism of Action

The mechanism of the antidepressant effect of EXXUA 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.

Structure

EXXUA contains gepirone, in the salt form as gepirone hydrochloride (HCl). The chemical name is 2,6- piperidinedione,4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-, monohydrochloride. The molecular weight of gepirone HCl is 395.93 and the structural formula is as follows: Chemical Structure Diagram Gepirone HCl is a white to off-white crystalline powder, which is readily soluble in water.

EXXUA is supplied as extended-release tablets for oral administration. Each extended-release tablet contains 18.2 mg, 36.3 mg, 54.5 mg, or 72.6 mg, gepirone equivalent to 20 mg, 40 mg, 60 mg, or 80 mg of gepirone HCl respectively. The extended-release tablets also contain the following inactive ingredients: colloidal silicon dioxide, Hypromellose, iron oxide (red and/or yellow colorants), magnesium stearate, and microcrystalline cellulose.

Pharmacodynamics

The pharmacological activity of gepirone is attributed to the parent drug and its major metabolites 3’-OH-gepirone and 1-PP. Gepirone and its 3’-OH metabolite bind to 5HT1A receptors (Ki = 38 nM and 58 nM, respectively), where they act as agonists, while the 1-PP metabolite binds to alpha2 receptors (Ki = 42 nM). Cardiac Electrophysiology In a thorough QT study, the largest mean increase in baseline- and placebo-corrected QTc interval with administration of 100 mg per day immediate-release formulation of gepirone was 18.4 msec

Pharmacokinetics

The drug exhibits linear and dose-proportional pharmacokinetics within the dose range of 18.2 mg to 72.6 mg, with steady-state plasma concentrations achieved within two to four days of daily dosing.

• Absorption: EXXUA has an absolute bioavailability of 14% to 17%, with peak plasma concentration reached within 6 hours post-dose. Food intake significantly affects the drug’s absorption, with higher fat content meals leading to increased systemic exposure.
• Distribution: The apparent volume of distribution of EXXUA is approximately 94.5 L, and plasma protein binding is not concentration-dependent for both the drug and its major metabolites.
• Elimination: The mean terminal half-life of EXXUA is approximately 5 hours.
• Metabolism: EXXUA is extensively metabolized by the enzyme CYP3A4, leading to the formation of major metabolites 1-PP and 3’-OH-gepirone, which are present in plasma at higher concentrations than the parent compound.
• Excretion: Following administration, approximately 81% and 13% of the drug’s radioactivity are recovered in the urine and feces, respectively, as metabolites. Hepatic or renal impairment does not significantly affect the drug’s clearance.

Nonclinical Toxicology

There is limited information regarding EXXUA Nonclinical Toxicology in the drug label.

Clinical Studies

The efficacy of EXXUA for treating major depressive disorder (MDD) in adults was assessed in two eight-week randomized, double-blind, placebo-controlled studies involving adults aged 18 to 69 years who met DSM-IV criteria for MDD.

• Study 1: Patients had a median age of 39 years, with 61% female, and predominantly Caucasian. The initial dosage was 18.2 mg once daily, titrated to 36.3 mg on Day 4, 54.5 mg on Day 7, and 72.6 mg after an additional week. The final daily dose of EXXUA was primarily 72.6 mg (64% of patients).
• Study 2: Patients had similar demographics, with a median age of 39 years, 69% female, and mainly Caucasian. The dosage regimen was the same as in Study 1, with the final daily dose of EXXUA primarily being 72.6 mg (66% of patients).

Both studies used the change from baseline in the Hamilton Depression Rating Scale (HAMD-17) total score at Week 8 as the primary efficacy measure. In both studies, patients treated with EXXUA showed significantly greater improvement compared to those receiving placebo.

How Supplied

EXXUA (gepirone) extended-release tablets are supplied in bottles of 100 with child-resistant caps and in four dosage strengths: 18.2-mg Tablets– pink, modified rectangular 36.3-mg Tablets– off-white, modified rectangular 54.5-mg Tablets– yellow, modified rectangular 72.6-mg Tablets– red-brown, modified rectangular

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F)

Images

Drug Images

{{#ask: Page Name::EXXUA |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

NDC83504-151-10 Rx only

EXXUA (gepirone) extended-release tablets

36.3 mg Federal Law requires dispensing of EXXUA with the Medication Guide provided with this bottle. 100 Tablets Fabre-Kramer Each extended-release tablet contains 36.3 mg gepirone equivalent to 40 mg gepirone hydrochloride. Recommended Dosage: See Prescribing Information. Dispense in a tight container with child-resistant closure. {{#ask: Label Page::EXXUA |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding EXXUA Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-EXXUA interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding EXXUA Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding EXXUA Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.