PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Sulopenem etzadroxil is 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 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 SubjectsParameterSulopenemProbenecidFastedFeda FastedFeda General InformationExposureb Cmax1.84 (39.1)2.66 (43.6)41.2 (38.2)30.4 (30.9)AUC0-inf4.85 (25.3)7.41 (22.7)255 (35.6)237 (35.2)Dose Proportionalityb Dose ProportionalunknownAccumulationNoneunknownAbsorptionBioavailability40%64%unknownTmaxMedian (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 FoodHigh fat meala (Fed:Fasted ratio)CmaxIncreased 45%Decreased 27%AUC0-infIncreased 48%Decreased 8%DistributionApparent Volume of Distribution (Liters) (mean (SD))134 (51.36)92.09 (33.43)8.81 (3.91)11.94 (3.46)Protein Bindingc 11%UnknownEliminationHalf-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)MetabolismPrimary PathwaySulopenem etzadroxil is hydrolyzed by esterases to active sulopenem then furthermetabolized by hydrolysis followed by dehydrogenationunknownMajor MetabolitesM1a and M1bd (inactive)unknownExcretioneFeces44.3%(26.9% unchanged)unknownUrine40.8%(3.1% unchanged)unknownAbbreviations: Cmax maximum plasma concentration; AUC= area under the time concentration curve; Tmax time to peak concentration A high fat meal is 800-1000 calories, approximately 50% of total calories from fat No clinically significant sulopenem divergence from dose-proportionally was observed over dose range of 400 mg to 2000 mg (0.8 to times the approved recommended sulopenem etzadroxil dosage) Independent of concentration over range of to 100 ug/mL Sulopenem, M1a and M1b, accounted for 32%, 21.8% and 43.6% of circulating radioactivity, respectively After single oral dose of radiolabeled sulopenem etzadroxil 2000 mg healthy adult subjectsSpecific PopulationsNo 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 ImpairmentSulopenem mean plasma AUC0-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 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 StudiesClinical StudiesEffect 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 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 AUC0-tau and Cmax by approximately 25% and 19%, respectively. However, no clinically significant differences in the pharmacokinetics of valproic acid were observed when administered concomitantly with ORLYNVAH. AUC0-tau and Cmax 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 substrate of OAT3 and does not inhibit BCRP, P-gp, BSEP, MATE1, MATE2K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, or OCT2. Probenecid is substrate for BCRP and an inhibitor of OAT1/3, but does not inhibit BSEP, P-gp, or MRP2.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE ORLYNVAH, combination of sulopenem etzadroxil, penem antibacterial, and probenecid, 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 UseORLYNVAH 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 BacteriaTo 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). 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). 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 UseORLYNVAH 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 )]. 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 )].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS 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 )] 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 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 controlled, multinational, randomized, double blind, double dummy clinical trials (Trial and Trial 2) in adult women with uUTI. Therapy with oral ORLYNVAH tablets was administered as one tablet twice daily for 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 DiscontinuationSerious 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 ReactionsAdverse reactions occurring at 2% or greater in patients receiving ORLYNVAH were diarrhea, nausea, vulvovaginal mycotic infection, headache, and vomiting.Table lists adverse reactions reported in >=1% of patients receiving ORLYNVAH in the phase uUTI trials (Trial 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 and Trial 2)Adverse ReactionORLYNVAHa N=1932n (%)Amoxicillin/Clavulanateb N=1107n (%)Ciprofloxacinc N=822n (%)Diarrhea1 194 (10)45 (4)21 (3)Nausea80 (4)32 (3)30 (4)Vulvovaginal mycotic infection2 46 (2)13 (1)7 (1)Headache42 (2)17 (2)18 (2)Vomiting29 (2)4 (0.4)11 (1)Abdominal pain3 22 (1)11 (1)9 (1)a ORLYNVAH tablets (sulopenem etzadroxil 500mg probenecid 500mg) tablet twice daily for days; bAmoxicillin/clavulanate tablets (875 mg /125 mg) tablet twice daily for days cCiprofloxacin tablets (250 mg) tablet twice daily for days. Diarrhea includes diarrhea and loose stools. Vulvovaginal mycotic infection includes vulvovaginal mycotic infection, vulvovaginal candidiasis, vaginal infection, fungal infection, genital infection fungal, and yeast infection. 