ORLYNVAH (sulopenem etzadroxil and probenecid) tablets contain sulopenem etzadroxil, a penem antibacterial drug, and probenecid, a renal tubular transport inhibitor. The chemical name of sulopenem etzadroxil is 4-Thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 6-[(1 R )-1- hydroxyethyl]-7-oxo-3-[[(1 R ,3 S )- tetrahydro-1-oxido-3-thienyl]thio]-, (2-ethyl-1-oxobutoxy)methyl ester, (5 R ,6 S )-. See Figure 1 for sulopenem etzadroxil chemical structure and chemical formula. The molecular weight of sulopenem etzadroxil is 477.61 g/mol. Figure 1. Sulopenem Etzadroxil Chemical Structure and Formula The chemical name for probenecid is 4-[(dipropylamino) sulfonyl] benzoic acid. See Figure 2 for probenecid chemical structure and chemical formula. The molecular weight of probenecid is 285.36 g/mol . Figure 2. Probenecid Chemical Structure and Formula ORLYNVAH are pink bilayer tablets for oral use containing 500 mg of sulopenem etzadroxil and 500 mg of probenecid and the following inactive ingredients: croscarmellose sodium, hydroxypropylcellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating contains carmine, lecithin polyvinyl alcohol, talc, titanium dioxide, and xanthan gum. Figure 1 Figure 2

ORLYNVAH, a combination of sulopenem etzadroxil, a penem antibacterial, and probenecid, a renal tubular transport inhibitor, 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. Limitations of Use ORLYNVAH is not indicated for the treatment of: Complicated urinary tract infections (cUTI) or as step-down treatment after intravenous antibacterial treatment of cUTI. ( 1.1 , 14.2 ) Complicated intra-abdominal infections (cIAI) or as step-down treatment after intravenous antibacterial treatment of cIAI. ( 1.1 , 14.3 ) Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of ORLYNVAH and other antibacterial drugs, ORLYNVAH 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

Uncomplicated Urinary Tract Infections ORLYNVAH 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. Limitations of Use ORLYNVAH is not indicated for the treatment of: Complicated urinary tract infections (cUTI) or as step-down treatment after intravenous antibacterial treatment of cUTI . Complicated intra-abdominal infections (cIAI)) or as step-down treatment after intravenous antibacterial treatment of cIAI

Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of ORLYNVAH and other antibacterial drugs, ORLYNVAH 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 .

ORLYNVAH (sulopenem etzadroxil 500 mg and probenecid 500 mg) tablets are supplied as pink, oval-shaped, film-coated, fixed-dose, bilayer combination tablets debossed with SULO on one side and plain on the other side. ORLYNVAH Tablets : 500 mg sulopenem etzadroxil and 500 mg probenecid.

The recommended dosage of ORLYNVAH is one tablet orally twice daily for 5 days. Administration of ORLYNVAH with food is recommended

Recommended Dosage The recommended dosage of ORLYNVAH is one tablet (sulopenem etzadroxil 500 mg and probenecid 500 mg) orally twice daily for 5 days. Administration of ORLYNVAH with food is recommended

Recommended Dosage in Patients with Renal Impairment Administration of ORLYNVAH is not recommended in patients with creatinine clearance (CrCL) less than 15 mL/min or patients on hemodialysis. No dosage adjustment is required for ORLYNVAH in patients with CrCL greater than or equal to15 mL/min

Recommendations Regarding Missed Dose(s) If a dose of ORLYNVAH is missed, instruct patients to take the dose as soon as possible. Do not double the dose to make up for the missed dose.

