Sulopenem etzadroxil and probenecid

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 [see Clinical Pharmacology ( 12.3 )]. If concomitant use with ORLYNVAH is necessary, monitor more frequently for adverse reactions associated with ORLYNVAH (e.g., diarrhea and nausea) [see Adverse Reactions ( 6.1 )].

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.

8.1 Pregnancy Risk Summary Sulopenem Etzadroxil 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.

Probenecid 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.

Data Animal Data Sulopenem etzadroxil: In an embryo-fetal development (EFD) study in mice, sulopenem etzadroxil was administered to pregnant females in oral doses of 100, 400, and 2000 mg/kg/day during the period of organogenesis from GD 6 to GD 15. Reduced fetal body weights and a fetal malformation, cleft palate, occurred with an increased fetal and litter incidence in the 2000 mg/kg/day group (approximately 23 times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). At the same dose, maternal clinical signs (rales, dyspnea, decreased…