Version July 2025
Cystitis, acute uncomplicated or acute simple cystitis (infection limited to the bladder without signs/symptoms of upper tract or systemic infection) (alternative agent):
Note: Reserve use for infection caused by drug-resistant pathogens with limited treatment options (Ref).
Females: Oral: One tablet (sulopenem etzadroxil 500 mg/probenecid 500 mg) twice daily for 5 days.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥15 mL/minute: No dosage adjustment necessary.
CrCl <15 mL/minute: Use is not recommended (has not been studied).
Hemodialysis: Use is not recommended (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
1% to 10%:
Gastrointestinal: Abdominal pain (1%), diarrhea (10%), nausea (4%), vomiting (2%)
Genitourinary: Vulvovaginal candidiasis: 2%
Nervous system: Headache (2%)
<1%:
Cardiovascular: Flushing, hypertension, peripheral edema, presyncope, syncope, tachycardia
Dermatologic: Pruritus, skin rash
Endocrine & metabolic: Polydipsia
Gastrointestinal: Abdominal distention, abnormal stools (including soft stools), ageusia, constipation, dysgeusia, dyspepsia, eructation, fecal discoloration, flatulence, gastroesophageal reflux disease, xerostomia
Genitourinary: Bacterial vaginosis, candiduria, malodorous urine, perineal pain, vaginal discharge, vulvovaginal pruritus
Hepatic: Hepatomegaly, increased serum transaminases
Hypersensitivity: Angioedema
Infection: Candidiasis
Nervous system: Asthenia, confusion, dizziness, drowsiness, fatigue, malaise, migraine, pain, paresthesia, vertigo
Neuromuscular & skeletal: Arthralgia, back pain, dystonia, myositis
Respiratory: Cough, dyspnea
Miscellaneous: Fever
Hypersensitivity to sulopenem etzadroxil, probenecid, other beta-lactam antibacterial drugs, or any component of the formulation; known blood dyscrasias; known uric acid kidney stones; concomitant use with ketorolac tromethamine.
Concerns related to adverse effects:
• Hypersensitivity: Hypersensitivity reactions, including angioedema, have been reported with sulopenem etzadroxil and probenecid. Serious, occasionally fatal hypersensitivity reactions, including anaphylaxis and serious skin reactions, have been reported in patients receiving beta-lactam antibacterials. Before initiating therapy, carefully investigate previous carbapenem, cephalosporin, penicillin, or other beta-lactam allergy; cross-sensitivity may occur. If an allergic reaction occurs, discontinue use and institute appropriate supportive therapy.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including Clostridioides difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months post antibiotic treatment.
Disease-related concerns:
• G6PD deficiency: Use probenecid with caution in patients with G6PD deficiency; may increase risk for hemolytic anemia.
• Gout: Use appropriate measures to reduce risk of uric acid kidney stone development (eg, increased fluid intake, alkalization of urine) in patients with a history of gout. May cause exacerbation of gout; ensure appropriate gout therapy is instituted in patients with a history of gout.
• Kidney impairment: Use is not recommended in patients with CrCl <15 mL/minute or patients on hemodialysis.
Orlynvah: FDA approved October 2024; anticipated availability is currently unknown.
Oral: Administer with food.
Cystitis, acute uncomplicated or acute simple cystitis (infection limited to the bladder without signs/symptoms of upper tract or systemic infection): Treatment of uncomplicated urinary tract infection caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis in adult females who have limited or no alternative oral antibacterial treatment options.
Limitations of use: Not for treatment of complicated urinary tract infections (cUTI) or as step-down treatment after IV antibacterial treatment of cUTI; complicated intra-abdominal infections (cIAI) or as step-down treatment after IV antibacterial treatment of cIAI.
