Gepotidacin (Monograph)

Brand name: Blujepa
Drug class: Triazaacenaphthylenes

Introduction

Gepotidacin mesylate is a triazaacenaphthylene bacterial type II topoisomerase inhibitor.

Uses for Gepotidacin

Gepotidacin mesylate has the following uses:

Gepotidacin mesylate is indicated for the treatment of female adult and pediatric patients 12 years of age and older weighing at least 40 kg with uncomplicated urinary tract infections (uUTI) caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundiicomplex, Staphylococcus saprophyticus,and Enterococcus faecalis.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of gepotidacin and other antibacterial drugs, gepotidacin should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.

Gepotidacin Dosage and Administration

General

Gepotidacin mesylate is available in the following dosage form(s) and strength(s):

Tablets: 750 mg of gepotidacin.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults and Pediatric Female Patients ≥12 Years of Age and Weighing ≥40 kg

• The recommended dosage of gepotidacin is 1,500 mg (two 750 mg tablets) taken orally, twice daily (approximately 12 hours apart), for 5 days.

• Administer gepotidacin tablets after a meal to reduce the possibility of GI intolerance.

Cautions for Gepotidacin

Contraindications

History of severe hypersensitivity to gepotidacin mesylate.

Warnings/Precautions

QTc Prolongation

A dose and concentration-dependent prolongation of the QTc interval has been observed with gepotidacin.

Avoid gepotidacin 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.

Due to an increase in gepotidacin exposure (C_max) and the risk of QTc interval prolongation, avoid concomitant administration of gepotidacin with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole), in patients with severe hepatic impairment (Child-Pugh Class C), and in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/minute). If administration of gepotidacin 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.

Acetylcholinesterase Inhibition

Gepotidacin 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. 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.

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

Because gepotidacin may antagonize the effects of systemic anticholinergic medications or non-depolarizing neuromuscular blocking agents, monitor patients if gepotidacin is concomitantly administered with these medications.

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving gepotidacin. Gepotidacin is contraindicated in patients with a history of severe hypersensitivity to the drug. Before therapy with gepotidacin is instituted, carefully inquire about previous hypersensitivity reactions to gepotidacin. If an allergic reaction occurs, discontinue the drug and institute appropriate supportive measures.

Clostridioides Difficile Infection

Clostridioides difficile (C. difficile) infection (CDI) has been reported for nearly all systemic antibacterial agents, including gepotidacin, and may range in severity from mild diarrhea to fatal colitis. 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.

Development of Drug-resistant Bacteria

Prescribing gepotidacin 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.

Specific Populations

Pregnancy

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

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

In embryofetal 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.

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.

Lactation

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. 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 gepotidacin and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of gepotidacin 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 gepotidacin in these patients is supported by evidence from adequate and well-controlled studies 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). The safety profile of gepotidacin in female pediatric patients 12 years of age and older was similar to female adults with uUTI treated with the drug.

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

Geriatric Use

Of the total number of patients who received treatment with gepotidacin 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. No overall differences in safety or effectiveness of gepotidacin 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.

Gepotidacin 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.

Renal Impairment

No dosage adjustment is required in patients with mild renal impairment (eGFR 60 to 89 mL/minute) or moderate renal impairment (eGFR 30 to 59 mL/minute). Avoid use of gepotidacin in patients with severe renal impairment or kidney failure (eGFR <30 mL/minute), including those receiving dialysis, due to increased exposure to gepotidacin and the risk of QTc prolongation.

Hepatic Impairment

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh Class A/B). Avoid use of gepotidacin in patients with severe hepatic impairment (Child-Pugh Class C) due to increased exposure to the drug and the risk of QTc prolongation.

Common Adverse Effects

The most common adverse reactions occurring in ≥1% of patients are diarrhea, nausea, abdominal pain, flatulence, headache, soft feces, dizziness, vomiting, and vulvovaginal candidiasis.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• CYP3A4 Inhibitors: Avoid coadministration of gepotidacin with strong CYP3A4 inhibitors.

• CYP3A4 Inducers: Avoid coadministration of gepotidacin with strong CYP3A4 inducers.

• CYP3A4 Substrates: Avoid coadministration of gepotidacin with drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window.

• Digoxin: Due to an increase in digoxin exposures, consider monitoring digoxin serum concentration, as appropriate, with concomitant administration of gepotidacin.

• Cholinergic/Anticholinergic Drugs: Monitor for exaggerated neuromuscular blockade or excessive cholinergic effects. Consider the potential for an antagonistic effect with systemic anticholinergic medications (e.g., benztropine, oxybutynin) or nondepolarizing neuromuscular blocking agents if gepotidacin is administered concomitantly with anticholinergic medications.

• Drugs that Prolong the QTc Interval: Avoid concomitant administration of gepotidacin with other medications that have the potential to prolong the QTc interval.

