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Probenecid
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Verified · Updated 01 Aug 2026 · Source: Local active-ingredient clinical extract; FDA drug label via OpenFDA/DailyMed; Professional class pharmacology (Therapeutic agent (verify pharmacological class))
Kenya market
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Risk first
Contraindications
- 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.
Precautions
- : 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 [see Adverse Reactions ( 6.1 )].
- Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs [see Contraindications ( 4 )].
- 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).
Point of care
Dosing
Adult
5 days. ( 2.1 ) Administration of ORLYNVAH with food is recommended. ( 2.1 ) 2.1 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 [see Clinical Pharmacology ( 12.3 )]. 2.2 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 [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. 2.3 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.
Paediatric
8.4 Pediatric Use The safety and effectiveness of ORLYNVAH in pediatric patients have not been established. Juvenile Animal Toxicity Data In a toxicology study with juvenile rats, sulopenem etzadroxil was orally administered from postnatal day (PND) 5 to PND 90 (85 days of dosing) in doses of 25, 75, and 225 mg/kg/day. Juvenile rats exhibited kidney toxicity including tubular epithelial degeneration and tubule concretions at doses ≥ 25 mg/kg/day (approximately 0.3 times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison).
Renal
Review renal impairment dosing; many agents need CrCl/eGFR adjustment.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Hepatic
Review hepatic impairment dosing; monitor LFTs if agent is hepatically cleared or hepatotoxic.
Safety
Drug interactions
- It is a sulfonamide-derivative.
- Aspirin [antagonizes uricosuric action]
- methotrexate [plasma level increased]
- indomethacin
- paracetamol
- naproxen
- lorazepam [plasma elimination reduced]
Safety
Adverse effects
- section.
- Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions ( 5.2 )] Risk of Uric Acid Kidney Stone Development [see Warnings and Precautions ( 5.3 )] Exacerbation of Gout [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (≥2%) in patients treated with ORLYNVAH were diarrhea, nausea, vulvovaginal mycotic infection, headache, and vomiting.
- ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Iterum Therapeutics at 1-866-414-SULO or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.
- ORLYNVAH was evaluated in two Phase 3 controlled, multinational, randomized, double blind, double dummy clinical trials (Trial 1 and Trial 2) in adult women with uUTI.
- Therapy with oral ORLYNVAH tablets was administered as one tablet twice daily for 5 days [see Clinical Studies ( 14 )].
- The trials included 1932 patients treated with ORLYNVAH and 1929 patients treated with comparator antibacterial drugs (ciprofloxacin or amoxicillin/clavulanate).
- The median age of patients treated with ORLYNVAH was 50 years, ranging between 18 and 91 years old.
- Patients treated with ORLYNVAH were all female (100%), predominantly White (83%) and from the United States (83%).
- Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation Serious adverse reactions occurred in 6/1932 (0.3%) of uUTI patients treated with ORLYNVAH and in 2/822 (0.2%) and 5/1107 (0.5%) of patients treated with ciprofloxacin or amoxicillin/clavulanate, respectively.
- Treatment discontinuation due to an adverse reaction occurred in 21/1932 (1%) of patients treated with ORLYNVAH, 8/822 (1%) of patients treated with ciprofloxacin, and 4/1107 (0.4%) of patients treated with amoxicillin/clavulanate.
- The most commonly reported adverse reactions leading to discontinuation of ORLYNVAH were nausea (6/1932
- 3%), diarrhea (5/1932
- 3%), as well as abdominal pain, gastroesophageal reflux disease, vomiting, and dizziness, each 0.2% (3/1932).
- Most Common Adverse Reactions Adverse reactions occurring at 2% or greater in patients receiving ORLYNVAH were diarrhea, nausea, vulvovaginal mycotic infection, headache, and vomiting.
Use
Indications
- 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.
- ( 1.1 ) 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.
- ( 1.2 , 5.5 ) 1.1 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 [see Clinical Studies ( 14.2 )].