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetaminophen: Probenecid may increase serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Management: Consider limiting acetaminophen use in combination with probenecid. Probenecid may reduce clearance of acetaminophen to one of its non-toxic metabolities, increasing the risk for acetaminophen toxicity, even a lower doses. Risk D: Consider Therapy Modification
Anagliptin: Probenecid may increase serum concentration of Anagliptin. Risk C: Monitor
Avibactam: Probenecid may increase serum concentration of Avibactam. Risk X: Avoid
Bacillus clausii: Antibiotics may decrease therapeutic effects of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider Therapy Modification
Baricitinib: Probenecid may increase serum concentration of Baricitinib. Management: When baricitinib is combined with probenecid, reduce baricitinib 4 mg daily to 2 mg daily or reduce baricitinib 2 mg daily to 1 mg daily. Don't use probenecid if recommended baricitinib dose is only 1 mg daily. Risk D: Consider Therapy Modification
BCG (Intravesical): Antibiotics may decrease therapeutic effects of BCG (Intravesical). Risk X: Avoid
BCG Vaccine (Immunization): Antibiotics may decrease therapeutic effects of BCG Vaccine (Immunization). Risk C: Monitor
Betalactamase Inhibitors: Probenecid may increase serum concentration of Betalactamase Inhibitors. Management: Coadministration of probenecid with amoxicillin/clavulanate is not recommended per official package labeling. Risk D: Consider Therapy Modification
Cabozantinib: MRP2 Inhibitors may increase serum concentration of Cabozantinib. Risk C: Monitor
Cefotaxime: Probenecid may increase serum concentration of Cefotaxime. Management: Avoid cefotaxime doses greater than 6 grams per day with concurrent probenecid. Any patients receiving this combination should be monitored for evidence of cefotaxime toxicity. Risk D: Consider Therapy Modification
Cephalosporins: Probenecid may increase serum concentration of Cephalosporins. Risk C: Monitor
Certoparin: Probenecid may increase anticoagulant effects of Certoparin. Risk C: Monitor
Cholera Vaccine: Antibiotics may decrease therapeutic effects of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid
Clofarabine: OAT1/3 Inhibitors may increase serum concentration of Clofarabine. Risk C: Monitor
Deferiprone: UGT1A6 Inhibitors may increase serum concentration of Deferiprone. Risk X: Avoid
Dexketoprofen: Probenecid may increase serum concentration of Dexketoprofen. Risk C: Monitor
Dichlorphenamide: OAT1/3 Inhibitors may increase serum concentration of Dichlorphenamide. Risk C: Monitor
Doripenem: Probenecid may increase serum concentration of Doripenem. Risk X: Avoid
Dyphylline: Probenecid may increase serum concentration of Dyphylline. Risk C: Monitor
Ertapenem: Probenecid may increase serum concentration of Ertapenem. Risk X: Avoid
Fecal Microbiota (Live) (Oral): May decrease therapeutic effects of Antibiotics. Risk X: Avoid
Fecal Microbiota (Live) (Rectal): Antibiotics may decrease therapeutic effects of Fecal Microbiota (Live) (Rectal). Risk X: Avoid
Fexinidazole: May increase serum concentration of OAT1/3 Substrates (Clinically Relevant). Management: Avoid use of fexinidazole with OAT1/3 substrates when possible. If combined, monitor for increased OAT1/3 substrate toxicities. Risk D: Consider Therapy Modification
Ganciclovir-Valganciclovir: Probenecid may increase serum concentration of Ganciclovir-Valganciclovir. Risk C: Monitor
Gemifloxacin: Probenecid may increase serum concentration of Gemifloxacin. Risk C: Monitor
Imipenem: Probenecid may increase serum concentration of Imipenem. Risk C: Monitor
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Antibiotics may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Ketoprofen: Probenecid may increase serum concentration of Ketoprofen. Risk X: Avoid
Ketorolac (Nasal): Probenecid may increase serum concentration of Ketorolac (Nasal). Risk X: Avoid
Ketorolac (Systemic): Probenecid may increase serum concentration of Ketorolac (Systemic). Risk X: Avoid
Lactobacillus and Estriol: Antibiotics may decrease therapeutic effects of Lactobacillus and Estriol. Risk C: Monitor
Leflunomide: May increase serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor
Loop Diuretics: Probenecid may decrease diuretic effects of Loop Diuretics. Probenecid may increase serum concentration of Loop Diuretics. Risk C: Monitor
LORazepam: Probenecid may increase serum concentration of LORazepam. Management: Reduce lorazepam dose 50% during coadministration with probenecid. Monitor for increased and prolonged lorazepam effects, particularly CNS depressant effects. Patients using lorazepam ER capsules should be switched to lorazepam tablets. Risk D: Consider Therapy Modification
Meropenem: Probenecid may increase serum concentration of Meropenem. Risk X: Avoid
Methotrexate: Probenecid may increase serum concentration of Methotrexate. Management: If possible, the concomitant use of methotrexate and probenecid should be avoided. If used concomitantly, monitor closely for increased methotrexate serum concentrations and toxicities. Methotrexate dose reductions may be needed. Risk D: Consider Therapy Modification
Mycophenolate: Probenecid may increase serum concentration of Mycophenolate. Risk C: Monitor
Nitisinone: May increase serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor
Nitrofurantoin: Probenecid may decrease therapeutic effects of Nitrofurantoin. Probenecid may increase serum concentration of Nitrofurantoin. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents: Probenecid may increase serum concentration of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor
OAT1/3 Inhibitors: May increase serum concentration of Sulopenem Etzadroxil. Risk C: Monitor
Oseltamivir: Probenecid may increase active metabolite exposure of Oseltamivir. Risk C: Monitor
