EXXUA

1 INDICATIONS AND USAGE EXXUA is indicated for the treatment of major depressive disorder (MDD) in adults. EXXUA is indicated for the treatment of major depressive disorder (MDD) in adults ( 1 ).

2 DOSAGE AND ADMINISTRATION Correct electrolyte abnormalities and perform electrocardiogram (ECG) prior to initiating treatment with EXXUA. Do not initiate EXXUA if QTc is > 450 msec ( 2.1 ). Perform ECGs during dosage titration and periodically during treatment ( 2.1 ). The recommended starting dose is 18.2 mg administered orally once daily with food at approximately the same time each day ( 2.2 , 2.3 ). Depending on clinical response and tolerability, the dosage may be increased to 36.3 mg once daily on Day 4. Dosage may be further titrated to 54.5 mg once daily after Day 7 and to 72.6 mg once daily after an additional week ( 2.3 ). Geriatric patients: Recommended starting dosage is 18.2 mg once daily. Dosage may be increased to 36.3 mg after 7 days ( 2.4 ). Renal Impairment (creatinine clearance < 50 mL/min): Recommended starting dosage is 18.2 mg once daily. Dosage may be increased to 36.3 mg once daily after 7 days ( 2.5 , 8.6 ). Moderate Hepatic Impairment (Child-Pugh B): Dosage may be increased to 36.3 mg once daily after 7 days ( 2.6 , 8.7 ). Adjust EXXUA dose by 50% when a moderate CYP3A4 inhibitor is administered ( 2.7 ). 2.1 Important Recommendations Prior to Initiating and During Treatment with EXXUA Electrocardiogram and Electrolyte Monitoring Correct electrolyte abnormalities prior to initiating EXXUA. In patients with electrolyte abnormalities, or who are receiving diuretics or glucocorticoids, or who have a history of hypokalemia or hypomagnesemia, also monitor electrolytes during dose titration and periodically during treatment with EXXUA [see Warnings and Precautions (5.2) ]. Perform an electrocardiogram (ECG) prior to initiating EXXUA, during dosage titration, and periodically during treatment. Do not initiate EXXUA if QTc is > 450 msec at baseline. Monitor ECGs more frequently if EXXUA is used: concomitantly with drugs known to prolong the QT interval in patients who develop QTc ≥ 450 msec during treatment in patients with a significant risk of developing torsade de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7) ]. Do not escalate the EXXUA dosage if the QTcF is > 450 msec [see Warnings and Precautions (5.2) ]. Bipolar Disorder, Mania, and Hypomania Screening Screen patients for a personal or family history of bipolar disorder, mania, or hypomania prior to initiating treatment with EXXUA [see Warnings and Precautions (5.3) ] . 2.2 Important Administration Instructions Take EXXUA orally with food at approximately the same time each day [see Clinical Pharmacology (12.3) ] . Swallow tablets whole. Do not split, crush, or chew EXXUA. 2.3 Recommended Dosage The recommended starting dosage of EXXUA is 18.2 mg once daily. Based on clinical response and tolerability, the dosage may be increased to 36.3 mg orally once daily on Day 4 and further titrated to 54.5 mg orally once daily after Day 7 and to 72.6 mg orally once daily after an additional week. The maximum recommended daily dosage of EXXUA is 72.6 mg once daily. 2.4 Dosage Recommendations in Geriatric Patients The recommended starting dosage of EXXUA in geriatric patients is 18.2 mg orally once daily. Based on clinical response and tolerability, the dosage may be increased to maximum recommended dosage of 36.3 mg orally once daily after Day 7 [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ]. 2.5 Recommended Dosage in Patients with Renal Impairment The recommended starting dosage of EXXUA 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. The recommended dosage in patients with creatinine clearance ≥ 50 mL/min is the same as in patients with normal renal function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.6 Recommended Dosage in Patients with Hepatic Impairment The recommended starting dose of EXXUA 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 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3 ) ] . EXXUA is contraindicated in patients with severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . The recommended dosage in patients with mild (Child-Pugh A) hepatic impairment is the same as patients with normal hepatic function. 2.7 Dosage Modifications for Concomitant Use with CYP3A4 Inhibitors Reduce the EXXUA dose by 50% when used concomitantly with a moderate CYP3A4 inhibitor [see Drug Interactions (7) ] . EXXUA is contraindicated in patients receiving strong CYP3A4 inhibitors [see Contraindications (4) and Drug Interactions (7) ] . 2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days must elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with EXXUA. Conversely, at least 14 days must be allowed after stopping EXXUA before starting an MAOI antidepressant [see Contraindications (4) and Drug Interactions (7) ] .

