ORLYNVAH

ORLYNVAH (sulopenem etzadroxil and probenecid) tablets contain sulopenem etzadroxil, a penem antibacterial drug, and probenecid, a renal tubular transport inhibitor . The chemical name of sulopenem etzadroxil is 4-Thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 6-[(1 R )-1- hydroxyethyl]-7-oxo-3-[[(1 R ,3 S )- tetrahydro-1-oxido-3-thienyl]thio]-, (2-ethyl-1-oxobutoxy)methyl ester, (5 R ,6 S )-. See Figure 1 for sulopenem etzadroxil chemical structure and chemical formula. The molecular weight of sulopenem etzadroxil is 477.61 g/mol. Figure 1. Sulopenem Etzadroxil Chemical Structure and Formula The chemical name for probenecid is 4-[(dipropylamino) sulfonyl] benzoic acid. See Figure 2 for probenecid chemical structure and chemical formula. The molecular weight of probenecid is 285.36 g/mol. Figure 2. Probenecid Chemical Structure and Formula ORLYNVAH are pink bilayer tablets for oral use containing 500 mg of sulopenem etzadroxil and 500 mg of probenecid and the following inactive ingredients: croscarmellose sodium, hydroxypropylcellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating contains carmine, lecithin polyvinyl alcohol, talc, titanium dioxide, and xanthan gum. Figure 1 Figure 2

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 Esch erichia 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 )] .

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 to 15 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.

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 blood dyscrasias 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 blood dyscrasias. ( 4 ) Patients with known uric acid kidney stones. ( 4 ) Concomitant use of ORLYNVAH and ketorolac tromethamine is contraindicated. ( 4 )

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 [ s ee 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 c Ciprofloxacin 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 d isorders : tachycardia Ear and lab yrinth 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 diso rders: 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 di sorders: 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.

16.2 Storage and Handling Store ORLYNVAH tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room temperature].