3Abdominal pain includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal discomfort.Other Adverse Reactions of ORLYNVAHThe following selected adverse reactions were reported in the ORLYNVAH-treated patients at rate of <1% in the uUTI Trial and Trial 2:Cardiac disorders: tachycardiaEar and labyrinth disorders: vertigoGastrointestinal disorders: abdominal distension, abnormal feces, constipation, dry mouth, dyspepsia, eructation, feces discolored, feces soft, flatulence, gastroesophageal reflux diseaseGeneral disorders: asthenia, fatigue, malaise, peripheral edema, pain, pyrexiaHepatobiliary disorders: elevated transaminases, hepatomegalyInfections and infestations: bacterial vaginosis, Candida infection, candiduriaMetabolism and nutrition disorders: polydipsiaMusculoskeletal and connective tissue disorders: arthralgia, back pain, myositisNervous system disorders: ageusia, dizziness, dysgeusia, dystonia, migraine, paresthesia, presyncope, somnolence, syncopePsychiatric disorders: confusionRenal and urinary disorders: urine odor abnormalReproductive system and breast disorders: perineal pain, vaginal discharge, vulvovaginal pruritusRespiratory disorders: cough, dyspneaSkin and subcutaneous tissue disorders: angioedema, pruritus, rashVascular disorders: flushing, hypertensionAdverse 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 gumsHematologic: 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, anemiaImmune system disorders: anaphylaxis, urticariaMetabolism and nutrition disorders: precipitation of acute gouty arthritisRenal and urinary disorders: nephrotic syndrome, uric acid stones with or without hematuria, renal colic, costovertebral pain, urinary frequencySkin and subcutaneous tissue disorders: alopecia.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisCarcinogenicity studies in animals have not been conducted with ORLYNVAH.MutagenesisSulopenem EtzadroxilSulopenem etzadroxil was negative for mutations in an in vitro Ames assay with and without metabolic activation but positive for chromosome aberrations with and without metabolic activation in vitro in peripheral human lymphocytes and Chinese hamster ovary cells. In vivo, sulopenem etzadroxil was negative for genetic toxicity in bone marrow micronucleus assay in rats.SulopenemSulopenem did not induce mutations in reverse mutation assay in bacterial cells with and without metabolic activation or in CHO HGPRT mammalian cell mutation assay with and without metabolic activation. Sulopenem was positive for chromosome aberrations in vitro in V79 Chinese hamster lung cells, but negative for genetic toxicity in vivo in bone marrow micronucleus assays in mice and rats.ProbenecidProbenecid was shown to be negative for mutagenicity in an in vitro Ames assay with and without metabolic activation and negative for chromosome aberrations in an in vitro chromosome aberration assay in Chinese hamster ovary cells with and without metabolic activation.Impairment of FertilitySulopenem etzadroxilMale and female fertility and early embryonic development were examined in rats (20/sex/group) orally administered sulopenem etzadroxil in daily doses of 100, 400, or 2000 mg/kg beginning 28 days prior to mating and throughout the mating period in males and for 14 days before mating, throughout the mating period, and until Gestation Day (GD) in females. There were no treatment-related effects on estrous cycle length, mating and fertility rates, implantation, conceptus viability, sperm concentration and motility, or accessory male sex glands weights. No adverse effects on male and female fertility or early embryonic development in female rats were observed at doses up to 2000 mg/kg/day (approximately 10- and 12-times in male and female rats, respectively, the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison).ProbenecidNo fertility studies have been conducted with probenecid.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ORLYNVAH is combination of sulopenem etzadroxil, penem antibacterial drug [see Microbiology 12.4 and probenecid, 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 ElectrophysiologyAt concentration of 40 times or greater than that achieved after single oral administration of ORLYNVAH, sulopenem does not prolong the QTc interval to clinically relevant extent.. 