Hypersensitivity Reactions : Hypersensitivity reactions have been reported in patients treated with ORLYNVAH. Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, have been reported with beta-lactam antibacterial drugs. Severe allergic reactions and anaphylaxis have been reported with the use of probenecid (a component of ORLYNVAH). If an allergic reaction to ORLYNVAH occurs, discontinue the drug and institute appropriate therapy. Clostridioides difficile -Associated Diarrhea (CDAD) : This has been reported with nearly all systemic antibacterial agents. Evaluate if diarrhea occurs. Exacerbation of Gout : When prescribing ORLYNVAH to patients with a known history of gout, ensure appropriate therapy of gout is instituted. Uric Acid Nephropathy in Patients at Risk for Tumor Lysis Syndrome : When prescribing ORLYNVAH to patients with risk factors for tumor lysis syndrome, take appropriate measures to reduce the risk. 5.1 Hypersensitivity Reactions Hypersensitivity reactions, specifically cases of angioedema, have been reported in patients treated with ORLYNVAH . 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 ORLYNVAH 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 (a component of ORLYNVAH). If an allergic reaction to ORLYNVAH 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 strains of 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 ORLYNVAH 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. ORLYNVAH is contraindicated in patients with known uric acid kidney stones

Exacerbation of Gout ORLYNVAH may cause exacerbation of gout. When prescribing ORLYNVAH to patients with a known history of gout, ensure appropriate therapy of gout is instituted

Uric Acid Nephropathy in Patients at Risk for Tumor Lysis Syndrome The probenecid component of ORLYNVAH may increase the risk of uric acid nephropathy in patients at risk for tumor lysis syndrome (TLS). When prescribing ORLYNVAH to patients with risk factors for TLS, take appropriate measures to reduce the risk

Development of Drug-Resistant Bacteria Prescribing ORLYNVAH 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 .

Ketoprofen : Concomitant use is not recommended See full prescribing information for additional clinically significant drug interactions with ORLYNVAH 7.1 Potential for ORLYNVAH to Affect Other Drugs Probenecid (a component of ORLYNVAH) is an inhibitor of organic anion transporters 1 and 3 (OAT1/3) and may increase plasma concentrations of drugs that are dependent on OAT1/3 for elimination. Table 2 provides a list of established or potentially clinically significant drug interactions. Table 2. Established and Other Potentially Clinically Significant Drug Interactions Concomitant Drug/Drug Class Effect on Drug Concentration Recommendation Ketorolac tromethamine ↑ ketorolac tromethamine Contraindicated Ketoprofen ↑ ketoprofen Concomitant use is not recommended. Indomethacin ↑ indomethacin May increase the risk of adverse reactions. Refer to drug-specific prescribing information for dosage adjustment instructions. Naproxen ↑ naproxen May increase the risk of adverse reactions. Refer to drug-specific prescribing information for dosage adjustment instructions. Methotrexate ↑ methotrexate If concomitant use cannot be avoided, monitor more frequently for adverse reactions associated with methotrexate as recommended in its prescribing information. Rifampin ↑ rifampin Monitor more frequently for adverse reactions associated with rifampin as recommended in its prescribing information. Lorazepam ↑ lorazepam Follow the recommended lorazepam dosage modifications outlined in its prescribing information. Oral Sulfonylureas ↑ antidiabetic Monitor more frequently for hypoglycemia. Follow recommended sulfonylurea dosage modifications in its prescribing information. Valproic Acid No valproic acid dosage adjustment is recommended when used concomitantly with ORLYNVAH. No clinically significant reduction in plasma valproic acid concentrations was observed following concomitant use with ORLYNVAH

Potential for Other Drugs to Affect ORLYNVAH Sulopenem is a substrate of OAT3; therefore, drugs that inhibit OAT3 may increase sulopenem plasma concentrations . If concomitant use with ORLYNVAH is necessary, monitor more frequently for adverse reactions associated with ORLYNVAH (e.g., diarrhea and nausea)

Drug/Laboratory Interactions Treatment with ORLYNVAH may interfere with copper sulfate urine glucose tests, resulting in false-positive readings for glycosuria. Suspected glycosuria should be confirmed by using a test specific for glucose. Falsely high readings for theophylline have been reported in an in vitro study, using the Schack and Waxler technique, when therapeutic concentrations of theophylline and probenecid (a component of ORLYNVAH) were added to human plasma.