Pegloticase: Probenecid may increase adverse/toxic effects of Pegloticase. Specifically, Probenecid may blunt increases in serum urate that would signal an elevated risk of anaphylaxis and infusion reactions. Risk X: Avoid
Penicillins: Probenecid may increase serum concentration of Penicillins. Risk C: Monitor
Pexidartinib: UGT1A4 Inhibitors may increase serum concentration of Pexidartinib. Management: If combined use cannot be avoided, pexidartinib dose should be reduced as follows: reduce pexidartinib doses of 500 mg or 375 mg daily to 125 mg twice daily; reduce pexidartinib 250 mg daily to 125 mg once daily. Risk D: Consider Therapy Modification
Phenprocoumon: Probenecid may decrease serum concentration of Phenprocoumon. Risk C: Monitor
PRALAtrexate: Probenecid may increase serum concentration of PRALAtrexate. Management: Avoid coadministration of pralatrexate with probenecid. If coadministration cannot be avoided, closely monitor for increased pralatrexate serum concentrations or possible toxicity with concomitant use of probenecid. Risk D: Consider Therapy Modification
Pretomanid: May increase serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor
Propacetamol: Probenecid may increase active metabolite exposure of Propacetamol. Specifically, accetaminophen exposure may be increased. Probenecid may also limit the formation of at least one major non-toxic acetaminophen metabolite, possibly increasing the formation of the toxic NAPQI metabolite. Management: Consider limiting the use of propacetamide in patients who are also taking probenecid. Patients may be at an increased risk for toxicity, even if reduced propacetamide doses are used. Risk D: Consider Therapy Modification
Quinolones: Probenecid may increase serum concentration of Quinolones. Probenecid may decrease excretion of Quinolones. Specifically, probenecid may decreased the renal excretion of quinolone antibiotics. Risk C: Monitor
RifAMPin: Probenecid may increase serum concentration of RifAMPin. Risk C: Monitor
Roxadustat: Probenecid may increase serum concentration of Roxadustat. Risk C: Monitor
Salicylates: May decrease therapeutic effects of Probenecid. Salicylates may increase serum concentration of Probenecid. Probenecid may increase serum concentration of Salicylates. Risk X: Avoid
Seladelpar: OAT1/3 Inhibitors may increase serum concentration of Seladelpar. Risk X: Avoid
Sodium Benzoate: Probenecid may decrease therapeutic effects of Sodium Benzoate. Risk C: Monitor
Sodium Picosulfate: Antibiotics may decrease therapeutic effects of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider Therapy Modification
Sulbactam: Probenecid may increase serum concentration of Sulbactam. Management: Recommendations for management of this interaction vary by specific sulbactam-containing product. Coadministration of probenecid with sulbactam/durlobactam is not recommended, but no specific actions are recommended for ampicillin/sulbactam. Risk D: Consider Therapy Modification
Sulfonylureas: Probenecid may increase serum concentration of Sulfonylureas. Risk C: Monitor
Taurursodiol: May increase serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk X: Avoid
Teriflunomide: May increase serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor
Thiopental: Probenecid may increase adverse/toxic effects of Thiopental. Specifically, anesthetic potency and duration may be enhanced. Risk C: Monitor
Typhoid Vaccine: Antibiotics may decrease therapeutic effects of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider Therapy Modification
Urea Cycle Disorder Agents: Probenecid may increase active metabolite exposure of Urea Cycle Disorder Agents. Specifically, concentrations of phenylacetate and phenylacetylglutamine may be increased. Risk C: Monitor
Vaborbactam: May increase serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor
Vadadustat: May increase serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor
Vadadustat: OAT1/3 Inhibitors may increase serum concentration of Vadadustat. Risk C: Monitor
Zidovudine: Probenecid may increase serum concentration of Zidovudine. Risk C: Monitor
Administration with a high-fat meal (800 to 1,000 calories, ~50% of calories from fat) increased sulopenem C max and AUC (45% and 48%, respectively), but decreased probenecid Cmax and AUC (27% and 8%, respectively). Management: Administer with food.
In animal reproduction studies conducted with oral sulopenem etzadroxil, maternal toxicity or adverse fetal events occurred with doses >3 times the maximum recommended human dose (MRHD, based on AUC) in mice and >2 times the MRHD in rats.
Probenecid crosses the placenta in humans. Refer to the Probenecid monograph for additional information.
Probenecid is present in breast milk. It is not known if sulopenem etzadroxil is present in human milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Take with food.
Signs/symptoms of hypersensitivity reaction, including anaphylaxis.
Sulopenem etzadroxil is a penem antibacterial prodrug that is hydrolyzed to active sulopenem. Sulopenem inhibits cell wall synthesis through binding to penicillin-binding proteins (PBPs), including (in order of affinity) PBP2, PBP1A, PBP1B, PBP4, PBP3, PBP5/6 in E. coli. Probenecid inhibits OAT3-mediated renal clearance of sulopenem, resulting in increased sulopenem plasma concentrations.
Distribution: Vd: Sulopenem: 92.09 L (fed), 134 L (fasted); Probenecid: 11.94 L (fed), 8.81 L (fasted).
Protein binding: Sulopenem: 11%.
Metabolism: Sulopenem: Sulopenem etzadroxil hydrolyzed by esterases to active sulopenem, then further metabolized by hydrolysis and dehydrogenation.
Bioavailability: Sulopenem: 64% (fed), 40% (fasted).
Half-life elimination: Sulopenem: 1.28 hours (fed), 1.18 hours (fasted); Probenecid: 3.83 hours (fed), 2.93 hours (fasted).
Excretion: Sulopenem: Feces: 44.3% (26.9% unchanged); Urine: 40.8% (3.1% unchanged).
Anti-infective considerations:
Parameters associated with efficacy: Time-dependent, associated with free drug concentration (fT) > minimum inhibitory concentration; specific goal has not been determined.