12.3 Pharmacokinetics Sulopenem etzadroxil is 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 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 SubjectsParameterSulopenemProbenecidFastedFeda FastedFeda General InformationExposureb Cmax1.84 (39.1)2.66 (43.6)41.2 (38.2)30.4 (30.9)AUC0-inf4.85 (25.3)7.41 (22.7)255 (35.6)237 (35.2)Dose Proportionalityb Dose ProportionalunknownAccumulationNoneunknownAbsorptionBioavailability40%64%unknownTmaxMedian (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 FoodHigh fat meala (Fed:Fasted ratio)CmaxIncreased 45%Decreased 27%AUC0-infIncreased 48%Decreased 8%DistributionApparent Volume of Distribution (Liters) (mean (SD))134 (51.36)92.09 (33.43)8.81 (3.91)11.94 (3.46)Protein Bindingc 11%UnknownEliminationHalf-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)MetabolismPrimary PathwaySulopenem etzadroxil is hydrolyzed by esterases to active sulopenem then furthermetabolized by hydrolysis followed by dehydrogenationunknownMajor MetabolitesM1a and M1bd (inactive)unknownExcretioneFeces44.3%(26.9% unchanged)unknownUrine40.8%(3.1% unchanged)unknownAbbreviations: Cmax maximum plasma concentration; AUC= area under the time concentration curve; Tmax time to peak concentration A high fat meal is 800-1000 calories, approximately 50% of total calories from fat No clinically significant sulopenem divergence from dose-proportionally was observed over dose range of 400 mg to 2000 mg (0.8 to times the approved recommended sulopenem etzadroxil dosage) Independent of concentration over range of to 100 ug/mL Sulopenem, M1a and M1b, accounted for 32%, 21.8% and 43.6% of circulating radioactivity, respectively After single oral dose of radiolabeled sulopenem etzadroxil 2000 mg healthy adult subjectsSpecific PopulationsNo 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 ImpairmentSulopenem mean plasma AUC0-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 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 StudiesClinical StudiesEffect 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 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 AUC0-tau and Cmax by approximately 25% and 19%, respectively. However, no clinically significant differences in the pharmacokinetics of valproic acid were observed when administered concomitantly with ORLYNVAH. AUC0-tau and Cmax 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 substrate of OAT3 and does not inhibit BCRP, P-gp, BSEP, MATE1, MATE2K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, or OCT2. Probenecid is substrate for BCRP and an inhibitor of OAT1/3, but does not inhibit BSEP, P-gp, or MRP2.. 12.4 Microbiology Mechanism of ActionSulopenem etzadroxil is 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.ResistanceResistance 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 frequency of 1x10- 8.Interaction with Other AntimicrobialsIn 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 ActivitySulopenem 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 mirabilisThe 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 agalactiaeGram-negative bacteria Citrobacter freundii Citrobacter koseri Enterobacter cloacae species Complex Klebsiella aerogenes Klebsiella oxytoca Proteus vulgaris Providencia alcalifaciens Providencia stuartiiSusceptibility TestingFor 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.

CLINICAL STUDIES SECTION.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 controlled, multinational, randomized, double blind, double dummy clinical trials (Trial and Trial 2) in adult women with uUTI. Therapy with oral ORLYNVAH tablets was administered as one tablet twice daily for 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 DiscontinuationSerious 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 ReactionsAdverse reactions occurring at 2% or greater in patients receiving ORLYNVAH were diarrhea, nausea, vulvovaginal mycotic infection, headache, and vomiting.Table lists adverse reactions reported in >=1% of patients receiving ORLYNVAH in the phase uUTI trials (Trial 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 and Trial 2)Adverse ReactionORLYNVAHa N=1932n (%)Amoxicillin/Clavulanateb N=1107n (%)Ciprofloxacinc N=822n (%)Diarrhea1 194 (10)45 (4)21 (3)Nausea80 (4)32 (3)30 (4)Vulvovaginal mycotic infection2 46 (2)13 (1)7 (1)Headache42 (2)17 (2)18 (2)Vomiting29 (2)4 (0.4)11 (1)Abdominal pain3 22 (1)11 (1)9 (1)a ORLYNVAH tablets (sulopenem etzadroxil 500mg probenecid 500mg) tablet twice daily for days; bAmoxicillin/clavulanate tablets (875 mg /125 mg) tablet twice daily for days cCiprofloxacin tablets (250 mg) tablet twice daily for days. Diarrhea includes diarrhea and loose stools. Vulvovaginal mycotic infection includes vulvovaginal mycotic infection, vulvovaginal candidiasis, vaginal infection, fungal infection, genital infection fungal, and yeast infection. 