- Complicated intra-abdominal infections (cIAI)) or as step-down treatment after intravenous antibacterial treatment of cIAI [see Clinical Studies ( 14.3 )]. 1.2 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 [see Warnings and Precautions ( 5.5 )].
Pharmacology
Mode of action
etzadroxil, a penem antibacterial drug [see Microbiology 12.
Full mechanism text
etzadroxil, a penem antibacterial drug [see Microbiology 12.4 ] and probenecid, a renal tubular transport inhibitor. Probenecid inhibits OAT3-mediated renal clearance of sulopenem, resulting in increased plasma concentrations of sulopenem .
ADME
Pharmacokinetics & PD
| Onset | Product-specific |
|---|---|
| Duration | Product-specific |
| Route | See product SmPC |
| Absorption | Bioavailability 40% 64% unknown T max Median (range) 1.0 (0.5 to 3.0) 2.0 (1.0 -3.0) 3.0 (1.0 – 10.0) 2.0 (1.50 to 6.0) Effect of Food High fat meal a (Fed:Fasted ratio) C max Increased 45% Decreased 27% AUC 0-inf Increased 48% Decreased 8% |
| Distribution | Apparent Volume of Distribution (Liters) (mean (SD)) 134 (51.36) 92.09 (33.43) 8.81 (3.91) 11.94 (3.46) Protein Binding c 11% Unknown |
| Metabolism | Primary Pathway Sulopenem etzadroxil is hydrolyzed by esterases to active sulopenem then further metabolized by hydrolysis followed by dehydrogenation unknown Major Metabolites M1a and M1b d (inactive) unknown |
| Elimination | Half-Life (hours) (mean (SD)) 1.18 (0.24) 1.28 (0.49) 2.93 (0.83) 3.83 (0.50) Apparent Clearance (L/hour) (mean (SD)) 77.6 (19.77) 50.55 (11.60) 2.06 (0.70) 2.22 (0.76) |
| Half-life | (hours) (mean (SD)) 1.18 (0.24) 1.28 (0.49) 2.93 (0.83) 3.83 (0.50) Apparent Clearance (L/hour) (mean (SD)) 77.6 (19.77) 50.55 (11.60) 2.06 (0.70) 2.22 (0.76) |
Full PK/PD text
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ORLYNVAH is a combination of sulopenem etzadroxil, a penem antibacterial drug [see Microbiology 12.4 ] and probenecid, a renal tubular transport inhibitor. Probenecid inhibits OAT3-mediated renal clearance of sulopenem, resulting in increased plasma concentrations of sulopenem . 12.2 Pharmacodynamics Similar to other beta-lactam antimicrobial drugs, the percentage of time that unbound plasma concentrations of sulopenem exceed the sulopenem minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in in vitro models of infection. Cardiac Electrophysiology At a concentration of 40 times or greater than that achieved after a single oral administration of ORLYNVAH, sulopenem does not prolong the QTc interval to a clinically relevant extent. 12.3 Pharmacokinetics Sulopenem etzadroxil is a prodrug [see Microbiology 12.4 ]. The pharmacokinetics of sulopenem and probenecid were characterized in healthy subjects following single oral administration of ORLYNVAH (500 mg sulopenem etzadroxil and 500 mg probenecid). Pharmacokinetic parameters are presented in Table 3 as mean [coefficient of variation (%CV)] unless otherwise specified. Table 3. Pharmacokinetics of Sulopenem and Probenecid in Plasma after Single Oral Dose Administration of ORLYNVAH in Healthy Subjects Parameter Sulopenem Probenecid Fasted Fed a Fasted Fed a General Information Exposure b C max 1.84 (39.1) 2.66 (43.6) 41.2 (38.2) 30.4 (30.9) AUC 0-inf 4.85 (25.3) 7.41 (22.7) 255 (35.6) 237 (35.2) Dose Proportionality b Dose Proportional unknown Accumulation None unknown Absorption Bioavailability 40% 64% unknown T max Median (range) 1.0 (0.5 to 3.0) 2.0 (1.0 -3.0) 3.0 (1.0 – 10.0) 2.0 (1.50 to 6.0) Effect of Food High fat meal a (Fed:Fasted ratio) C max Increased 45% Decreased 27% AUC 0-inf Increased 48% Decreased 8% Distribution Apparent Volume of Distribution (Liters) (mean (SD)) 134 (51.36) 92.09 (33.43) 8.81 (3.91) 11.94 (3.46) Protein Binding c 11% Unknown Elimination Half-Life (hours) (mean (SD)) 1.18 (0.24) 1.28 (0.49) 2.93 (0.83) 3.83 (0.50) Apparent Clearance (L/hour) (mean (SD)) 77.6 (19.77) 50.55 (11.60) 2.06 (0.70) 2.22 (0.76) Metabolism