4 CONTRAINDICATIONS EXXUA is contraindicated in patients: with known hypersensitivity to gepirone or components of EXXUA [see Adverse Reactions (6.1) ] . with prolonged QTc interval > 450 msec at baseline [see Warnings and Precautions (5.2) ]. with congenital long QT syndrome [see Warnings and Precautions (5.2) ]. receiving concomitant strong CYP3A4 inhibitors [see Warnings and Precautions (5.2) and Drug Interactions (7) ]. with severe hepatic impairment [see Warnings and Precautions (5.2) and Use in Specific Populations (8.7) ]. taking, or within 14 days of stopping, MAOIs due to the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome [see Warnings and Precautions (5.3) and Drug Interactions (7) ] . Starting EXXUA in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is also contraindicated. Known hypersensitivity to gepirone or components of EXXUA ( 4 ). Prolonged QTc interval > 450 msec at baseline ( 4 ). Congenital long QT syndrome ( 4 ). Concomitant use of strong CYP3A4 inhibitors ( 4 ). Severe hepatic impairment ( 4 ). Use with an MAOI or within 14 days of stopping treatment with EXXUA. Do not use EXXUA within 14 days of discontinuing an MAOI ( 4 ).

5 WARNINGS AND PRECAUTIONS QT Interval Prolongation: EXXUA prolongs the QTc. Correct electrolyte abnormalities. Perform ECGs prior to initiation, during dose titration, and periodically during treatment with EXXUA. Monitor ECGs more frequently when EXXUA is used concomitantly with drugs known to prolong the QT interval, in patients who develop QTc ≥ 450 msec during treatment or are at significant risk of developing torsade de pointes. Do not escalate dosage if QTc > 450 msec ( 2.1 , 5.2 , 7 ). Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents. If serotonin syndrome occurs, discontinue EXXUA and initiate supportive measures ( 5.3 ). Activation of Mania/Hypomania: Screen patients for bipolar disorder ( 5.4 ). 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients aged 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1 . Table 1 Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric EXXUA is not approved for use in pediatric patients. and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo < 18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo 25-64 years old 1 fewer patient ≥ 65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that the use of antidepressants can delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing EXXUA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 QT Prolongation EXXUA prolongs the QTc interval [see Clinical Pharmacology (12.2) ] . EXXUA is contraindicated in patients with congenital long QT syndrome and in patients with severe hepatic impairment or in patients receiving concomitant strong CYP3A4 inhibitors as they increase EXXUA plasma concentrations [see Contraindications (4) , Drug Interactions (7) , and Use in Specific Populations (8.7) ] . Do not initiate EXXUA if QTc is > 450 msec at baseline [see Dosage and Administration (2.1) and Contraindications (4) ] . Correct electrolyte abnormalities prior to EXXUA initiation. In patients with electrolyte abnormalities, who are receiving diuretics or glucocorticoids, or have a history of hypokalemia or hypomagnesemia, also monitor electrolytes during dose titration and periodically during treatment with EXXUA. Perform an ECG prior to EXXUA initiation, during dosage titration, and periodically during treatment. Monitor patients with ECGs more frequently: If EXXUA is used concomitantly with drugs known to prolong the QT interval [ see Drug Interactions (7) ]. In patients who develop QTc ≥450 msec during treatment with EXXUA. Do not escalate the EXXUA dosage if QTcF is > 450 msec [see Dosage and Administration (2.1) ] . 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. Reduce the EXXUA dosage when used concomitantly with moderate CYP3A4 inhibitors, as they may increase EXXUA concentrations [see Dosage and Administration (2.7) and Drug Interactions (7) ] . 5.3 Serotonin Syndrome Concomitant use of EXXUA with 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 [see Drug Interactions (7) ] . The concomitant use of EXXUA with MAOIs is contraindicated. In addition, do not initiate EXXUA in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking EXXUA discontinue EXXUA before initiating treatment with the MAOI [see Contraindications (4) and Drug Interactions (7) ] . If concomitant use of EXXUA with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. Discontinue EXXUA and/or concomitant serotonergic drug immediately if the above symptoms occur and initiate supportive symptomatic treatment. 5.4 Activation of Mania or Hypomania Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating treatment with EXXUA, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression) [see Dosage and Administration (2.1) ]. EXXUA is not approved for use in treating bipolar depression.