3Abdominal pain includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal discomfort.Other Adverse Reactions of ORLYNVAHThe following selected adverse reactions were reported in the ORLYNVAH-treated patients at rate of <1% in the uUTI Trial and Trial 2:Cardiac disorders: tachycardiaEar and labyrinth disorders: vertigoGastrointestinal disorders: abdominal distension, abnormal feces, constipation, dry mouth, dyspepsia, eructation, feces discolored, feces soft, flatulence, gastroesophageal reflux diseaseGeneral disorders: asthenia, fatigue, malaise, peripheral edema, pain, pyrexiaHepatobiliary disorders: elevated transaminases, hepatomegalyInfections and infestations: bacterial vaginosis, Candida infection, candiduriaMetabolism and nutrition disorders: polydipsiaMusculoskeletal and connective tissue disorders: arthralgia, back pain, myositisNervous system disorders: ageusia, dizziness, dysgeusia, dystonia, migraine, paresthesia, presyncope, somnolence, syncopePsychiatric disorders: confusionRenal and urinary disorders: urine odor abnormalReproductive system and breast disorders: perineal pain, vaginal discharge, vulvovaginal pruritusRespiratory disorders: cough, dyspneaSkin and subcutaneous tissue disorders: angioedema, pruritus, rashVascular disorders: flushing, hypertensionAdverse 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 gumsHematologic: 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, anemiaImmune system disorders: anaphylaxis, urticariaMetabolism and nutrition disorders: precipitation of acute gouty arthritisRenal and urinary disorders: nephrotic syndrome, uric acid stones with or without hematuria, renal colic, costovertebral pain, urinary frequencySkin and subcutaneous tissue disorders: alopecia.

DRUG INTERACTIONS SECTION.

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). 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 and (OAT1/3) and may increase plasma concentrations of drugs that are dependent on OAT1/3 for elimination. Table provides list of established or potentially clinically significant drug interactions.Table 2. Established and Other Potentially Clinically Significant Drug InteractionsConcomitant Drug/Drug ClassEffect on Drug ConcentrationRecommendationKetorolac tromethamine ketorolac tromethamineContraindicatedKetoprofen ketoprofenConcomitant use is not recommended.Indomethacin indomethacinMay increase the risk of adverse reactions. Refer to drug-specific prescribing information for dosage adjustment instructions.Naproxen naproxenMay increase the risk of adverse reactions. Refer todrug-specific prescribing information for dosage adjustment instructions.Methotrexate methotrexateIf concomitant use cannot be avoided, monitor more frequently for adverse reactions associated with methotrexate as recommended in its prescribing information.Rifampin rifampinMonitor more frequently for adverse reactionsassociated with rifampin as recommended in its prescribing information.Lorazepam lorazepamFollow the recommended lorazepam dosage modifications outlined in its prescribing information.Oral Sulfonylureas antidiabeticMonitor more frequently for hypoglycemia. Follow recommended sulfonylurea dosage modifications in its prescribing information.Valproic AcidNo 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 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 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Allergic ReactionsAdvise patients that allergic reactions, including serious allergic reactions, could occur, and that serious allergic reactions require immediate treatment. Patients should inform their healthcare provider about any previous hypersensitivity reactions to ORLYNVAH, other beta-lactam antibacterial drugs or probenecid [see Warnings and Precautions 5.1 )]. DiarrheaAdvise patients that diarrhea is common problem caused by antibacterial drugs, including ORLYNVAH, and usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be sign of more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider [see Warnings and Precautions 5.2 and Adverse Reactions 6.1 )]. Antibacterial ResistancePatients should be counseled that ORLYNVAH should only be used to treat proven or strongly suspected susceptible uUTI. Antibacterial drugs do not treat viral infections (e.g., the common cold). When ORLYNVAH is prescribed to treat proven or strongly suspected susceptible uUTI, patients should be told that although it is common to feel better early in the course of therapy, ORLYNVAH should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ORLYNVAH or other antibacterial drugs in the future [see Warnings and Precautions 5.5 )]. KetoprofenAdvise patients that concomitant use of ketoprofen with ORLYNVAH is not recommended [see Drug Interactions 7.1 )]. Manufactured for: Iterum Therapeutics U.S. Limited, Chicago, IL 60606US Patent Numbers: Available online at https://www.iterumtx.com/ORLYNVAHTM is registered trademark of Iterum Therapeutics.

