Sulopenem etzadroxil, probenecid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]
Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
Overview
Sulopenem etzadroxil, probenecid is a Probenecid inhibits OAT3 that is FDA approved 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.. Common adverse reactions include diarrhea, nausea, vulvovaginal mycotic infection, headache, and vomiting..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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.
- Complicated intra-abdominal infections (cIAI)) or as step-down treatment after intravenous antibacterial treatment of cIAI.
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.
DOSAGE AND ADMINISTRATION
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.
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.
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.
DOSAGE FORMS AND STRENGTHS
- ORLYNVAH (sulopenem etzadroxil 500 mg and probenecid 500 mg) tablets are supplied as pink, ovalshaped, film-coated, fixed-dose, bilayer combination tablets debossed with SULO on one side and plain on the other side.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sulopenem etzadroxil, probenecid in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulopenem etzadroxil, probenecid in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sulopenem etzadroxil, probenecid FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sulopenem etzadroxil, probenecid in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulopenem etzadroxil, probenecid in pediatric patients.
Contraindications
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.
- Known blood dyscrasias.
- Known uric acid kidney stones.
Concomitant use of ORLYNVAH and ketorolac tromethamine is contraindicated.
Warnings
Hypersensitivity Reactions
*Hypersensitivity reactions, specifically cases of angioedema, have been reported in patients treated with ORLYNVAH.
- Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs.
- Before therapy with ORLYNVAH is instituted, carefully inquire about previous hypersensitivity reactions to other carbapenems, cephalosporins, penicillins, or other beta-lactams because crosshypersensitivity 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.
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.
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.
- 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.
- 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.
Adverse Reactions
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. 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.
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 1and 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, Skin and subcutaneous tissue disorders: alopecia.
Postmarketing Experience
There is limited information regarding Sulopenem etzadroxil, probenecid Postmarketing Experience in the drug label.
Drug Interactions
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.
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.
Potential for Other Drugs to Affect ORLYNVAH
- Sulopenem is a substrate of OAT3; therefore, drugs that inhibit OAT3 may increase sulopenem plasma concentrations.
*If concomitant use with ORLYNVAH is necessary, monitor more frequently for adverse reactions associated with ORLYNVAH (e.g., diarrhea and nausea.
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.
Use in Specific Populations
Pregnancy
Risk Summary
Sulopenem Etzadroxil
- There are no available data on sulopenem etzadroxil use in pregnant women to evaluate for a 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 a 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 2 and 6 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.
Probenecid
- Available published data over several decades of probenecid use in pregnant woman have not identified a drugassociated 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 a 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.
Data
Animal Data
Sulopenem 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 6 to GD 15. Reduced fetal body weights and a 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 3 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 6 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 2 times respectively the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil based on plasma AUC comparison).
- In a pre- postnatal study in rats, sulopenem etzadroxil was administered by oral gavage to pregnant females from GD 6 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).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sulopenem etzadroxil, probenecid in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Sulopenem etzadroxil, probenecid during labor and delivery.
Nursing Mothers
Risk Summary
- There 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 a 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 a 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 mother’s clinical
need for ORLYNVAH and any potential adverse effects on the breast-fed child from ORLYNVAH or from the underlying maternal condition.
Pediatric Use
- The safety and effectiveness of ORLYNVAH in pediatric patients have not been established.
Juvenile Animal Toxicity Data
- In a toxicology study with juvenile rats, sulopenem etzadroxil was orally administered from postnatal day (PND) 5
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).
Geriatic 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 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.
- 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.
Gender
There is no FDA guidance on the use of Sulopenem etzadroxil, probenecid with respect to specific gender populations.
Race
There is no FDA guidance on the use of Sulopenem etzadroxil, probenecid with respect to specific racial populations.
Renal Impairment
Increases in sulopenem plasma concentrations were observed with mild, moderate and severe renal impairment; however, the available safety information does not suggest a need for dosage adjustments in these patients.
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.
