RECARBRIO

1 INDICATIONS AND USAGE RECARBRIO is a combination of imipenem, a penem antibacterial, cilastatin, a renal dehydropeptidase inhibitor, and relebactam, a beta-lactamase inhibitor, indicated in adult and pediatric patients weighing at least 2 kg for the treatment of the following infections caused by susceptible gram-negative microorganisms: Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). ( 1.1 ) Complicated urinary tract infections, including pyelonephritis (cUTI) in patients who have limited or no alternative treatment options. ( 1.2 ) Complicated intra-abdominal infections (cIAI) in patients who have limited or no alternative treatment options. ( 1.3 ) Approval of the cUTI and cIAI indications is based on limited clinical safety and efficacy data for RECARBRIO. ( 1.2 , 1.3 , 14 ) Limitations of Use RECARBRIO is not recommended in pediatric patients less than 37 weeks post-menstrual age (gestational age at birth plus post-natal age). ( 1.4 , 2.2 ). RECARBRIO is not recommended in pediatric patients weighing less than 30 kg with renal impairment. ( 1.4 , 2.3 ). Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of RECARBRIO and other antibacterial drugs, RECARBRIO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.5 ) 1.1 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) RECARBRIO ® is indicated in adult and pediatric patients weighing at least 2 kg for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible gram-negative microorganisms: Acinetobacter calcoaceticus-baumannii complex, Enterobacter cloacae , Escherichia coli , Haemophilus influenzae , Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. 1.2 Complicated Urinary Tract Infections (cUTI), including Pyelonephritis RECARBRIO is indicated in adult and pediatric patients weighing at least 2 kg who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible gram-negative microorganisms: Enterobacter cloacae , Escherichia coli , Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa . Approval of this indication is based on limited clinical safety and efficacy data for RECARBRIO [see Clinical Studies (14.2) ] . 1.3 Complicated Intra-abdominal Infections (cIAI) RECARBRIO is indicated in adult and pediatric patients weighing at least 2 kg who have limited or no alternative treatment options for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible gram-negative microorganisms: Bacteroides caccae , Bacteroides fragilis , Bacteroides ovatus , Bacteroides stercoris , Bacteroides thetaiotaomicron , Bacteroides uniformis , Bacteroides vulgatus , Citrobacter freundii , Enterobacter cloacae , Escherichia coli , Fusobacterium nucleatum , Klebsiella aerogenes, Klebsiella oxytoca , Klebsiella pneumoniae , Parabacteroides distasonis , and Pseudomonas aeruginosa . Approval of this indication is based on limited clinical safety and efficacy data for RECARBRIO [see Clinical Studies (14.2) ] . 1.4 Limitations of Use RECARBRIO is not recommended in pediatric patients less than 37 weeks post-menstrual age (gestational age at birth plus post-natal age) [see Dosage and Administration (2.2) and Use in Specific Populations (8.4) ] . RECARBRIO is not recommended in pediatric patients weighing less than 30 kg with renal impairment [see Dosage and Administration (2.4) , Use in Specific Populations (8.4 , 8.6) and Clinical Pharmacology (12.3) ]. 1.5 Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug…