Primary Pathway Sulopenem etzadroxil is hydrolyzed by esterases to active sulopenem then further metabolized by hydrolysis followed by dehydrogenation unknown Major Metabolites M1a and M1b d (inactive) unknown Excretion e Feces 44.3% (26.9% unchanged) unknown Urine 40.8% (3.1% unchanged) unknown Abbreviations : C max = maximum plasma concentration; AUC= area under the time concentration curve; T max = time to peak concentration a A high fat meal is 800-1000 calories, approximately 50% of total calories from fat b No clinically significant sulopenem divergence from dose-proportionally was observed over a dose range of 400 mg to 2000 mg (0.8 to 4 times the approved recommended sulopenem etzadroxil dosage) c Independent of concentration over a range of 1 to 100 µg/mL d Sulopenem, M1a and M1b, accounted for 32%, 21.8% and 43.6% of circulating radioactivity, respectively e After a single oral dose of radiolabeled sulopenem etzadroxil 2000 mg healthy adult subjects Specific Populations No clinically significant differences in the pharmacokinetics of sulopenem were observed based on age, sex or weight. The effect of hepatic impairment on sulopenem pharmacokinetics is unknown. Patients with Renal Impairment Sulopenem mean plasma AUC 0-inf increased by 2-fold in patients with mild (CrCL 60 to 89 mL/min), estimated by Cockcroft-Gault equation), by 3-fold in patients with moderate (CrCL 30 to 59 mL/min) and by 7.4-fold in patients with severe (CrCL15 to 29 mL/min) renal impairment following administration of 1000 mg oral sulopenem etzadroxil (not a recommended dosing regimen) [see Dosage and Administration ( 2.1 )]. The effect of kidney failure (CrCL<15 mL/min) or hemodialysis on sulopenem pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies Effect of Other Drugs on the Pharmacokinetics of ORLYNVAH: No clinically significant differences in the pharmacokinetics of sulopenem were observed when ORLYNVAH was administered concomitantly with oral itraconazole (P-gp inhibitor), pantoprazole (gastric-acid reducing agent) or aluminum hydroxide (gastric acid-reducing agent). No clinically significant differences in the pharmacokinetics of valproic acid were observed when used concomitantly with ORLYNVAH. Although there are case reports in the published literature that suggest concomitant use of carbapenems result in a reduction in valproic acid concentrations, the probenecid component of ORLYNVAH appears to counteract any potential effect of sulopenem on valproic acid [see Drug Interactions ( 7.1 )]. Effect of ORLYNVAH on the Pharmacokinetics of Other Drugs: Coadministration of multiple doses of 500 mg sulopenem etzadroxil with valproic acid decreased valproic acid plasma AUC 0-tau and C max by approximately 25% and 19%, respectively. However, no clinically significant differences in the pharmacokinetics of valproic acid were observed when administered concomitantly with ORLYNVAH. AUC 0-tau and C max decreased by 8.4% and 7%, respectively, with concomitant administration of ORLYNVAH. In Vitro Studies CYP450 Enzymes: Sulopenem does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A or induce CYP1A2, CYP2B6, or CYP3A4/5. Transporter Systems: Sulopenem is a substrate of OAT3 and does not inhibit BCRP, P-gp, BSEP, MATE1, MATE2K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, or OCT2. Probenecid is a substrate for BCRP and an inhibitor of OAT1/3, but does not inhibit BSEP, P-gp, or MRP2. 