Hepatic Impairment
There is no FDA guidance on the use of Sulopenem etzadroxil, probenecid in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sulopenem etzadroxil, probenecid in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Sulopenem etzadroxil, probenecid in patients who are immunocompromised.
Administration and Monitoring
Administration
DOSAGE AND ADMINISTRATION
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.
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.
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.
Monitoring
Concomitant use of ORLYNVAH and ketorolac tromethamine is contraindicated.
- monitor more frequently for adverse reactions associated with methotrexate as recommended in its prescribing
information.
IV Compatibility
There is limited information regarding the compatibility of Sulopenem etzadroxil, probenecid and IV administrations.
Overdosage
- There is no information on clinical signs and symptoms associated with an overdose of ORLYNVAH. No clinical
information is available on the use of hemodialysis to treat ORLYNVAH overdosage.
Pharmacology
There is limited information regarding Sulopenem etzadroxil, probenecid Pharmacology in the drug label.
Mechanism of Action
ORLYNVAH is a combination of sulopenem etzadroxil, a penem antibacterial drug and probenecid, a renal tubular inhibitor. Probenecid inhibits OAT3-mediated renal clearance of sulopenem, resulting in increased plasma concentrations of sulopenem.
Structure
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- [ ( 1R ) -1- hydroxyethyl ] -7-oxo-3 - [ [ ( 1R,3S )- tetrahydro-1-oxido-3-thienyl ] thio ] -, ( 2-ethyl-1-oxobutoxy ) methyl ester, ( 5R,6S ) -. See Figure 1 for sulopenem etzadroxil chemical structure and chemical formula. The molecular weight of sulopenem etzadroxil is 477.61 g/mol.
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.
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.
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 Electrophysiology
- At a concentration of 40 times or greater than that achieved after a single oral administration of ORLYNVAH,
sulopenem does not prolong the QTc interval to a clinically relevant extent.
Pharmacokinetics
Sulopenem etzadroxil is a prodrug . 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.
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 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 a recommended dosing regimen). 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.
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.
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.
Nonclinical Toxicology
There is limited information regarding Sulopenem etzadroxil, probenecid Nonclinical Toxicology in the drug label.
Clinical Studies
Uncomplicated Urinary Tract Infections
====Trial 1====
- A total of 2222 adult women with uncomplicated urinary tract infections (uUTI) were randomized and 2214 received trial medications in a randomized, double-blind clinical trial (Trial 1) (NCT05584657) comparing oral ORLYNVAH (sulopenem etzadroxil 500 mg and probenecid 500 mg) twice daily for 5 days to oral amoxicillin/clavulanate 875 mg/125 mg twice daily for 5 days.
- The microbiological modified intent-to-treat (micro-MITT) population, which included all patients who had at least one uropathogen isolated at baseline (≥105 CFU/mL) and received at least one dose of study drug, consisted of 990 patients; the median age was 51 years and median weight was 73.5 kg. Patients were enrolled only from the United States. Patients were Caucasian (79.7%), African American (17.0%) or of another race (3.3%).
- Composite response (combined microbiological response and clinical cure rates) was determined by comparing the response rate of ORLYNVAH to amoxicillin/clavulanate at the TOC visit (12 days after randomization) in the micro-MITT population as well as in two sub-populations: a) micro-MITTS (micro-MITT population with baseline pathogens susceptible to amoxicillin/clavulanate, MIC ≤8/4 µg/mL) and b) micro-MITTR (micro-MITT population with baseline pathogens non-susceptible to amoxicillin/clavulanate, MIC ≥16/8 µg/mL). Clinical cure was defined as the resolution of patient-reported uUTI symptoms and no new uUTI symptoms. Microbiological response was defined as a reduction of all baseline uropathogens to less than 103 CFU/mL in the urine.
- ORLYNVAH demonstrated efficacy in the micro-MITTS population. The micro-MITTR population was small (N=67) and had insufficient power to draw conclusions regarding efficacy (Table 4). Table 4.
