BLUJEPA Film-coated tablet Ref.[115538] Active ingredients: Gepotidacin

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 concomitant administration of BLUJEPA with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole), in patients with severe hepatic impairment (Child‑Pugh Class C), or in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min) [see Drug Interactions (7.1), and Use in Specific Populations (8.6, 8.7)].

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, 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, seizures/convulsions, and vasovagal syncope. Monitor patients with medical conditions that may be exacerbated by acetylcholinesterase inhibition.

BLUJEPA, as an acetylcholinesterase inhibitor, may exaggerate the neuromuscular effects of succinylcholine‑type muscle relaxation during anesthesia. BLUJEPA may exaggerate the effects of other acetylcholinesterase inhibitors. Monitor patients for exaggerated neuromuscular blockade or excessive cholinergic effects.

Because BLUJEPA may antagonize the effects of systemic anticholinergic medications or non‑depolarizing neuromuscular blocking agents, monitor patients if BLUJEPA is concomitantly administered with these medications [see Drug Interactions (7.3)].

5.3 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving BLUJEPA [see Adverse Reactions (6.1)]. BLUJEPA is contraindicated in patients with a history of severe hypersensitivity to BLUJEPA [see Contraindications (4)]. Before therapy with BLUJEPA is instituted, carefully inquire about previous hypersensitivity reactions to BLUJEPA. If an allergic reaction to BLUJEPA occurs, discontinue the drug and institute appropriate supportive measures.

5.4 Clostridioides difficile Infection

Clostridioides difficile (C. difficile) infection (CDI) has been reported for nearly all systemic antibacterial agents, including BLUJEPA, and may range in severity from mild diarrhea to fatal colitis [see Adverse Reactions (6)]. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDI. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDI must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDI has been reported to occur over 2 months after the administration of antibacterial agents.

If CDI is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 Development of Drug-Resistant Bacteria

Prescribing BLUJEPA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug‑resistant bacteria [see Indications and Usage (1.2)].

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)].

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.

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%) patient treated with BLUJEPA and 1/1,558 (<1%) patient 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%) of patients treated with BLUJEPA and 30/1,558 (2%) of 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 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.

Diarrhea: In Trial 1 and 2, diarrhea was reported in 258/1,570 (16%) 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 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 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)

7.1 Effect of Other Drugs on BLUJEPA

CYP3A4 Inhibitors

Due to an increase in gepotidacin exposures, avoid concomitant administration of BLUJEPA with strong inhibitors of CYP3A4 [see Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

CYP3A4 Inducers

Due to a decrease in gepotidacin exposures, avoid concomitant administration of BLUJEPA with strong inducers of CYP3A4 [see Clinical Pharmacology (12.3)].

7.2 Effect of BLUJEPA on Other Drugs

CYP3A4 Substrates

Avoid concomitant administration of BLUJEPA with drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic index (e.g., quinidine, cyclosporine) [see Clinical Pharmacology (12.3)].

Digoxin

Due to an increase in digoxin exposures, consider monitoring digoxin serum concentrations, as appropriate, with concomitant administration of BLUJEPA [see Clinical Pharmacology (12.3)].

7.3 Cholinergic/Anticholinergic Drugs

As gepotidacin is an acetylcholinesterase inhibitor, there is potential for an exaggerated effect of concomitantly administered succinylcholine‑type neuromuscular blocking agents resulting in a delay in recovery of neuromuscular function. Gepotidacin may augment the effect of other acetylcholinesterase inhibitors (e.g., donepezil). Monitor for exaggerated neuromuscular blockade or excessive cholinergic effects [see Warnings and Precautions (5.2)].

There is potential for an antagonistic effect with systemic anticholinergic medications (e.g., benztropine, oxybutynin) or non‑depolarizing neuromuscular blocking agents. Consider the potential for this interaction if BLUJEPA is administered concomitantly with anticholinergic medications [see Warnings and Precautions (5.2)].

