Gepirone

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) ] .

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.

12.3 Pharmacokinetics The pharmacokinetics of EXXUA are linear and dose proportional from 18.2 mg to 72.6 mg. Steady-state plasma concentration are typically achieved within two to four days of daily dosing. Absorption The absolute bioavailability is 14% to 17%. The maximal plasma EXXUA concentration (C max­ ) after dosing is reached within 6 hours post dose (T max ). Effect of Food After a high fat meal, T max is reached at 3 hours. A significant effect of food has been observed on the peak plasma concentration (C max ) of EXXUA and, to a lesser extent, on the total exposure (AUC0-tlast, AUC0-∞) to EXXUA. The magnitude of the food-effect was dependent of the fat content of the meal. The systemic exposure of EXXUA and major metabolites was consistently higher under fed conditions as compared to the fasted state. Gepirone C max 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. The AUC after intake of low-fat breakfast was about 14% higher, after a medium-fat breakfast 22% higher and after a high-fat breakfast 32 to 37% higher as compared to the fasted state. The effect of varying amounts of fat on C max and AUC of the major metabolites 3’-OH-gepirone and 1-PP were similar to that found for gepirone [see Dosage and Administration (2.2) ]. Distribution The apparent volume of distribution of EXXUA is approximately 94.5L. The in vitro plasma protein binding in human is 72% and is not concentration dependent. The in vitro plasma proteinbinding for metabolite 3’-OH-gepirone is 59%and 42% for 1-PP. Elimination The mean terminal half-life is approximately 5 hours. Metabolism EXXUA is extensively metabolized and both major metabolites 1-PP and 3’-OH-gepirone are present in plasma in higher concentrations than the parent compound. CYP3A4 is the primary enzyme catalyzing the metabolism of EXXUA to its major pharmacologically active metabolites. Excretion Following a single oral dose of [ 14 C]-labeled gepirone, approximately 81% and 13% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. 60% of the gepirone was eliminated in the urine within the first 24 hours. The presence of hepatic or renal impairment did affect the apparent clearance of EXXUA. Specific Populations Exposures of gepirone in specific populations are summarized in Figure 1 [see Dosage and Administration (2.3, 2.4 , 2.5) , Contraindications (4) , and Use in Specific Populations (8.5, 8.6, 8.7) ] . Figure 1 Effects of Specific Populations on the Pharmacokinetics of Gepirone Gepirone dose: 36.3 mg in renal, 18.2 mg in hepatic; steady-state at 18.2 mg for race and 18.2-72.6 mg for age. Data are GMRs and 90% CIs, except for Age groups (arithmetic mean ratios). AUC = area under the plasma concentration-time curve; CI = confidence interval; C max = maximum plasma concentration; GMR = geometric mean ratio. Drug Interactions Studies In Vivo Studies The effect of co-administered drugs on the pharmacokinetics of gepirone is summarized in Figure 2 [see Dosage and Administration (2.6) and Drug Interactions (7) ] . Figure 2 Effect of Co-Administered Drugs on the Pharmacokinetics of Gepirone Rifampin The effect of multiple oral dosing of potent cytochrome P450 3A4 inducer rifampin on the steady-state pharmacokinetics of EXXUA and its major metabolites 1-PP and 3’-OH-gepirone was investigated in 24 subjects. Combined therapy with rifampin (600 mg daily) and EXXUA (20 mg for two days, then 40 mg daily) decreased C max and AUC0-24 of EXXUA 20 times (EXXUA C max alone 9.63 ng/mL, with rifampin 0.491 ng/mL) and 29 times (EXXUA AUC0-24 alone 123 ng·hr/mL, with rifampin 4.19 ng·hr/mL), respectively. The C max and AUC0-24 of 3’-OH gepirone were decreased 2.5 times (3’-OH gepirone C max alone 23.0 ng/mL, with rifampin 9.30 ng/mL) and three times (3’-OH gepirone AUC0-24 alone 371 ng·hr/mL, with rifampin 126 ng·hr/mL), respectively. There was no effect on the pharmacokinetics of 1-PP (1-PP C max alone 6.37 ng/mL, with rifampin 6.02 ng/mL; 1-PP AUC0-24 alone 92.5 ng·hr/mL, with rifampin 81.1 ng·hr/mL). Glyburide Under steady-state conditions for glyburide, the addition of 36.3 mg daily of EXXUA for six days in 16 patients with stable Type II diabetes resulted in statistically significantly lower AUC (glyburide AUC 0-12 alone 574.8 ng·h/mL, with EXXUA 483.0 ng·h/mL) and C max (glyburide C max alone 121.0 ng/mL, with EXXUA 96.6 ng/mL) values for glyburide. Drugs that Interfere with Hemostasis Following coadministration of stable dose of warfarin (INR 1.4 to 2.0) with multiple daily doses of EXXUA, no significant effect was observed in INR, prothrombin values, or total warfarin (protein bound plus free drug) pharmacokinetics for warfarin. Drugs that Interfere with Protein Binding Gepirone is not highly bound to plasma protein and is not likely to be involved in interactions due to altered protein binding. In a clinical study with coadministration of EXXUA (18.2 mg) and warfarin, a highly protein-bound drug, no significant change in international normalized ratio (INR) was observed. In Vitro Studies Gepirone at concentrations of 0.5, 5, and 50 ng/mL was shown to have no significant impact on the plasma protein binding of chlorpromazine, desipramine, diazepam, phenytoin, prazosin, propranolol, verapamil, or warfarin. The binding of digoxin and haloperidol were decreased (at maximum) by 5% and 9%, respectively. The plasma protein binding of lidocaine appeared to be increased by 4.9% in the presence of gepirone. Alcohol : An in vitro study showed dissolution rate for both 18.2 mg and 72.6 mg gepirone ER tablets decreased slightly as ethanol concentration increased in 0.01N HCl and 0.1N HCl at 0%, 5%, 10%, 20% and 40% alcohol. At 20 hours and 40% alcohol, approximately (mean) 76.8% and 80.7% were dissolved for the 18.2 mg and 72.6 mg gepirone ER tablets, respectively. Transporter Systems : EXXUA and its metabolites are unlikely to cause clinically significant inhibition of the following transporters based on in vitro data: P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K. As such, no clinically relevant interactions with drugs metabolized/transported by these CYP enzymes or transporters would be expected. Enzyme systems : In addition, EXXUA has not been shown to be an inhibitor or inducer of any of the cytochrome P450 enzymes [see Clinical Pharmacology (12.3) ] . Chronic administration of EXXUA is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Figure 1 Figure 2