Sulopenem Etzadroxil and Probenecid

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 )].

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. ( 3 )

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 )

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 [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). 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 [see Contraindications ( 4 )] .

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 [see Indications and Usage ( 1.2 )].

The following adverse reactions are described in greater detail in the Warnings and Precautions 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; 0.3%), diarrhea (5/1932; 0.3%), 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. Table 1 lists adverse reactions reported in ≥1% of patients receiving ORLYNVAH in the phase 3 uUTI trials (Trial 1 and Trial 2). The most common adverse reactions in patients treated with ORLYNVAH were diarrhea (10%) and nausea (4%). Table 1. Adverse Reactions Occurring in ≥ 1% of Patients Receiving ORLYNVAH in the Uncomplicated Urinary Tract Infection Clinical Trials (Trial 1 and Trial 2) Adverse Reaction ORLYNVAH a N=1932 n (%) Amoxicillin/Clavulanate b N=1107 n (%) Ciprofloxacin c N=822 n (%) Diarrhea 1 194 (10) 45 (4) 21 (3) Nausea 80 (4) 32 (3) 30 (4) Vulvovaginal mycotic infection 2 46 (2) 13 (1) 7 (1) Headache 42 (2) 17 (2) 18 (2) Vomiting 29 (2) 4 (0.4) 11 (1) Abdominal pain 3 22 (1) 11 (1) 9 (1) a ORLYNVAH tablets (sulopenem etzadroxil 500mg / probenecid 500mg) 1 tablet twice daily for 5 days; b Amoxicillin/clavulanate tablets (875 mg /125 mg) 1 tablet twice daily for 5 days cCiprofloxacin tablets (250 mg) 1 tablet twice daily for 3 days. 1 Diarrhea includes diarrhea and loose stools. 2 Vulvovaginal mycotic infection includes vulvovaginal mycotic infection, vulvovaginal candidiasis, vaginal infection, fungal infection, genital infection fungal, and yeast infection. 3 Abdominal pain includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal discomfort. Other Adverse Reactions of ORLYNVAH The following selected adverse reactions were reported in the ORLYNVAH-treated patients at a rate of <1% in the uUTI Trial 1 and Trial 2: Cardiac disorders: tachycardia Ear and labyrinth disorders: vertigo Gastrointestinal disorders: abdominal distension, abnormal feces, constipation, dry mouth, dyspepsia, eructation, feces discolored, feces soft, flatulence, gastroesophageal reflux disease General disorders: asthenia , fatigue, malaise, peripheral edema, pain, pyrexia Hepatobiliary disorders: elevated transaminases, hepatomegaly Infections and infestations: bacterial vaginosis, Candida infection, candiduria Metabolism and nutrition disorders: polydipsia Musculoskeletal and connective tissue disorders: arthralgia, back pain, myositis Nervous system disorders: ageusia, dizziness, dysgeusia, dystonia, migraine, paresthesia, presyncope, somnolence, syncope Psychiatric disorders: confusion Renal and urinary disorders: urine odor abnormal Reproductive system and breast disorders: perineal pain, vaginal discharge, vulvovaginal pruritus Respiratory disorders: cough, dyspnea Skin and subcutaneous tissue disorders: angioedema, pruritus, rash Vascular disorders: flushing, hypertension Adverse Reactions Occurring with Probenecid (a component of ORLYNVAH) The following adverse reactions associated with the use of probenecid (a component of ORLYNVAH) were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions not observed in clinical studies of ORLYNVAH that have been observed with probenecid (a component of ORLYNVAH) include: Gastrointestinal disorders : hepatic necrosis, anorexia, sore gums Hematologic : aplastic anemia, leukopenia, and hemolytic anemia which in some patients could be related to genetic deficiency of glucose-6-phosphate dehydrogenase in red blood cells, anemia Immune system disorders: anaphylaxis, urticaria Metabolism and nutrition disorders: precipitation of acute gouty arthritis Renal and urinary disorders: nephrotic syndrome, uric acid stones with or without hematuria, renal colic, costovertebral pain, urinary frequency Skin and subcutaneous tissue disorders: alopecia

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 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 )]. […]

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 .