Sulopenem Etzadroxil And Probenecid

1 INDICATIONS AND USAGE 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 )].

2 DOSAGE AND ADMINISTRATION The recommended dosage of ORLYNVAH is one tablet orally twice daily for 5 days. ( 2.1 ) Administration of ORLYNVAH with food is recommended. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of ORLYNVAH is one tablet (sulopenem etzadroxil 500 mg and probenecid 500 mg) orally twice daily for 5 days. Administration of ORLYNVAH with food is recommended [see Clinical Pharmacology ( 12.3 )]. 2.2 Recommended Dosage in Patients with Renal Impairment Administration of ORLYNVAH is not recommended in patients with creatinine clearance (CrCL) less than 15 mL/min or patients on hemodialysis. No dosage adjustment is required for ORLYNVAH in patients with CrCL greater than or equal to15 mL/min [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. 2.3 Recommendations Regarding Missed Dose(s) If a dose of ORLYNVAH is missed, instruct patients to take the dose as soon as possible. Do not double the dose to make up for the missed dose.

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 )] 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

12.3 Pharmacokinetics Sulopenem etzadroxil is a prodrug [see Microbiology 12.4 ]. The pharmacokinetics of sulopenem and probenecid were characterized in healthy subjects following single oral administration of ORLYNVAH (500 mg sulopenem etzadroxil and 500 mg probenecid). Pharmacokinetic parameters are presented in Table 3 as mean [coefficient of variation (%CV)] unless otherwise specified. Table 3. Pharmacokinetics of Sulopenem and Probenecid in Plasma after Single Oral Dose Administration of ORLYNVAH in Healthy Subjects Parameter Sulopenem Probenecid Fasted Fed a Fasted Fed a General Information Exposure b C max 1.84 (39.1) 2.66 (43.6) 41.2 (38.2) 30.4 (30.9) AUC 0-inf 4.85 (25.3) 7.41 (22.7) 255 (35.6) 237 (35.2) Dose Proportionality b Dose Proportional unknown Accumulation None unknown Absorption Bioavailability 40% 64% unknown T max Median (range) 1.0 (0.5 to 3.0) 2.0 (1.0 -3.0) 3.0 (1.0 – 10.0) 2.0 (1.50 to 6.0) Effect of Food High fat meal a (Fed:Fasted ratio) C max Increased 45% Decreased 27% AUC 0-inf Increased 48% Decreased 8% Distribution Apparent Volume of Distribution (Liters) (mean (SD)) 134 (51.36) 92.09 (33.43) 8.81 (3.91) 11.94 (3.46) Protein Binding c 11% Unknown Elimination Half-Life (hours) (mean (SD)) 1.18 (0.24) 1.28 (0.49) 2.93 (0.83) 3.83 (0.50) Apparent Clearance (L/hour) (mean (SD)) 77.6 (19.77) 50.55 (11.60) 2.06 (0.70) 2.22 (0.76) Metabolism Primary Pathway Sulopenem etzadroxil is hydrolyzed by esterases to active sulopenem then further metabolized by hydrolysis followed by dehydrogenation unknown Major Metabolites M1a and M1b d (inactive) unknown Excretion e Feces 44.3% (26.9% unchanged) unknown Urine 40.8% (3.1% unchanged) unknown Abbreviations : C max = maximum plasma concentration; AUC= area under the time concentration curve; T max = time to peak concentration a A high fat meal is 800-1000 calories, approximately 50% of total calories from fat b No clinically significant sulopenem divergence from dose-proportionally was observed over a dose range of 400 mg to 2000 mg (0.8 to 4 times the approved recommended sulopenem etzadroxil dosage) c Independent of concentration over a range of 1 to 100 µg/mL d Sulopenem, M1a and M1b, accounted for 32%, 21.8% and 43.6% of circulating radioactivity, respectively e After a single oral dose of radiolabeled sulopenem etzadroxil 2000 mg healthy adult subjects Specific Populations No clinically significant differences in the pharmacokinetics of sulopenem were observed based on age, sex or weight. The effect of hepatic impairment on sulopenem pharmacokinetics is unknown. Patients with Renal Impairment Sulopenem mean plasma AUC 0-inf increased by 2-fold in patients with mild (CrCL 60 to 89 mL/min), estimated by Cockcroft-Gault equation), by 3-fold in patients with moderate (CrCL 30 to 59 mL/min) and by 7.4-fold in patients with severe (CrCL15 to 29 mL/min) renal impairment following administration of 1000 mg oral sulopenem etzadroxil (not a recommended dosing regimen) [see Dosage and Administration ( 2.1 )]. The effect of kidney failure (CrCL<15 mL/min) or hemodialysis on sulopenem pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies Effect of Other Drugs on the Pharmacokinetics of ORLYNVAH: No clinically significant differences in the pharmacokinetics of sulopenem were observed when ORLYNVAH was administered concomitantly with oral itraconazole (P-gp inhibitor), pantoprazole (gastric-acid reducing agent) or aluminum hydroxide (gastric acid-reducing agent). No clinically significant differences in the pharmacokinetics of valproic acid were observed when used concomitantly with ORLYNVAH. Although there are case reports in the published literature that suggest concomitant use of carbapenems result in a reduction in valproic acid concentrations, the probenecid component of ORLYNVAH appears to counteract any potential effect of sulopenem on valproic acid [see Drug Interactions ( 7.1 )]. Effect of ORLYNVAH on the Pharmacokinetics of Other Drugs: Coadministration of multiple doses of 500 mg sulopenem etzadroxil with valproic acid decreased valproic acid plasma AUC 0-tau and C max by approximately 25% and 19%, respectively. However, no clinically significant differences in the pharmacokinetics of valproic acid were observed when administered concomitantly with ORLYNVAH. AUC 0-tau and C max decreased by 8.4% and 7%, respectively, with concomitant administration of ORLYNVAH. In Vitro Studies CYP450 Enzymes: Sulopenem does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A or induce CYP1A2, CYP2B6, or CYP3A4/5. Transporter Systems: Sulopenem is a substrate of OAT3 and does not inhibit BCRP, P-gp, BSEP, MATE1, MATE2K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, or OCT2. Probenecid is a substrate for BCRP and an inhibitor of OAT1/3, but does not inhibit BSEP, P-gp, or MRP2.