Actions and Spectrum

Mechanism of Action

Gepotidacin mesylate is a triazaacenaphthylene antibacterial that inhibits Type II topoisomerases including bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, thereby inhibiting DNA replication.

Gepotidacin has bactericidal activity against pathogens as determined by time-kill studies. In vitro studies demonstrated a gepotidacin post-antibiotic effect ranging from 1.8 to 2.2 hours for E. coli, 1 to >6.6 hours for K. pneumoniae, 1.4 to 3 hours for P. mirabilis, 1 to 2.6 hours for C. freundii, 2.7 to 4.3 hours for S. saprophyticus, and 1.2 to 2.7 hours for E. faecalis at 5 times the MIC.

Although no clear mechanisms of resistance have been identified for gepotidacin, potential mechanisms that may impact gepotidacin activity are gepotidacin-specific alterations of DNA gyrase (gyrA, gyrB) and/or topoisomerase IV (parC, parE) gene targets, plasmid-mediated quinolone resistance genes (especially qnr), and efflux. The following amino acids may be important for gepotidacin activity GyrA P35, V44, D82, A175, GyrB D426, P445 and ParC D79 as shown through studies with isogenic mutants in E. coli and K. pneumoniae. A single target-specific mutation may not significantly impact gepotidacin activity. The relationship between gepotidacin and fluoroquinolone susceptibility does not appear to include amino acid substitutions in GyrA and ParC that are known to reduce fluoroquinolone susceptibility in E. coli. Gepotidacin activity against E. coli and K. pneumoniae is unrelated to beta-lactam resistance mechanisms.

The frequency of resistance development to gepotidacin due to spontaneous mutations in the gram-negative and gram-positive uropathogens tested in vitro at 10 times MIC ranged from 10^-9 to 10^-10.

Target-specific cross-resistance with other classes of antibacterial drugs has not been identified; therefore, isolates resistant to other drugs may be susceptible to gepotidacin. However, isolates of Enterobacterales with ≥4-fold increases in gepotidacin MIC have been identified in vitro and in clinical studies.

During clinical studies, gepotidacin demonstrated activity against some isolates of the following multilocus sequence typing (MLST) for E. coli: ST10, ST131, ST1193, ST69, ST95 and ST73.

In in vitro studies, no antagonism against Enterobacterales or gram-positive isolates was observed for gepotidacin in combination with multiple antibacterial drugs, including fluoroquinolones, sulfonamides, cephalosporins, macrolides, tetracyclines, aminoglycosides, glycopeptides, carbapenems, nitrofurans, monobactams, and oxazolidinones.

Gepotidacin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections:

Gram-positive bacteria: Enterococcus faecalis, Staphylococcus saprophyticus.

Gram-negative bacteria: Citrobacter freundii, Escherichia coli, Klebsiella pneumoniae.

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for gepotidacin against isolates of similar genus or organism group. However, the efficacy of gepotidacin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials: Citrobacter koseri, Klebsiella aerogenes, Klebsiella oxytoca/ Raoltella ornithinolytica, Morganella morganii, Proteus mirabilis, Providencia rettgeri.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Counsel patients to take gepotidacin after a meal to reduce the possibility of GI intolerance.

• Counsel patients to inform their healthcare provider of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia, or if they are taking any antiarrhythmic agents. Advise patients to notify their healthcare providers if they have any symptoms of prolongation of the QTc interval, including prolonged heart palpitations or a loss of consciousness.

• Counsel patients that gepotidacin can cause dysarthria and other symptoms such as presyncope, muscle spasms, diarrhea, nausea, vomiting, abdominal pain, hypersalivation, and hyperhidrosis. Advise patients to inform their healthcare provider if they experience these symptoms or if they have an underlying medical condition that may be exacerbated by acetylcholinesterase inhibition or are planning to receive anesthesia where they may receive neuromuscular blocking agents, or if they are receiving other acetylcholinesterase inhibitors, or systemic anticholinergic medications.

• Advise patients that hypersensitivity reactions, including anaphylaxis, could occur and require immediate treatment. Advise patients to inform their healthcare provider about any previous hypersensitivity reactions to gepotidacin.

• Counsel patients that diarrhea is a common problem caused by antibacterials, including gepotidacin, and it usually ends when the antibacterial is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider.

• Patients should be counseled that antibacterial drugs, including gepotidacin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When gepotidacin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by gepotidacin or other antibacterial drugs in the future.

• Advise patients of the potential interactions other medications may have with gepotidacin or the effect gepotidacin may have on other medications, as these may result in decreased effectiveness or increased toxicities of either gepotidacin or the other medications. Patients should alert their healthcare provider if they are currently taking any medications, including herbal nutritional supplements, or are prescribed new medications during treatment with gepotidacin.

• Advise patients who are exposed to gepotidacin during pregnancy to contact GlaxoSmithKline at 1-888-825-5249.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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