12.4 Microbiology Mechanism of Action Sulopenem etzadroxil is a prodrug that is hydrolyzed to the active drug sulopenem after oral administration. Sulopenem has in vitro activity against gram-positive and gram-negative aerobic and anaerobic bacteria. The bactericidal activity of sulopenem results from the inhibition of cell wall synthesis and is mediated through sulopenem binding to penicillin binding proteins (PBPs). In Escherichia coli , sulopenem demonstrated binding affinity for PBPs in the following order: PBP2 > PBP1A > PBP1B > PBP4 > PBP3 > PBP5/6. Resistance Resistance to sulopenem is caused by certain extended spectrum beta-lactamases (ESBLs) including carbapenemases, alteration of PBPs, over expression of efflux pumps and loss of outer membrane porins. Sulopenem demonstrated activity against Enterobacterales in the presence of certain beta-lactamases and ESBLs, e.g., AmpC, CTX-M, TEM, SHV. Sulopenem resistant mutants were selected in vitro at a frequency of 1×10 - 8 . Interaction with Other Antimicrobials In vitro studies with sulopenem did not demonstrate antagonism with any of the following antimicrobials: amoxicillin, aztreonam, ceftriaxone, doxycycline, gentamicin, levofloxacin, nitrofurantoin, vancomycin or trimethoprim-sulfamethoxazole. The clinical significance of these in vitro findings is unknown. Antimicrobial Activity Sulopenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage ( 1.1 )]: Gram-negative bacteria Escherichia coli Klebsiella pneumoniae Proteus mirabilis 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 sulopenem against isolates of similar genus or organism group. However, the efficacy of sulopenem in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Staphylococcus saprophyticus Streptococcus agalactiae Gram-negative bacteria Citrobacter freundii Citrobacter koseri Enterobacter cloacae species Complex Klebsiella aerogenes Klebsiella oxytoca Proteus vulgaris Providencia alcalifaciens Providencia stuartii Susceptibility Testing For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see https://www.fda.gov/STIC .
Kenya
Brands & prices
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Special populations
Pregnancy & lactation
Pregnancy
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 motor activity) were observed, and maternal body weight gains were reduced. No maternal toxicity or fetal malformations occurred with doses ≤ 400 mg/kg/day (approximately 3 times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). In an EFD study in rats, 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 17. Maternal body weights and food consumption were reduced in the 400 and 2000 mg/kg/day groups. No fetal malformations were observed at any sulopenem etzadroxil dose, but fetal body weights were reduced in the 2000 mg/kg/day group (approximately equal to 11 times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). The doses at which no maternal toxicity or fetal toxicity occurred were, respectively, 100 mg/kg/day and 400 mg/kg/day (less than or equal to and approximately 2 times respectively the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). In an EFD study in rabbits, sulopenem etzadroxil was administered intravenously to pregnant females in doses of 5, 15, and 50 mg/kg/day during the period of organogenesis from GD 7 to GD 19. Maternal body weight gain and food consumption were decreased in all the sulopenem etzadroxil dose groups. No fetal malformations occurred, but the number of fetal resorptions and postimplantation loss were increased and the number of viable fetuses and fetal body weights were decreased in the 15 and 50 mg/kg/day groups (approximately 0.2-times and equal to, respectively, the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). The dose at which no fetal toxicity occurred was 5 mg/kg/day (approximately 0.1-times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). In a pre- postnatal study in rats, sulopenem etzadroxil was administered by oral gavage to pregnant females from GD 6 through the lactation period to Lactation Day (LD) 20 in maternal doses of 100, 300, and 1000 mg/kg/day. No adverse effects on the survival, growth, behavior, or reproduction of first-generation offspring occurred with any of the sulopenem etzadroxil doses up to the high dose of 1000 mg/kg/day (approximately 10-times the MRHD of sulopenem etzadroxil based on body surface area comparison).
