Gepotidacin

1 INDICATIONS AND USAGE BLUJEPA is a triazaacenaphthylene bacterial type II topoisomerase inhibitor indicated for the treatment of the following infections caused by susceptible microorganisms: • Uncomplicated urinary tract infections (uUTI) in female adult and pediatric patients 12 years of age and older weighing at least 40 kilograms (kg). ( 1.1 ) • Uncomplicated urogenital gonorrhea in adult and pediatric patients 12 years of age and older weighing at least 45 kilograms who have limited or no alternative treatment options. Approval of this indication is based on limited clinical safety data for this indication. ( 1.2 , 6.1 ) Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of BLUJEPA and other antibacterial drugs, BLUJEPA should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. ( 1.3 ) 1.1 Treatment of Uncomplicated Urinary Tract Infections BLUJEPA is indicated in female adult and pediatric patients 12 years of age and older weighing at least 40 kilograms (kg) for the treatment of uncomplicated urinary tract infections (uUTI) caused by the following susceptible microorganisms: Escherichia coli , Klebsiella pneumoniae , Citrobacter freundii complex, Staphylococcus saprophyticus , and Enterococcus faecalis . 1.2 Treatment of Uncomplicated Urogenital Gonorrhea BLUJEPA is indicated in adult and pediatric patients 12 years of age and older weighing at least 45 kilograms (kg) who have limited or no alternative options for the treatment of uncomplicated urogenital gonorrhea caused by susceptible strains of Neisseria gonorrhoeae. Approval of this indication is based on limited clinical safety data for BLUJEPA [see Adverse Reactions ( 6.1 )]. 1.3 Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of BLUJEPA and other antibacterial drugs, BLUJEPA should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION • uUTI: The recommended dosage of BLUJEPA is 1,500 mg (two 750 mg tablets) taken orally, twice daily (approximately 12 hours apart), for 5 days. ( 2.1 ) • Uncomplicated Urogenital Gonorrhea: The recommended dosage of BLUJEPA is 3,000 mg (four 750 mg tablets) taken orally, followed by a second dose of 3,000 mg (four 750 mg tablets) approximately 12 hours later. ( 2.2 ) • Administer BLUJEPA tablets after a meal to reduce the possibility of gastrointestinal intolerance. ( 2.3 ) 2.1 Recommended Dosage for Female Adult and Pediatric Patients 12 Years of Age and Older Weighing at Least 40 kg for Uncomplicated UTI The recommended dosage of BLUJEPA is 1,500 mg (two 750 mg tablets) taken orally, twice daily (approximately 12 hours apart) for 5 days in female adult and pediatric patients 12 years of age and older with uncomplicated uUTI [see Dosage and Administration ( 2.3 )] . 2.2 Recommended Dosage for Adult and Pediatric Patients 12 Years of Age and Older Weighing at Least 45 kg for Uncomplicated Urogenital Gonorrhea The recommended dose of BLUJEPA is 3,000 mg (four 750 mg tablets) taken orally, followed by a second dose of 3,000 mg (four 750 mg tablets) approximately 12 hours later in adult and pediatric patients 12 years of age and older weighing at least 45 kg with uncomplicated urogenital gonorrhea [see Dosage and Administration ( 2.3 )]. Do not increase the dose, extend the duration of treatment, or reduce the interval between doses due to the risk of QTc interval prolongation [see Warnings and Precautions ( 5.1 )]. 2.3 Important Administration Instructions Administer BLUJEPA tablets after a meal to reduce the possibility of gastrointestinal intolerance [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 )] . 2.4 Recommendations Regarding Missed Dose(s) If a dose is missed, instruct patients to take the missed dose as soon as possible. For uUTI, do not double the dose to make up for a missed dose.