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.

12.1 Mechanism of Action BLUJEPA is an antibacterial drug [see Microbiology ( 12.4 )] .

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 treatm

5 WARNINGS AND PRECAUTIONS • QTc Prolongation: • Avoid use of BLUJEPA in patients with a history of QTc prolongation, or with relevant pre‑existing cardiac disease, or in patients receiving drugs that prolong the QTc interval. ( 5.1 ) • Due to an increase in gepotidacin exposure and the risk of QTc interval prolongation, avoid use of BLUJEPA in patients who have any of the following risk factors: ( 5.1 , 7.1 , 8.6 , 8.7 ) • Concomitant use of strong CYP3A4 inhibitors • Severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min) • Severe hepatic impairment (Child-Pugh Class C) • Additionally, avoid BLUJEPA in uncomplicated urogenital gonorrhea patients, who have any of the following risk factors for increased gepotidacin exposure: ( 5.1 , 7.1 , 8.6 , 8.7 ) • Concomitant use of moderate CYP3A4 inhibitors • Two or more of the following risk factors: Body weight between 45 kilograms and 60 kilograms, Moderate renal impairment (eGFR 30 to 59 mL/min), Moderate hepatic impairment (Child-Pugh Class B) • Acetylcholinesterase Inhibition: Dysarthria and other adverse reactions have been reported in patients receiving BLUJEPA. Monitor patients with underlying medical conditions that may be exacerbated by acetylcholinesterase inhibition and patients receiving succinylcholine‑type neuromuscular blocking agents, systemic anticholinergic medications, or non‑depolarizing neuromuscular blocking agents. ( 5.2 ) • Hypersensitivity Reactions: Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving BLUJEPA. If an allergic reaction to BLUJEPA occurs, discontinue the drug and institute appropriate supportive measures. ( 5.3 ) • Clostridioides difficile Infection (CDI): CDI has been reported with nearly all systemic antibacterial agents, including BLUJEPA. Evaluate patients who develop diarrhea. ( 5.4 ) 5.1 QTc Prolongation A dose and concentration-dependent prolongation of the QTc interval has been observed with BLUJEPA [see Clinical Pharmacology ( 12.2 )]. Avoid BLUJEPA in patients with a history of QTc interval prolongation or those with relevant pre ‑ existing cardiac disease, patients taking antiarrhythmic agents, or other medications that may potentially prolong the QTc interval [ see Drug Interactions ( 7.4 )]. Due to an increase in gepotidacin exposure (C max ), and the risk of QTc interval prolongation, avoid BLUJEPA in patients who have any of the following risk factors [see Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.6 , 8.7 )]: • Concomitant use of strong CYP3A4 inhibitors • Severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min) • Severe hepatic impairment (Child-Pugh Class C) Additionally, avoid BLUJEPA in uncomplicated urogenital gonorrhea patients who also have any of the following risk factors for increased gepotidacin exposure [see Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.6 , 8.7 )]: • Concomitant use of moderate CYP3A4 inhibitors • Two or more of the following risk factors: o Body weight between 45 kg and 60 kg o Moderate renal impairment (eGFR 30 to 59 mL/min) o Moderate hepatic impairment (Child ‑ Pugh Class B) If administration of BLUJEPA cannot be avoided in these patients, monitor and correct serum electrolyte abnormalities and collect an ECG prior to administration and during treatment, as clinically indicated. 5.2 Acetylcholinesterase Inhibition BLUJEPA is a reversible acetylcholinesterase inhibitor in in vitro laboratory studies. Adverse reactions including dysarthria, syncope, presyncope, muscle spasms, diarrhea, nausea, vomiting, abdominal pain, hypersalivation, and hyperhidrosis which are potentially attributed to acetylcholinesterase inhibition, have been observed in clinical trials [see Adverse Reactions ( 6.1 )] . Increased cholinergic effects can be associated with severe adverse reactions including atrioventricular block, bradycardia, bronchospasm, and seizures/convulsions. Monitor patients with medical

4 CONTRAINDICATIONS BLUJEPA is contraindicated in patients with a history of severe hypersensitivity to BLUJEPA [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 )] . A history of severe hypersensitivity to BLUJEPA. ( 4 )

10 OVERDOSAGE There is a risk of QTc prolongation with overdosage. Intermittent hemodialysis is not likely to substantially remove BLUJEPA from the systemic circulation. Consider contacting the Poison Help line (1‑800‑222‑1222) or a medical toxicologist for additional overdose management recommendations.