PROBENECID: 94 Adverse Event Reports & Safety Profile

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

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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span>. Complicated intra-abdominal infections (cIAI)) or as step-down treatment after intravenous antibacterial treatment of cIAI <span class="opacity-50 text-xs">[see Clinical Studies ( 14.3 )]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span>.

DOSAGE AND ADMINISTRATION Gout Therapy with probenecid should not be started until an acute gouty attack has subsided. However, if an acute attack is precipitated during therapy, probenecid may be continued without changing the dosage, and full therapeutic dosage of colchicine or other appropriate therapy should be given to control the acute attack. The recommended adult dosage is 250 mg (1/2 tablet of probenecid) twice a day for one week, followed by 500 mg (1 tablet) twice a day thereafter. Some degree of renal impairment may be present in patients with gout. A daily dosage of 1000 mg may be adequate. However, if necessary, the daily dosage may be increased by 500 mg increments every 4 weeks within tolerance (and usually not above 2000 mg per day) if symptoms of gouty arthritis are not controlled or the 24 hour uric acid excretion is not above 700 mg. As noted, probenecid may not be effective in chronic renal insufficiency, particularly when the glomerular filtration rate is 30 mL/minute or less. Gastric intolerance may be indicative of overdosage, and may be corrected by decreasing the dosage. As uric acid tends to crystallize out of an acid urine, a liberal fluid intake is recommended, as well as sufficient sodium bicarbonate (3 to 7.5 g daily), or potassium citrate (7.5 g daily) to maintain an alkaline urine (see PRECAUTIONS ). Alkalization of the urine is recommended until the serum urate level returns to normal limits and tophaceous deposits disappear, i.e., during the period when urinary excretion of uric acid is at a high level. Thereafter, alkalization of the urine and the usual restriction of purine-producing foods may be somewhat relaxed. Probenecid should be continued at the dosage that will maintain normal serum urate levels. When acute attacks have been absent for 6 months or more and serum urate levels remain within normal limits, the daily dosage may be decreased by 500 mg every 6 months. The maintenance dosage should not be reduced to the point where serum urate levels tend to rise. Probenecid and Penicillin Therapy (General)

Adults

The recommended dosage is 2000 mg (4 tablets of probenecid) daily in divided doses. This dosage should be reduced in older patients in whom renal impairment may be present.

Children

2 to 14 years of age Initial dose: 25 mg/kg body weight ( or 0.7 g/square meter body surface). Maintenance dose: 40 mg/kg body weight ( or 1.2 g/square meter body surface) per day, divided into 4 doses. For children weighing more than 50 kg (110 lb) the adult dosage is recommended. Probenecid is contraindicated in children under 2 years of age. The PSP excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. The renal clearance of PSP is reduced to about one-fifth the normal rate when dosage of probenecid is adequate.

Penicillin

Therapy (Gonorrhea)* In uncomplicated gonococcal infections in men and women (urethral, cervical, rectal), 1 g of probenecid should be given orally with 4.8 million units of aqueous procaine penicillin G ** (given IM), or 3 g of amoxicillin ** (given orally), or 3.5 g of ampicillin ** (given orally). For further guidance, see CDC recommendations for definition of regimens of choice, alternative regimens, treatment of hypersensitive patients, and other aspects of therapy. * Recommended by the Centers for Disease Control, U.S. Department of Health and Human Services, Public Health Service (Morbidity and Mortality Weekly Report Supplement, Volume 34, Number 4S, October 18, 1985). ** See package circulars of manufacturers for detailed information about CONTRAINDICATIONS , WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS .

ORLYNVAH is contraindicated in patients with:

• A history of hypersensitivity to the components of ORLYNVAH (sulopenem etzadroxil and probenecid) or other beta-lactam antibacterial drugs [see Warnings and Precautions ( 5.1 )]
• Known uric acid kidney stones [see Warnings and Precautions ( 5.3 )] Concomitant use of ORLYNVAH and ketorolac tromethamine is contraindicated [see Drug Interactions ( 7.1 )] Patients with a history of hypersensitivity to the components of ORLYNVAH (sulopenem etzadroxil and probenecid) or other beta- lactam antibacterial drugs. ( 4 ) Patients with known uric acid kidney stones. ( 4 ) Concomitant use of ORLYNVAH and ketorolac tromethamine is contraindicated. ( 4 )

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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span>. 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

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

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 <span class="opacity-50 text-xs">[see Indications and Usage ( 1.2 )]</span>.

PRECAUTIONS GENERAL PRECAUTIONS Hematuria, renal colic, costovertebral pain, and formation of uric acid stones associated with the use of probenecid in gouty patients may be prevented by alkalization of the urine and a liberal fluid intake (see DOSAGE AND ADMINISTRATION ). In these cases when alkali is administered, the acid-base balance of the patient should be watched. Use with caution in patients with a history of peptic ulcer. Probenecid has been used in patients with some renal impairment but dosage requirements may be increased. Probenecid may not be effective in chronic renal insufficiency particularly when the glomerular filtration rate is 30 mL/minute or less. Because of its mechanism of action, probenecid is not recommended in conjunction with a penicillin in the presence of known renal impairment. A reducing substance may appear in the urine of patients receiving probenecid. This disappears with discontinuance of therapy. Suspected glycosuria should be confirmed by using a test specific for glucose.

Drug Interactions

When probenecid is used to elevate plasma concentrations of penicillin or other beta-lactams, or when such drugs are given to patients taking probenecid therapeutically, high plasma concentrations of the other drug may increase the incidence of adverse reactions associated with that drug. In the case of penicillin or other beta-lactams, psychic disturbances have been reported. The use of salicylates antagonizes the uricosuric action of probenecid (see WARNINGS ). The uricosuric action of probenecid is also antagonized by pyrazinamide. Probenecid produces an insignificant increase in free sulfonamide plasma concentrations but a significant increase in total sulfonamide plasma levels. Since probenecid decreases the renal excretion of conjugated sulfonamides, plasma concentrations of the latter should be determined from time to time when a sulfonamide and probenecid are coadministered for prolonged periods. Probenecid may prolong or enhance the action of oral sulfonylureas and thereby increase the risk of hypoglycemia. It has been reported that patients receiving probenecid require significantly less thiopental for induction of anesthesia. In addition, ketamine and thiopental anesthesia were significantly prolonged in rats receiving probenecid. The concomitant administration of probenecid increases the mean plasma elimination half-life of a number of drugs which can lead to increased plasma concentrations. These include agents such as indomethacin, acetaminophen, naproxen, ketoprofen, meclofenamate, lorazepam, and rifampin. Although the clinical significance of this observation has not been established, a lower dosage of the drug may be required to produce a therapeutic effect, and increases in dosage of the drug in question should be made cautiously and in small increments when probenecid is being co-administered. Although specific instances of toxicity due to this potential interaction have not been observed to date, physicians should be alert to this possibility. Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest reduction in the uricosuric action of probenecid, which probably is not significant under most circumstances. In animals and in humans, probenecid has been reported to increase plasma concentrations of methotrexate (see WARNINGS ). 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 were added to human plasma.

INTERACTIONS 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. If concomitant use with ORLYNVAH is necessary, monitor more frequently for adverse reactions associated with ORLYNVAH (e.g., diarrhea and nausea) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>.

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.