Brand name: Orlynvah™
Drug class: Urinary Anti-infectives

Introduction

Sulopenem etzadroxil and probenecid (sulopenem etzadroxil/probenecid) is a fixed combination of sulopenem etzadroxil (a penem antibacterial) and probenecid (a renal tubular transport inhibitor).

Uses for Sulopenem etzadroxil and probenecid

Sulopenem etzadroxil and probenecid has the following uses:

Sulopenem etzadroxil/probenecid is indicated for the treatment of uncomplicated urinary tract infections (uUTI) caused by the designated microorganisms Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis in adult women who have limited or no alternative oral antibacterial treatment options.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulopenem etzadroxil/probenecid and other antibacterial drugs, the combination drug should be used only to treat uUTI that are proven or strongly suspected to be caused by susceptible bacteria. Culture and susceptibility information should be utilized in selecting or modifying antibacterial therapy.

Sulopenem etzadroxil/probenecid is not indicated for the treatment of complicated urinary tract infections (cUTI) or as step-down treatment after IV antibacterial treatment of cUTI. The combination drug also is not indicated for treatment of complicated intra-abdominal infections (cIAI)) or as step-down treatment after IV antibacterial treatment of cIAI.

Sulopenem etzadroxil and probenecid Dosage and Administration

General

Sulopenem etzadroxil/probenecid is available in the following dosage form(s) and strength(s):

Tablets: 500 mg sulopenem etzadroxil and 500 mg probenecid

Dosage

Adults

Dosage and Administration

• The recommended dosage is one tablet (sulopenem etzadroxil 500 mg and probenecid 500 mg) orally twice daily for 5 days.

• Administration of sulopenem etzadroxil/probenecid with food is recommended.

• Administration of sulopenem etzadroxil/probenecid is not recommended in patients with creatinine clearance (CrCL) less than 15 mL/min or patients on hemodialysis. No dosage adjustment is required for patients with CrCL greater than or equal to15 mL/min.

• If a dose of sulopenem etzadroxil/probenecid is missed, instruct patients to take the dose as soon as possible. Do not double the dose to make up for the missed dose.

Cautions for Sulopenem etzadroxil and probenecid

Contraindications

• Patients with a history of hypersensitivity to the components of sulopenem etzadroxil/probenecid or other beta-lactam antibacterial drugs.

• Patients with known blood dyscrasias.

• Patients with known uric acid kidney stones.

• Concomitant use of sulopenem etzadroxil/probenecid and ketorolac tromethamine.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, specifically cases of angioedema, have been reported in patients treated with sulopenem etzadroxil/probenecid. Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with sulopenem etzadroxil/probenecid is instituted, carefully inquire about previous hypersensitivity reactions to other carbapenems, cephalosporins, penicillins, or other beta-lactams because cross-hypersensitivity among beta-lactam antibacterial drugs has been reported. Severe allergic reactions and anaphylaxis have been reported with the use of probenecid. If an allergic reaction to sulopenem etzadroxil/probenecid occurs, discontinue the drug and institute appropriate supportive measures.

Clostridioides difficile-Associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strainsof C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Risk of Uric Acid Kidney Stone Development

When prescribing sulopenem etzadroxil/probenecid to patients with a history of gout, appropriate measures to reduce the risk of uric acid kidney stone development should be instituted, such as increased fluid intake and alkalization of the urine. Sulopenem etzadroxil/probenecid is contraindicated in patients with known uric acid kidney stones.

Exacerbation of Gout

Sulopenem etzadroxil/probenecid may cause exacerbation of gout. When prescribing sulopenem etzadroxil/probenecid to patients with a known history of gout, ensure appropriate therapy of gout is instituted.

Development of Drug-Resistant Bacteria

Prescribing sulopenem etzadroxil/probenecid in the absence of a proven or strongly suspected susceptible uUTI is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Specific Populations

Pregnancy

There are no available data on sulopenem etzadroxil use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Sulopenem etzadroxil was orally administered during organogenesis in embryo-fetal studies in mice, rats, and rabbits. In pregnant mice, maternal toxicity and an increased litter incidence of a fetal malformation, cleft palate, was observed with an oral dose of sulopenem etzadroxil associated with plasma sulopenem exposure approximately 23 times the clinical sulopenem exposure for the maximum recommended human dose (MRHD) of 1000 mg/day sulopenem etzadroxil. In pregnant rats and rabbits, orally administered sulopenem etzadroxil was not associated with fetal malformations at any dose, but in rats, maternal toxicity and reduced fetal body weights occurred at sulopenem etzadroxil doses associated with sulopenem plasma exposures approximately 2 and 6 times, respectively, the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil. In rabbits, maternal toxicity and reduced fetal body weights occurred at sulopenem etzadroxil doses associated with sulopenem plasma exposures approximately 0.1 and 0.2 times, respectively, the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil.