2 DOSAGE AND ADMINISTRATION Adult Patients: The recommended dosage of RECARBRIO is 1.25 grams (imipenem 500 mg, cilastatin 500 mg, relebactam 250 mg) administered by intravenous (IV) infusion over 30 minutes every 6 hours to adult patients with creatinine clearance (CLcr) 90 mL/min or greater. ( 2.1 ) Pediatric Patients weighing at least 2 kg: The recommended dosage of RECARBRIO for pediatric patients weighing at least 2kg varies by patient weight and age, with specific dosing recommendations as shown in the table below, ( 2.2 ): Recommended Dosage of RECARBRIO In Pediatric Patients Weighing at Least 2 kg Age Range Body Weight Dose Dosing Frequency Infusion Duration Birth Pediatric patients from birth (includes pediatric patients at least 37 weeks post-menstrual age) to less than 3 months 2 kg or greater RECARBRIO 37.5 Provides 15 mg/kg imipenem, 15 mg/kg cilastatin, and 7.5 mg/kg relebactam mg/kg Every 8 hours 60 minutes 3 months to less than 18 years less than 30 kg RECARBRIO 37.5 mg/kg Every 6 hours 60 minutes 3 months to less than 18 years 30 kg or greater RECARBRIO 1.25 Provides 500 mg imipenem, 500 mg cilastatin, and 250 mg, relebactam grams Every 6 hours 30 minutes Dose reduction is required in adult and pediatric (weighing at least 30 kg) patients with renal impairment. ( 2.3 , 2.4 ) Do not administer RECARBRIO to adults with CLcr less than 15 mL/min unless hemodialysis is instituted within 48 hours after dose administration. ( 2.3 ) Do not administer RECARBRIO to pediatric patients weighing at least 30 kg with an eGFR less than 15 mL/min/1.73m 2 unless hemodialysis is instituted within 48 hours after dose administration. ( 2.4 ) See Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution. ( 2.5 ) See Full Prescribing Information for drug compatibilities and incompatibilities. ( 2.7 , 2.8 ) 2.1 Recommended Dosage in Adult Patients The recommended dosage of RECARBRIO is 1.25 grams (imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg) administered by intravenous (IV) infusion over 30 minutes every 6 hours in adult patients with creatinine clearance (CLcr) of 90 mL/min or greater). The recommended duration of treatment with RECARBRIO is 4 days to 14 days. The duration of therapy should be guided by the severity and location of infection and clinical response. 2.2 Recommended Dosage in Pediatric Patients Weighing at Least 2 kg The recommended dosage of RECARBRIO in pediatric patients weighing at least 2 kg varies by patient weight and age, with specific dosing recommendations shown in Table 1 . The recommended duration of treatment with RECARBRIO is 4 days to 14 days. The duration of therapy should be guided by the severity and location of infection and clinical response. RECARBRIO is not recommended in pediatric patients less than 37 weeks post-menstrual age (gestational age at birth plus post-natal age ) [see Indications and Usage (1.4) and Use in Specific Populations (8.4) ]. RECARBRIO is not recommended for pediatric patients weighing less than 30 kg with renal impairment [see Dosage and administration (2.4) and Use in Specific Populations (8.4) ] . Table 1: Recommended Dosage of RECARBRIO In Pediatric Patients Weighing at Least 2 kg Age Range Body Weight Dose Dosing Frequency Infusion Duration Birth Pediatric patients from birth (includes pediatric patients at least 37 weeks post-menstrual age) to less than 3 months 2 kg or greater RECARBRIO 37.5 Provides 15 mg/kg imipenem, 15 mg/kg cilastatin, and 7.5 mg/kg relebactam mg/kg Every 8 hours 60 minutes 3 months to less than 18 years less than 30 kg RECARBRIO 37.5 mg/kg Every 6 hours 60 minutes 3 months to less than 18 years 30 kg or greater RECARBRIO 1.25 Provides 500 mg imipenem, 500 mg cilastatin, and 250 mg, relebactam grams Every 6 hours 30 minutes 2.3 Recommended Dosage in Adult Patients with Renal Impairment Adult patients who have a CLcr less than 90 mL/min require dosage reduction of RECARBRIO. The…

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta lactam drugs. Discontinue RECARBRIO immediately if a hypersensitivity reaction occurs. ( 5.1 ) Seizures and Central Nervous System Adverse Reactions: CNS adverse reactions such as seizures have been reported with imipenem/cilastatin, a component of RECARBRIO. If focal tremors, myoclonus, or seizures occur, evaluate patients, to determine whether RECARBRIO should be discontinued. ( 5.2 ) Increased Seizure Potential Due to Interaction with Valproic Acid: Concomitant use of RECARBRIO with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid which may increase the risk of breakthrough seizures. Avoid concomitant use or consider alternative antibacterial drugs other than carbapenems. ( 5.3 , 7.2 ) Clostridioides difficile -Associated Diarrhea (CDAD): Has been reported with RECARBRIO. Evaluate if diarrhea occurs. ( 5.4 ) 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta lactams. Before initiating therapy with RECARBRIO, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta lactams, and other allergens. If a hypersensitivity reaction to RECARBRIO occurs, discontinue the therapy immediately. RECARBRIO is contraindicated in patients with a history of severe hypersensitivity to any component of RECARBRIO [see Contraindications (4) ]. 5.2 Seizures and Other Central Nervous System (CNS) Adverse Reactions CNS adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with imipenem/cilastatin, a component of RECARBRIO, especially when recommended dosages of imipenem were exceeded . These have been reported most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function . Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether RECARBRIO should be discontinued. 5.3 Increased Seizure Potential Due to Interaction with Valproic Acid Concomitant use of RECARBRIO, with valproic acid or divalproex sodium may increase the risk of breakthrough seizures. Avoid concomitant use of RECARBRIO with valproic acid or divalproex sodium or consider alternative antibacterial drugs other than carbapenems [see Drug Interactions (7.2) ]. 5.4 Clostridioides difficile -Associated Diarrhea (CDAD) Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including RECARBRIO, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to 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 antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.5 Development of Drug-resistant Bacteria Prescribing RECARBRIO in the absence of a proven or strongly suspe…

