PROBENECID Drug Interactions: What You Need to Know

INTERACTIONS Ketoprofen : Concomitant use is not recommended ( 7.1 ) See full prescribing information for additional clinically significant drug interactions with ORLYNVAH ( 7.1 )

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 [see Clinical Pharmacology ( 12.3 )] .

7.2 Potential for Other Drugs to Affect ORLYNVAH Sulopenem is a substrate of OAT3; therefore, drugs that inhibit OAT3 may increase sulopenem plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. If concomitant use with ORLYNVAH is necessary, monitor more frequently for adverse reactions associated with ORLYNVAH (e.g., diarrhea and nausea) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>.

7.3 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.

ORLYNVAH is contraindicated in patients with:

• A history of hypersensitivity to the components of ORLYNVAH (sulopenem etzadroxil and probenecid) or other beta-lactam antibacterial drugs [see Warnings and Precautions ( 5.1 )]
• Known uric acid kidney stones [see Warnings and Precautions ( 5.3 )] Concomitant use of ORLYNVAH and ketorolac tromethamine is contraindicated [see Drug Interactions ( 7.1 )] Patients with a history of hypersensitivity to the components of ORLYNVAH (sulopenem etzadroxil and probenecid) or other beta- lactam antibacterial drugs. ( 4 ) Patients with known uric acid kidney stones. ( 4 ) Concomitant use of ORLYNVAH and ketorolac tromethamine is contraindicated. ( 4 )

AND PRECAUTIONS 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. ( 5.1 ) Clostridioides difficile -Associated Diarrhea (CDAD) : This has been reported with nearly all systemic antibacterial agents. Evaluate if diarrhea occurs. ( 5.2 ) Exacerbation of Gout : When prescribing ORLYNVAH to patients with a known history of gout, ensure appropriate therapy of gout is instituted. ( 5.4 )

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. ( 5.5 )

5.1 Hypersensitivity Reactions Hypersensitivity reactions, specifically cases of angioedema, have been reported in patients treated with ORLYNVAH <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. 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.

5.2 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.

5.3 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

5.4 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.

5.5 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.

5.6 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 <span class="opacity-50 text-xs">[see Indications and Usage ( 1.2 )]</span>.