A total of 1660 adult women with uUTI were randomized and received trial medications in a multinational randomized, double-blind clinical trial (Trial 2) (NCT03354598) comparing oral ORLYNVAH (sulopenem etzadroxil 500 mg and probenecid 500 mg) twice daily for 5 days to oral ciprofloxacin 250 mg twice daily for 3 days. The micro-MITT population, which included all patients who had at least one uropathogen isolated at baseline (≥105 CFU/mL), consisted of 1105 patients; the median age was 53 years; median weight in the randomized population was 70.4 kg. Patients were enrolled from the United States (55%) and Eastern Europe (45%). Patients were Caucasian (90%), African American (9%) or of other races (1%). Composite response (combined microbiological response and clinical cure) was determined by comparing the response rate of ORLYNVAH to ciprofloxacin at the TOC visit (12 days after randomization) in two primary populations: a) micro-MITTS (micro-MITT population with baseline pathogens susceptible to ciprofloxacin, MIC ≤1 µg/mL) and b) micro-MITTR (micro-MITT population with baseline pathogens non-susceptible to ciprofloxacin, MIC ≥2 µg/mL). Clinical cure was defined as the resolution of patient-reported uUTI symptoms and no new uUTI symptoms. Microbiological response was defined as a reduction of all baseline uropathogens to less than 103 CFU/mL in the urine. ORLYNVAH demonstrated efficacy in the micro-MITTR population but did not demonstrate efficacy in the microMITTS population (Table 6).
Complicated Urinary Tract Infections - Lack of Efficacy
- ORLYNVAH is not indicated for the treatment of complicated urinary tract infections. Trial 3 (NCT03357614) was a phase 3, multi-center, double-blind, randomized trial designed to compare the efficacy, tolerability, and safety of IV sulopenem followed by oral sulopenem etzadroxil and probenecid with that of IV ertapenem followed by oral ciprofloxacin or amoxicillin/clavulanate for the treatment of complicated urinary tract infections (cUTI). Trial 3 did not demonstrate the efficacy of sulopenem IV followed by oral sulopenem etzadroxil and probenecid for the primary endpoint of composite response (combined clinical and microbiologic response) in the microbiologic modified intentto-treat (micro-MITT) population at the test-of-cure visit on Day 21.
Complicated Intra-abdominal Infections - Lack of Efficacy
- ORLYNVAH is not indicated for the treatment of complicated intra-abdominal infections. Trial 4 (NCT03358576)
was a phase 3, multi-center, double-blind, randomized trial designed to compare the efficacy, tolerability, and safety of IV sulopenem followed by oral sulopenem etzadroxil and probenecid with that of IV ertapenem followed by oral ciprofloxacin and metronidazole or amoxicillin/clavulanate for the treatment of complicated intra-abdominal infections (cIAI). Trial 4 did not demonstrate the efficacy of IV sulopenem followed by oral sulopenem etzadroxil and probenecid for the primary endpoint of clinical response in the micro-MITT at the test-of-cure visit on Day 28.
How Supplied
ORLYNVAH tablets are supplied as pink, oval-shaped, film-coated, fixed-dose, bilayer combination tablets debossed with SULO on one side and plain on the other side, containing 500 mg of sulopenem etzadroxil and 500 mg of probenecid. They are supplied as follows:
- Bottles of 10 tablets with child-resistant caps (NDC pending).
- Bottles of 30 tablets with child-resistant caps (NDC pending).
Storage
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].
Images
Drug Images
{{#ask: Page Name::Sulopenem etzadroxil, probenecid |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}
Package and Label Display Panel
{{#ask: Label Page::Sulopenem etzadroxil, probenecid |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}
Patient Counseling Information
Allergic Reactions
- Advise 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.
Diarrhea
- Advise patients that diarrhea is a 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 a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider.
Antibacterial Resistance
- Patients 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.
Precautions with Alcohol
Alcohol-Sulopenem etzadroxil, probenecid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Ketoprofen
- Advise patients that concomitant use of ketoprofen with ORLYNVAH is not recommended.
Brand Names
Orlynvah
Look-Alike Drug Names
There is limited information regarding Sulopenem etzadroxil, probenecid Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.