4 CONTRAINDICATIONS RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of RECARBRIO. RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity to any component of RECARBRIO. ( 4 )

7 DRUG INTERACTIONS Ganciclovir: Avoid concomitant use. ( 7.1 ) Valproic Acid or Divalproex Sodium: Avoid concomitant use. ( 7.2 ) 7.1 Ganciclovir Generalized seizures have been reported in patients who received ganciclovir concomitantly with imipenem/cilastatin, a component of RECARBRIO. Ganciclovir should not be used concomitantly with RECARBRIO unless the potential benefits outweigh the risks. 7.2 Valproic Acid Based on case reports in the literature concomitant use of carbapenems, including imipenem/cilastatin, components of RECARBRIO, with valproic acid or divalproex sodium may decrease valproic acid concentrations which may increase the risk of breakthrough seizures [see Warnings and Precautions (5.3) ] . Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid . Avoid concomitant use of RECARBRIO with valproic acid or divalproex sodium. Consider alternative antibacterials other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium.

8.1 Pregnancy Risk Summary Embryonic loss was observed in monkeys treated with imipenem/cilastatin, and fetal abnormalities were observed in relebactam-treated mice; therefore, advise pregnant women of the potential risks to pregnancy and the fetus. There are insufficient human data to establish whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with RECARBRIO, imipenem, cilastatin, or relebactam in pregnant women. Developmental toxicity studies with imipenem and cilastatin (alone or in combination) administered parenterally during organogenesis to mice, rats, rabbits, and monkeys at doses 1 to 5 times the maximum recommended human dose (MRHD of imipenem 500 mg/cilastatin 500 mg every 6 hours for total daily doses of imipenem 2000 mg/cilastatin 2000 mg) based on body surface area comparison, showed no drug-induced fetal malformations. Embryofetal development studies with imipenem/cilastatin administered to cynomolgus monkeys at doses similar to the MRHD (based on body surface area comparison) showed an increase in embryonic loss. In an embryofetal study, parental administration of relebactam to pregnant mice during the period of organogenesis was associated with a non-dose responsive increase in the litter incidence of cleft palate at a plasma relebactam exposure approximately equal to the human exposure at the MRHD (250 mg every 6 hours for a daily dose of 1000 mg) and an increased percent litter incidence of total skeletal malformations at a plasma exposure approximately 6 times the human exposure at the MRHD. Reproductive studies with relebactam administered parenterally to pregnant rats and rabbits during the period of organogenesis at plasma exposures up to 7 and 24 times, respectively, the plasma exposure in humans at the MRHD showed no adverse effects on pregnancy or embryofetal development. Relebactam administered to rats during gestation through lactation was not associated with fetal toxicity, developmental delays, or impaired reproduction in first generation offspring at plasma exposures equivalent to 8 times the human exposure at the MRHD (see Data ) . The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects is 2 to 4% and miscarriage is 15 to 20% of clinically recognized pregnancies within the U.S. general population. Data Animal Data Imipenem and Cilastatin Reproductive toxicity studies with imipenem and cilastatin (alone or in combination) administered parenterally to mice, rats, and rabbits showed no evidence of effects on embryofetal (mice, rats, and rabbits) or pre/postnatal (rats) development. In embryofetal development studies, imipenem was administered intravenously to rats (gestation days (GD) 7 to 17), and rabbits (GD 6 to 18), at doses up to 900 and 60 mg/kg/day, respectively, approximately 4 and 0.6 times the MRHD (based on body surface area comparison). Cilastatin was administered subcutaneously to rats (GD 6 to 17) and intravenously to rabbits (GD 6 to 18) at doses up to 1000 and 300 mg/kg/day, respectively, approximately 5 and 3 times the MRHD (based on body surface area comparison). Imipenem/cilastatin was administered intravenously to mice at doses up to 320 mg/kg/day (GD 6 to 15) which is approximately equivalent to the MRHD based on body surface area comparison, and to rats at intravenous doses up to 80 mg/kg/day and a subcutaneous dose of 320 mg/kg/day (GD 6 to 17). In a separate pre-postnatal development study, rats were administered subcutaneous imipenem/cilastatin at doses up to 320 mg/kg/day (GD 15 to day 21 postpartum). The subcutaneous dose of 320 mg/kg/day in rats is approximately double the MRHD based on body surface area comparison. Imipenem/cilastatin administered intravenously to pregnant cynomolgus monkeys during organogenesis (GD 21 to…