Lactation
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 motor activity) were observed, and maternal body weight gains were reduced. No maternal toxicity or fetal malformations occurred with doses ≤ 400 mg/kg/day (approximately 3 times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). In an EFD study in rats, 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 17. Maternal body weights and food consumption were reduced in the 400 and 2000 mg/kg/day groups. No fetal malformations were observed at any sulopenem etzadroxil dose, but fetal body weights were reduced in the 2000 mg/kg/day group (approximately equal to 11 times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). The doses at which no maternal toxicity or fetal toxicity occurred were, respectively, 100 mg/kg/day and 400 mg/kg/day (less than or equal to and approximately 2 times respectively the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). In an EFD study in rabbits, sulopenem etzadroxil was administered intravenously to pregnant females in doses of 5, 15, and 50 mg/kg/day during the period of organogenesis from GD 7 to GD 19. Maternal body weight gain and food consumption were decreased in all the sulopenem etzadroxil dose groups. No fetal malformations occurred, but the number of fetal resorptions and postimplantation loss were increased and the number of viable fetuses and fetal body weights were decreased in the 15 and 50 mg/kg/day groups (approximately 0.2-times and equal to, respectively, the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). The dose at which no fetal toxicity occurred was 5 mg/kg/day (approximately 0.1-times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). In a pre- postnatal study in rats, sulopenem etzadroxil was administered by oral gavage to pregnant females from GD 6 through the lactation period to Lactation Day (LD) 20 in maternal doses of 100, 300, and 1000 mg/kg/day. No adverse effects on the survival, growth, behavior, or reproduction of first-generation offspring occurred with any of the sulopenem etzadroxil doses up to the high dose of 1000 mg/kg/day (approximately 10-times the MRHD of sulopenem etzadroxil based on body surface area comparison). 8.2 Lactation Risk Summary 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 ORLYNVAH and any potential adverse effects on the breast-fed child from ORLYNVAH or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ORLYNVAH in pediatric patients have not been established. Juvenile Animal Toxicity Data In a toxicology study with juvenile rats, sulopenem etzadroxil was orally administered from postnatal day (PND) 5 to PND 90 (85 days of dosing) in doses of 25, 75, and 225 mg/kg/day. Juvenile rats exhibited kidney toxicity including tubular epithelial degeneration and tubule concretions at doses ≥ 25 mg/kg/day (approximately 0.3 times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison). 8.5 Geriatric Use In uUTI Trial 1, there were 436 patients 65 years of age and older [see Clinical Studies ( 14.1 )]. Of the total number of ORLYNVAH-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 ORLYNVAH 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 [see Clinical Studies ( 14.1 )]. Of the total number of ORLYNVAH-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 ORLYNVAH were observed between patients 65 years and older and younger adult patients. No clinically meaningful differences in the pharmacokinetics of ORLYNVAH were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology ( 12.3 )]. No dosage adjustment based on age is required. ORLYNVAH 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 [see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. 8.6 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 [see Clinical Pharmacology ( 12.3 )] . Administration of ORLYNVAH 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.
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- Drug & food interactions (label) 7 DRUG 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 [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.
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Source: Local active-ingredient clinical extract; FDA drug label via OpenFDA/DailyMed; Professional class pharmacology (Therapeutic agent (verify pharmacological class))
Last reviewed: 01 Aug 2026
Decision support only — not a substitute for clinical judgment, product SmPC, or Kenya STG/EML.