Available published data over several decades of probenecid use in pregnant woman have not identified a drug-associated risk of miscarriage, major birth defects, or adverse maternal or fetal outcomes. Probenecid crosses the placental barrier and appears in cord blood. The estimated 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 sulopenem etzadroxil or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. The active metabolite of sulopenem etzadroxil, sulopenem, was present in rat milk after oral dosing of sulopenem etzadroxil to lactating female rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Probenecid is present in human milk based on a case report. There are no reports of adverse effects in infants associated with probenecid exposure through breastmilk. There is no information on the effects of probenecid on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sulopenem etzadroxil/probenecid and any potential adverse effects on the breast-fed child from the drugs or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of sulopenem etzadroxil/probenecid in pediatric patients have not been established.

Geriatric Use

In uUTI Trial 1, there were 436 patients 65 years of age and older. Of the total number of sulopenem etzadroxil/probenecid-treated patients in this study, 224 (20.2%) were 65 years of age and older, while 80 (7.2%) were 75 years of age and older. No overall differences in safety or effectiveness of sulopenem etzadroxil/probenecid were observed between patients 65 years and older and younger adult patients. In uUTI Trial 2, there were 452 patients 65 years of age and older. Of the total number of sulopenem etzadroxil/probenecid-treated patients in this study, 218 (26.2%) were 65 years of age and older, while 86 (10.3%) were 75 years of age and older. No overall differences in safety or effectiveness of sulopenem etzadroxil/probenecid were observed between patients 65 years and older and younger adult patients.

No clinically meaningful differences in the pharmacokinetics of sulopenem etzadroxil/probenecid were observed in geriatric patients compared to younger adult patients. No dosage adjustment based on age is required. Sulopenem etzadroxil/probenecid is known to be substantially excreted by the kidney, and geriatric patients are anticipated to have reduced renal function. Recommendations for use in elderly patients should be based on renal function.

Renal Impairment

Increases in sulopenem plasma concentrations were observed with mild, moderate and severe renal impairment; however, the available safety information does not suggest a need for dosage adjustments in these patients. Administration of sulopenem etzadroxil/probenecid is not recommended in patients with CrCL less than 15 mL/min and patients on hemodialysis because the pharmacokinetics of sulopenem have not been studied in this population.

Common Adverse Effects

The most common adverse reactions (≥2%) in patients treated with sulopenem etzadroxil/probenecid were diarrhea, nausea, vulvovaginal mycotic infection, headache, and vomiting.

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:

• Ketoprofen: Concomitant use is not recommended.

• Ketorolac tromethamine: Contraindicated.

• Indomethacin, Naproxen, Methotrexate, Rifampin, Lorazepam, Oral Sulfonylureas: See full prescribing information for specific recommendations.

• Valproic Acid: No valproic acid dosage adjustment is recommended when used concomitantly with sulopenem etzadroxil/probenecid. No clinically significant reduction in plasma valproic acid concentrations was observed following concomitant use with sulopenem etzadroxil/probenecid.

• Sulopenem is a substrate of OAT3; therefore, drugs that inhibit OAT3 may increase sulopenem plasma concentrations. If concomitant use with sulopenem etzadroxil/ probenecid is necessary, monitor more frequently for adverse reactions.

Actions

Mechanism of Action

Sulopenem etzadroxil/probenecid is a combination of sulopenem etzadroxil, a penem antibacterial drug and probenecid, a renal tubular inhibitor. Probenecid inhibits OAT3-mediated renal clearance of sulopenem, resulting in increased plasma concentrations of sulopenem.

Advice to Patients

• Advise patients that allergic reactions, including serious allergic reactions, could occur, and that serious allergic reactions require immediate treatment. Patients should inform their healthcare provider about any previous hypersensitivity reactions to sulopenem etzadroxil/probenecid, other beta-lactam antibacterial drugs or probenecid.

• Advise patients that diarrhea is a common problem caused by antibacterial drugs, including sulopenem etzadroxil/probenecid, and usually resolves when the drug 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 sulopenem etzadroxil/probenecid should only be used to treat proven or strongly suspected susceptible urinary tract infections (uUTI). Antibacterial drugs do not treat viral infections (e.g., the common cold). When sulopenem etzadroxil/probenecid is prescribed to treat proven or strongly suspected susceptible uUTI, patients should be told that although it is common to feel better early in the course of therapy, sulopenem etzadroxil/probenecid 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 sulopenem etzadroxil/probenecid or other antibacterial drugs in the future.

• Advise patients that concomitant use of ketoprofen with sulopenem etzadroxil/probenecid is not recommended.

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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