7 DRUG INTERACTIONS Table 3 displays clinically important drug interactions with EXXUA. Table 3 Clinically Important Drug Interactions with EXXUA CYP3A4 Inhibitors Clinical Impact Strong CYP3A4 Inhibitors Concomitant use of EXXUA with a strong CYP3A4 inhibitor increases EXXUA exposure by ~ 5-fold [see Clinical Pharmacology (12.3) ] . Moderate CYP3A4 Inhibitors Concomitant use with a moderate CYP3A4 inhibitor increases EXXUA exposure by ~ 2.6-fold [see Clinical Pharmacology (12.3) ] . Intervention Strong CYP3A4 Inhibitors EXXUA is contraindicated in patients taking strong CYP3A4 inhibitors [see Dosage and Administration (2.7) , Contraindications (4) , and Warnings and Precautions (5.2) ] . Moderate CYP3A4 Inhibitors If EXXUA is used with a moderate CYP3A4 inhibitor, reduce the dosage of EXXUA [see Dosage and Administration (2.7) and Warnings and Precautions (5.2) ]. Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of EXXUA with MAOIs increases the risk of serotonin syndrome. Intervention EXXUA is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue or in patients who have taken MAOIs within the preceding 14 days. Allow at least 14 days after stopping EXXUA before starting an MAOI [see Dosage and Administration (2.8) , Contraindications (4) , and Warnings and Precautions (5.3) ]. Drugs that Prolong the QTc Interval Clinical Impact Concomitant use of drugs that prolong the QTc interval may add to the QTc prolonging effects of EXXUA and increase the risk of cardiac arrhythmias. Intervention Monitor patients with ECGs more frequently if EXXUA is administered with other drugs known to prolong QT interval [see Warnings and Precautions (5.2) ] . CYP3A4 Inducers Clinical Impact Concomitant use of EXXUA with a strong CYP3A4 inducer reduces EXXUA exposure by 20- to 29-fold [see Clinical Pharmacology (12.3) ] . Intervention Avoid concomitant use of EXXUA in patients taking strong CYP3A4 inducers. Other Serotonergic Drugs Clinical Impact Concomitant use of EXXUA and serotonergic drugs increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when EXXUA is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of EXXUA and/or concomitant serotonergic drug [see Warnings and Precautions (5.3) ] . Strong CYP3A4 inducers: Reduces EXXUA exposure. Avoid concomitant use ( 7 ).

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1) ] QT Prolongation [see Warnings and Precautions (5.2) ] Serotonin Syndrome [see Warnings and Precautions (5.3) ] Activation of Mania or Hypomania [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence of ≥ 5% and at least twice incidence of placebo) were dizziness, nausea, insomnia, abdominal pain, and dyspepsia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Aytu Therapeutics at 1-855-298-8246 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 EXXUA 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 EXXUA 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 EXXUA 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 [see Clinical Studies (14) ] . 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 EXXUA 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 EXXUA were dizziness and nausea. The most common adverse reactions (≥ 5% and twice the incidence of placebo) in EXXUA-treated patients were dizziness, nausea, insomnia, abdominal pain, and dyspepsia. Table 2 presents the adverse reactions that occurred at an incidence of ≥ 2% of patients treated with EXXUA and at a higher incidence than in the placebo-treated patients. Table 2 Adverse Reactions that Occurred in ≥ 2% of Patients Treated with EXXUA and Greater than the Incidence in Placebo-Treated Patients in Pooled MDD Studies (Study 1 and Study 2) Adverse Reaction Placebo (N=230) (%) EXXUA (18.2 mg to 76.2 mg) (N=226) (%) Dizziness 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. 10 49 Nausea 13 35 Headache 20 31 Feeling Sleepy or Tired 14 15 Insomnia 5 14 Diarrhea 9 10 Upper Respiratory Tract Infection 7 8 Dry Mouth 5 8 Vomiting 4 7 Abdominal Pain 3 7 Dyspepsia 2 6 Increased Appetite 3 5 Constipation 3 4 Nasopharyngitis 3 4 Nasal Congestion 2 4 Paresthesia 1 4 Hyperhidrosis 0 4 Palpitations 0 4 Weight Increased 1 3 Agitation 0 3 Feeling Jittery 0 3 Heart Rate Increased 0 2 Lethargy 0 2 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 EXXUA andat 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 Reactions Observed in Clinical Studies Hypersensitivity reactions including rash, pruritus, and urticaria were reported in clinical studies with EXXUA.

8.1 Pregnancy Pregnancy Exposure Registry 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 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/. 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/m 2 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/m 2 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 [See Warnings and Precautions (5.3) ]. 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/m 2 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/m 2 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/m 2 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/m 2 basis). The NOAEL (27 mg/kg) for still births was associated with a maternal dose 3 times the MRHD on a mg/m 2 basis. Fetal weights were decreased at 27 mg/kg (3 times the MRHD on a mg/m 2 basis) and fetal lengths were decreased at 64 mg/kg (8 times the MRHD on a mg/m 2 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/m 2 basis.