7.4 Drugs that Prolong the QTc Interval

Due to the increased risk of QTc prolongation, avoid concomitant administration of BLUJEPA with other medications that have the potential to prolong the QTc interval [see Warnings and Precautions (5.1)].

Pregnancy Exposure Registry

A pregnancy exposure registry will be established to monitor pregnancy outcomes in women exposed to BLUJEPA during pregnancy. Pregnant women exposed to BLUJEPA, and healthcare providers are encouraged to contact GlaxoSmithKline at 1‑888‑825‑5249.

Risk Summary

There are no available data on the use of BLUJEPA in pregnant women to evaluate for a drug‑associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

In embryo‑fetal development studies in mice and rats, decreased fetal weights and increased fetal mortality (late resorptions) were observed at exposures about 0.8-to-1-times the maximum recommended human dose (MRHD). In a mouse pre- and postnatal development study, there were no adverse developmental effects at exposures of approximately 3-times the MRHD (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Data

Animal Data

Gepotidacin did not cause malformations when orally administered in embryo‑fetal development studies during organogenesis. Decreased fetal weights were seen in rats dosed orally with 450 mg/kg/day or greater (approximately equal to the MRHD based on AUC extrapolated from nonpregnant rats) and decreased fetal weights and increased late fetal resorptions were seen in mice at oral doses 500 mg/kg/day or greater (approximately 0.8-times the MRHD based on AUC extrapolated from nonpregnant mice).

In a pre- and post‑natal development study in mice given oral doses of up to 1,000 mg/kg/day (approximately 3‑times the MRHD), there were no gepotidacin effects on parturition, or post‑natal growth and development of the offspring.

Risk Summary

There are no data on the presence of gepotidacin in human milk, its effects on the breastfed child, or on milk production. Based on a study in lactating mice, gepotidacin is likely transferred into milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BLUJEPA and any potential adverse effects on the breastfed child from BLUJEPA or from the underlying maternal condition.

Data

Gepotidacin concentrations in milk have not been measured directly in animals. However, in a pre- and post‑natal development study when gepotidacin was orally administered to maternal mice during pregnancy and lactation, at all tested doses, gepotidacin was detected in the plasma of their nursing offspring (with dosing 200 mg/kg/day or greater, which was expected to result in exposures 0.5-times the MHRD and higher as extrapolated from exposures in nonpregnant mice).

The safety and effectiveness of BLUJEPA for the treatment of uUTI have been established in female pediatric patients 12 years of age and older, weighing at least 40 kg. Use of BLUJEPA in these patients is supported by evidence from adequate and well‑controlled studies of BLUJEPA in female adult and pediatric patients 12 years of age and older with uUTI and additional pharmacokinetic data in pediatric patients (12 to <18 years of age) [see Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. The safety profile of BLUJEPA in female pediatric patients 12 years of age and older was similar to female adults with uUTI treated with BLUJEPA [see Adverse Reactions (6.1), and Clinical Studies (14.1)].

The safety and effectiveness of BLUJEPA have not been established in pediatric patients less than 12 years of age or weighing less than 40 kg.

Of the total number of patients who received treatment with BLUJEPA in the uUTI studies (Trials 1 and 2), 226 (14%) were 65 to less than 75 years of age and 127 (8%) were 75 years of age and older [see Clinical Studies (14.1)]. No overall differences in safety or effectiveness of BLUJEPA were observed between patients 65 years of age and older and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

BLUJEPA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function [see Warnings and Precautions (5.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

No dosage adjustment is required in patients with mild renal impairment (eGFR 60 to 89 mL/min) or moderate renal impairment (eGFR 30 to 59 mL/min). Avoid use of BLUJEPA in patients with severe renal impairment or kidney failure (eGFR <30 mL/min), including those receiving dialysis, due to increased exposure to gepotidacin and the risk of QTc prolongation [see Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child‑Pugh Class A/B). Avoid use of BLUJEPA in patients with severe hepatic impairment (Child‑Pugh Class C) due to increased exposure to gepotidacin and the risk of QTc prolongation [see Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].