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • QTc Prolongation [see Warnings and Precautions ( 5.1 )] . • Acetylcholinesterase Inhibition [see Warnings and Precautions ( 5.2 )] . • Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] . • Clostridioides difficile Infection [see Warnings and Precautions ( 5.4 )] . • uUTI: The most common adverse reactions occurring in ≥1% of patients are diarrhea, nausea, abdominal pain, flatulence, headache, soft feces, dizziness, vomiting, and vulvovaginal candidiasis. ( 6.1 ) • Uncomplicated Urogenital Gonorrhea: The most common adverse reactions occurring in ≥2% of patients are diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, soft feces, headache, fatigue, and hyperhidrosis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trial Experience in Patients with Uncomplicated UTI The safety of BLUJEPA was evaluated in 2 double‑blind, active‑controlled, randomized trials in female adult and pediatric patients 12 years of age and older with uUTI (Trial 1 and Trial 2). A total of 1,570 patients were treated with BLUJEPA and 1,558 patients were treated with nitrofurantoin (pooled safety populations for BLUJEPA and nitrofurantoin, respectively). Patients received treatment for a median duration of 5 days. In Trials 1 and 2 (pooled, intent-to-treat [ITT] population), the median age of patients treated with BLUJEPA was 49 (range 13 to 89) years; <1% were <18 years, 77% of patients were 18 to 64 years, 14% were 65 to 74 years, and 8% were ≥75 years. Patients were female (100%) and White (83%), Black or African American (7%), Asian (5%), or American Indian or Alaskan Native (4%); for ethnicity, 33% identified as Hispanic/Latino and 67% as non-Hispanic/Latino. The majority of patients were enrolled from the U.S. (55%). Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation: In the pooled trials (Trials 1 and 2), serious adverse reactions occurred in 1/1,570 (<1%) uUTI patients treated with BLUJEPA and 1/1,558 (<1%) uUTI patients treated with nitrofurantoin. The serious adverse reaction reported with BLUJEPA was dysarthria. No adverse reaction led to death in either treatment group. In the pooled trials, adverse reactions leading to discontinuation of treatment occurred in 79/1,570 (5%) uUTI patients treated with BLUJEPA and 30/1,558 (2%) uUTI patients treated with nitrofurantoin. Adverse reactions occurring in >1% of patients leading to treatment discontinuation in patients treated with BLUJEPA included diarrhea (3%) and nausea (1%). Common Adverse Reactions: Table 1 lists the adverse reactions occurring in ≥1% of uUTI patients receiving BLUJEPA in the pooled trials (Trials 1 and 2). Table 1. Adverse Reactions Occurring in ≥1% of Uncomplicated Urinary Tract Infection Patients Treated with BLUJEPA (Trials 1 and 2 Pooled Data; Safety Population) a Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. Adverse Reaction BLUJEPA N = 1,570 n (%) Nitrofurantoin N = 1,558 n (%) Diarrhea 258 (16) 51 (3) Nausea 146 (9) 64 (4) Abdominal pain a 60 (4) 34 (2) Flatulence 43 (3) 8 (<1) Headache 38 (2) 40 (3) Soft feces 37 (2) 8 (<1) Dizziness 29 (2) 19 (1) Vomiting 28 (2) 10 (<1) Vulvovaginal candidiasis 20 (1) 18 (1) Diarrhea: In Trials 1 and 2, diarrhea was reported in 258/1,570 (16%) uUTI patients receiving BLUJEPA; 11% mild, 5% moderate, and <1% severe. The diarrhea started within the first 2 days of treatment for the majority of patients and the median duration of diarrhea was 4 days. Adverse Reactions Occurring in Less than 1% of uUTI Patients Receiving BLUJEPA in Trials 1 and 2 (Pooled): Gastrointestinal Disorders: Abdominal distension, dyspepsia (includes epigastric discomfort, eructation) Nervous System Disorders: Presyncope, dysarthria Infections and Infestations: Clostridioides difficile infection Musculoskeletal and Connective Tissue Disorders: Muscle spasms Vascular Disorders: Hot flush Cardiac Disorders: Tachycardia Eye Disorders: Blurred vision Ear and Labyrinth Disorders: Vertigo General Disorders and Administration Site Disorders: Fatigue Investigations: Alanine aminotransferase/aspartate aminotransferase increased Skin and Subcutaneous Tissue: Rash, hyperhidrosis Immune System Disorders: Hypersensitivity reactions Select Adverse Reactions Occurring in uUTI Patients Receiving BLUJEPA in Phase 1 and 2 Clinical Studies: Gastrointestinal Disorders: Hypersalivation (with oral daily doses ranging from 100 mg to 6,000 mg, which includes not approved doses) Clinical Trial Experience in Patients with Uncomplicated Urogenital Gonorrhea The safety of BLUJEPA was evaluated in a randomized, active‑controlled trial (Trial 3) comparing BLUJEPA to ceftriaxone and azithromycin in adult and pediatric patients 12 years of age and older with uncomplicated urogenital gonorrhea. A total of 309 patients received at least one dose of BLUJEPA (safety population). In Trial 3 (ITT population), the median age of patients randomized to receive BLUJEPA was 33 (range 16 to 64) years; >99% of patients were 18 to 65 years (no patients were >65 years). Overall, patients randomized to receive BLUJEPA treatment were predominately male (89%) and White (74%). Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation: No serious adverse reactions occurred in uncomplicated urogenital gonorrhea patients treated with BLUJEPA in Trial 3. Adverse reactions leading to discontinuation of treatment occurred in 3/309 (<1%) of uncomplicated urogenital gonorrhea patients treated with BLUJEPA. Common Adverse Reactions: Table 2 lists the adverse reactions occurring in ≥2% of uncomplicated urogenital gonorrhea patients receiving BLUJEPA in Trial 3. Table 2. Adverse Reactions Occurring in ≥2% of Uncomplicated Urogenital Gonorrhea Patients Treated with BLUJEPA (Trial 3; Safety Population) a Abdominal pain includes abdominal pain, abdominal pain upper, and abdominal discomfort. b Fatigue includes fatigue and lethargy. Adverse Reaction BLUJEPA N = 309 n (%) Ceftriaxone and Azithromycin N = 313 n (%) Diarrhea 151 (49) 30 (10) Nausea 73 (24) 9 (3) Abdominal pain a 25 (8) 6 (2) Vomiting 20 (6) 2 (<1) Flatulence 20 (6) 1 (<1) Dizziness 16 (5) 2 (<1) Soft feces 16 (5) 1 (<1) Headache 10 (3) 8 (3) Fatigue b 10 (3) 0 Hyperhidrosis 7 (2) 0 Diarrhea: In Trial 3, diarrhea was reported in 151/309 (49%) uncomplicated urogenital gonorrhea patients receiving BLUJEPA (38% mild severity, 11% moderate severity). Most episodes of diarrhea started on the same day as dosing, with few diarrhea episodes after day 2. The median duration was 2 days. Discontinuation of BLUJEPA due to diarrhea was reported in 1/309 (<1%) uncomplicated urogenital gonorrhea patients. Adverse Reactions Occurring in Less than 2% of Uncomplicated Urogenital Gonorrhea Patients Receiving BLUJEPA in Trial 3: Skin and Subcutaneous Tissue: Rash Cardiac Disorders: Tachycardia Nervous System Disorders: Dysarthria, presyncope, syncope Musculoskeletal and Connective Tissue Disorders: Muscle spasms, myalgia, arthralgia Vascular Disorders: Hot flush Gastrointestinal Disorders: Hypersalivation, abdominal distension Eye Disorders: Vision blurred Ear and Labyrinth Disorders: Vertigo

12.3 Pharmacokinetics Pharmacokinetic Parameters The pharmacokinetic properties of gepotidacin are summarized in Table 4 as mean (standard deviation [SD]) unless otherwise specified. Table 4. Pharmacokinetic Parameters of Gepotidacin a Pharmacokinetic parameters are presented at steady state in patients with uUTI and eGFR greater than or equal to 90 mL/min after oral administration of BLUJEPA 1,500 mg every 12 hours over 5 days, and in simulated results in adults with eGFR greater than or equal to 90 mL/min after oral administration of 2 doses of BLUJEPA (3,000 mg) taken 12 hours apart. b AUC 0-12 at steady state in patients with uUTI; simulated AUC 0-24 on day 1 in simulated results with uncomplicated urogenital gonorrhea. c Studies evaluating the effect on food were performed with standard and moderate fat meal. Clinical studies were not performed with a high fat meal (1,000 calories, 50% fat). Dosing Regimen 1,500 mg Every 12 Hours over 5 Days 2 Doses of 3,000 mg 12 Hours Apart Exposure C max (mcg/mL) a 6.3 (1.0) 11 (2.7) AUC (mcg*hour/mL) a,b 22.8 (4.8) 75.9 (25.9) Dose Proportionality Approximately dose proportional from 1,500 to 3,000 mg Accumulation 40% and steady state was achieved by day 3 Absorption Absolute Bioavailability ~45% T max (hours) ~2.0 Effect of food (moderate fat meal) c No clinically significant effect on PK Distribution V ss (L) a 172.9 (42.5) 188.0 (63.7) Plasma Protein Binding ~25 to ~41% Elimination Terminal Half-life (hours) a 9.3 (1.3) 9.4 (2.3) Total Clearance (L/hour) a 33.4 (6.7) 34.8 (8.7) Metabolism Primary Pathway Oxidative metabolism mediated by CYP3A4, producing several circulating metabolites Major Metabolite (%) M4 which is ~11% of circulating drug‑related materials Excretion Feces ~52% (30% unchanged drug) Urine ~31% (20% unchanged drug; major route of elimination for absorbed gepotidacin) Specific Populations Modelling and simulation analyses of gepotidacin showed that age, sex, and race have no clinically relevant effect on gepotidacin exposure. Body