MICROBIOLOGY SECTION.

12.4 Microbiology Mechanism of ActionSulopenem etzadroxil is 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.ResistanceResistance 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 frequency of 1x10- 8.Interaction with Other AntimicrobialsIn 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 ActivitySulopenem 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 mirabilisThe 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 agalactiaeGram-negative bacteria Citrobacter freundii Citrobacter koseri Enterobacter cloacae species Complex Klebsiella aerogenes Klebsiella oxytoca Proteus vulgaris Providencia alcalifaciens Providencia stuartiiSusceptibility TestingFor 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisCarcinogenicity studies in animals have not been conducted with ORLYNVAH.MutagenesisSulopenem EtzadroxilSulopenem etzadroxil was negative for mutations in an in vitro Ames assay with and without metabolic activation but positive for chromosome aberrations with and without metabolic activation in vitro in peripheral human lymphocytes and Chinese hamster ovary cells. In vivo, sulopenem etzadroxil was negative for genetic toxicity in bone marrow micronucleus assay in rats.SulopenemSulopenem did not induce mutations in reverse mutation assay in bacterial cells with and without metabolic activation or in CHO HGPRT mammalian cell mutation assay with and without metabolic activation. Sulopenem was positive for chromosome aberrations in vitro in V79 Chinese hamster lung cells, but negative for genetic toxicity in vivo in bone marrow micronucleus assays in mice and rats.ProbenecidProbenecid was shown to be negative for mutagenicity in an in vitro Ames assay with and without metabolic activation and negative for chromosome aberrations in an in vitro chromosome aberration assay in Chinese hamster ovary cells with and without metabolic activation.Impairment of FertilitySulopenem etzadroxilMale and female fertility and early embryonic development were examined in rats (20/sex/group) orally administered sulopenem etzadroxil in daily doses of 100, 400, or 2000 mg/kg beginning 28 days prior to mating and throughout the mating period in males and for 14 days before mating, throughout the mating period, and until Gestation Day (GD) in females. There were no treatment-related effects on estrous cycle length, mating and fertility rates, implantation, conceptus viability, sperm concentration and motility, or accessory male sex glands weights. No adverse effects on male and female fertility or early embryonic development in female rats were observed at doses up to 2000 mg/kg/day (approximately 10- and 12-times in male and female rats, respectively, the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison).ProbenecidNo fertility studies have been conducted with probenecid.. 13.2 Animal Toxicology and/or Pharmacology In toxicology study in monkeys, daily oral administration of sulopenem etzadroxil for 30 days was associated with reduced red blood cell counts and increased reticulocytes at doses of >= 400 mg/kg/day (approximately 6-times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on AUC comparison). In the same animals, positive Coombs assay results demonstrated positive reactions for polyspecific anti-human globulin and anti-IgG suggesting red cell loss may have been mediated by antibodies. Similar findings were also observed in toxicology studies with sulopenem administered intravenously to monkeys.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummarySulopenem EtzadroxilThere are no available data on sulopenem etzadroxil use in pregnant women to evaluate for 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 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 and 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.ProbenecidAvailable published data over several decades of probenecid use in pregnant woman have not identified 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 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.DataAnimal DataSulopenem 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 to GD 15. Reduced fetal body weights and 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 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 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 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 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 mg/kg/day (approximately 0.1-times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison).In pre- postnatal study in rats, sulopenem etzadroxil was administered by oral gavage to pregnant females from GD 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).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk SummarySulopenem EtzadroxilThere are no available data on sulopenem etzadroxil use in pregnant women to evaluate for 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 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 and 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.ProbenecidAvailable published data over several decades of probenecid use in pregnant woman have not identified 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 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.DataAnimal DataSulopenem 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 to GD 15. Reduced fetal body weights and 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 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 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 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 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 mg/kg/day (approximately 0.1-times the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison).In pre- postnatal study in rats, sulopenem etzadroxil was administered by oral gavage to pregnant females from GD 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 SummaryThere 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 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 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 mothers 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 DataIn toxicology study with juvenile rats, sulopenem etzadroxil was orally administered from postnatal day (PND) 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 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS 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 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). 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 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 and 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 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 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 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 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 )].