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section. Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions (5.2) ] Increased Seizure Potential Due to Interaction with Valproic Acid [see Warnings and Precautions (5.3) ] Clostridioides difficile -Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4) ] Adult HABP/VABP Patients: The most frequently reported adverse reactions occurring in greater than or equal to 5% of patients treated with RECARBRIO were aspartate aminotransferase increased, anemia, alanine aminotransferase increased, diarrhea, hypokalemia, and hyponatremia. ( 6 ) Adult cUTI and cIAI Patients: The most frequently reported adverse reactions occurring in greater than or equal to 2% of patients treated with imipenem/cilastatin plus relebactam 250 mg, the components of RECARBRIO, were diarrhea, nausea, headache, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, phlebitis/infusion site reactions, pyrexia, and hypertension. ( 6 ) Pediatric HABP/VABP, cUTI, and cIAI Patients: The most frequently reported adverse reactions occurring in greater than 3% of pediatric patients treated with RECARBRIO were vomiting, diarrhea, nausea, headache, phlebitis/infusion site reactions, and rash. To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 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 the rates observed in practice. Adult Patients Overview of the Safety Evaluation of RECARBRIO in Adult Patients Safety was primarily evaluated in three active-controlled, double-blind trials in HABP/VABP, cUTI, and cIAI (Trials 1, 2, and 3, respectively). In the HABP/VABP trial (Trial 1), patients were treated with either RECARBRIO or piperacillin and tazobactam (4.5 grams). In the cUTI trial (Trial 2) and cIAI trial (Trial 3), patients in the treatment arms were treated with either imipenem 500 mg/cilastatin 500 mg and relebactam 250 mg or imipenem 500 mg/cilastatin 500 mg and relebactam 125 mg (not an approved dose), and patients in the control arm were treated with imipenem 500 mg/cilastatin 500 mg plus placebo (IV normal saline). Across Trials 2 and 3, the mean duration of IV therapy in patients treated with imipenem/cilastatin plus relebactam 250 mg was approximately 7 days. Clinical Trial Experience in Adult Patients with HABP/VABP Trial 1 included 266 adult patients treated with RECARBRIO and 269 patients treated with piperacillin and tazobactam (4.5 grams) administered intravenously over 30 minutes every 6 hours. The mean age was 60 years, 43% of patients were 65 years of age and older, 31% were female and 22% had polymicrobial infection. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 15 and 48% of patients had an APACHE II score greater than or equal to 15 at baseline. Overall, 260 (49%) patients were ventilated at enrollment, including 194 (36%) patients with VABP and 66 (12%) patients with ventilated HABP. Clinical Trial Experience in Adult Patients with cUTI including, Pyelonephritis Trial 2 included 198 adult patients treated with imipenem/cilastatin and relebactam (99 patients each with imipenem 500 mg/cilastatin 500 mg plus relebactam 125 mg or relebactam 250 mg) and 100 patients treated with imipenem 500 mg/cilastatin 500 mg, administered intravenously over 30 minutes every 6 hours. After a minimum of 4 days of IV therapy, patients could be switched to oral ciprofloxacin (500 mg daily every 12 hours) to complete the treatment course of 4 to 14 days total (IV plus oral), at the discre…