ORLYNVAH

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 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 )].

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

<table><caption>Table 1. Adverse Reactions Occurring in &#x2265; 1% of Patients Receiving ORLYNVAH in the Uncomplicated Urinary Tract Infection Clinical Trials (Trial 1 and Trial 2)</caption><col width="136"/><col width="138"/><col width="158"/><col width="138"/><tbody><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Adverse</content><content styleCode="bold"> </content><content styleCode="bold">Reaction</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">ORLYNVAH</content><content styleCode="bold">^a</content><content styleCode="bold"> N=1932</content> <content styleCode="bold">n</content><content styleCode="bold"> </content><content styleCode="bold">(%)</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Amoxicillin/Clavulanate</content><content styleCode="bold">^b</content><content styleCode="bold"> N=1107</content> <content styleCode="bold">n</content><content styleCode="bold"> </content><content styleCode="bold">(%)</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Ciprofloxacin</content><content styleCode="bold">^c</content><content styleCode="bold"> N=822</content> <content styleCode="bold">n</content><content styleCode="bold"> </content><content styleCode="bold">(%)</content></td></tr><tr><td styleCode="Toprule Lrule Rrule ">Diarrhea¹</td><td styleCode="Toprule Lrule Rrule " align="center">194 (10)</td><td styleCode="Toprule Lrule Rrule " align="center">45 (4)</td><td styleCode="Toprule Lrule Rrule " align="center">21 (3)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Nausea</td><td styleCode="Toprule Lrule Rrule " align="center">80 (4)</td><td styleCode="Toprule Lrule Rrule " align="center">32 (3)</td><td styleCode="Toprule Lrule Rrule " align="center">30 (4)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Vulvovaginal mycotic infection²</td><td styleCode="Toprule Lrule Rrule " align="center">46 (2)</td><td styleCode="Toprule Lrule Rrule " align="center">13 (1)</td><td styleCode="Toprule Lrule Rrule " align="center">7 (1)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Headache</td><td styleCode="Toprule Lrule Rrule " align="center">42 (2)</td><td styleCode="Toprule Lrule Rrule " align="center">17 (2)</td><td styleCode="Toprule Lrule Rrule " align="center">18 (2)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Vomiting</td><td styleCode="Toprule Lrule Rrule " align="center">29 (2)</td><td styleCode="Toprule Lrule Rrule " align="center">4 (0.4)</td><td styleCode="Toprule Lrule Rrule " align="center">11 (1)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Abdominal pain³</td><td styleCode="Toprule Lrule Rrule " align="center">22 (1)</td><td styleCode="Toprule Lrule Rrule " align="center">11 (1)</td><td styleCode="Toprule Lrule Rrule " align="center">9 (1)</td></tr><tr><td styleCode="Toprule " colspan="4">^a ORLYNVAH tablets (sulopenem etzadroxil 500mg / probenecid 500mg) 1 tablet twice daily for 5 days; ^bAmoxicillin/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. ³Abdominal pain includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal discomfort.</td></tr></tbody></table>