weight alone does not result in clinically significant effects on gepotidacin exposure [see Use in Specific Populations ( 8.4 ), ( 8.5 )] . Patients with Renal Impairment: The pharmacokinetics of gepotidacin were evaluated in subjects with moderate renal impairment (eGFR 30 to 59 mL/min) and in subjects with severe renal impairment/end stage renal disease (ESRD) on intermittent hemodialysis and not on intermittent hemodialysis (eGFR <30 mL/min). Gepotidacin plasma C max and AUC in subjects with moderate renal impairment were 1.2-fold and 1.5-fold higher than matched healthy controls, respectively. Gepotidacin plasma C max and AUC in severe renal impairment/ESRD not on intermittent hemodialysis were 1.7-fold and 2.1‑fold higher than matched healthy controls, respectively. Gepotidacin plasma C max and AUC in ESRD subjects requiring intermittent hemodialysis were 2.3‑fold and 2.5-fold higher before intermittent hemodialysis than healthy matching subjects, respectively, and were 6.2‑fold and 4.2‑fold higher after intermittent hemodialysis than matched healthy controls, respectively [see Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment: Mild hepatic impairment did not have a clinically relevant effect on gepotidacin pharmacokinetics. Moderate hepatic impairment resulted in an approximately 1.2‑fold increase in gepotidacin plasma C max and AUC compared with normal hepatic function. In subjects with severe hepatic impairment compared with subjects with normal hepatic function, gepotidacin plasma exposure parameters (C max and AUC) were increased by approximately 1.9‑fold and 1.7‑fold, respectively [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies Clinical Drug Interaction Studies and Model Informed Approaches: Effect of CYP3A4 Strong Inhibitors on the Pharmacokinetics of Gepotidacin: Concomitant administration of a strong inhibitor of CYP3A4 (itraconazole; 200 mg per day for 3 days), and a single 1,500 mg dose of BLUJEPA resulted in an increase in the maximum concentration (C max ) of gepotidacin of approximately 1.4‑fold and area under the curve (AUC) of approximately 1.5‑fold [see Drug Interactions ( 7.1 )] . Effect of CYP3A4 Strong Inducers on the Pharmacokinetics of Gepotidacin: Concomitant administration of BLUJEPA (single 1,500 mg dose) with a strong CYP3A4 inducer (rifampin; 600 mg once daily for 7 days) resulted in a decrease of 52% in gepotidacin plasma AUC (0-∞) [see Drug Interactions ( 7.1 )]. Effect of BLUJEPA on Pharmacokinetics of Other Drugs: Concomitant administration of a single 0.5 mg dose of digoxin with two 3,000 mg doses of BLUJEPA (an in vitro P‑glycoprotein inhibitor), given 12 hours apart (not an approved dosage of BLUJEPA), resulted in a 1.5‑fold increase in the digoxin C max (at 3 hours post dose), a 1.1‑fold increase in the digoxin AUC (0-∞) , and a delayed digoxin T max [see Drug Interactions ( 7.2 )]. Concomitant administration of midazolam (2 mg single dose) with BLUJEPA (2 doses of 3,000 mg, given 12 hours apart; not an approved dosage of BLUJEPA) resulted in a 1.9‑fold increase in midazolam AUC (0-∞) [see Drug Interactions ( 7.2 )]. Effect of Moderate CYP3A Inhibitors on the Pharmacokinetics of Gepotidacin: Concomitant administration of a moderate CYP3A inhibitor (fluconazole) and single 1,500 mg dose of BLUJEPA is predicted to increase gepotidacin Cmax by 1.3‑fold and AUC by 1.5‑fold [see Drug Interactions ( 7.1 )]. Effect of Moderate CYP3A Inducers on the Pharmacokinetics of Gepotidacin: Concomitant administration of a moderate CYP3A inducer (efavirenz) and single 1,500 mg dose of BLUJEPA is predicted to decrease AUC and Cmax by 49% and 34%, respectively [see Drug Interactions ( 7.1 )]. In Vitro Drug Interaction Studies: In vitro, gepotidacin was not an inducer of CYP1A2, 2B6 or 3A4. In vitro, gepotidacin is not a substrate of any of the hepatic organic anion transporting polypeptides (OATPs) 1B1, 1B3, and 2B1, organic anion transporters (OATs) OAT1, OAT2 and OAT3, organic cation transporters (OCTs) OCT2 and OCT3. In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically: In vitro, gepotidacin inhibited multidrug and toxin extrusion (MATEs) MATE1 (IC 50 =16.6 µM), and MATE2‑K (IC 50 =6.9 μM). In vitro, gepotidacin is a substrate of breast cancer resistance protein (max flux rate ratio of 11.0).