CILASTATIN: 117 Adverse Event Reports & Safety Profile

Imipenem and Cilastatin for Injection, USP (I.V.) (imipenem and cilastatin) for Injection is a sterile formulation of imipenem, a penem antibacterial, and cilastatin, a renal dehydropeptidase inhibitor with sodium bicarbonate added as a buffer. Imipenem and Cilastatin for Injection, USP (I.V.) is an antibacterial drug for intravenous administration. Imipenem (N-formimidoylthienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Streptomyces cattleya . Its chemical name is (5 R ,6 S )-3-[[2-(formimidoylamino)ethyl]thio]-6-[( R )-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate. It is an off-white, nonhygroscopic crystalline compound with a molecular weight of 317.37. It is sparingly soluble in water and slightly soluble in methanol. Its empirical formula is C 12 H 17 N 3 O 4 S•H 2 O, and its structural formula is: Cilastatin sodium is the sodium salt of a derivatized heptenoic acid. Its chemical name is sodium ( Z )-7[[( R )-2-amino-2-carboxyethyl]thio]-2-[( S )-2,2-dimethylcyclopropanecarboxamido]-2-heptenoate. It is an off-white to yellowish-white, hygroscopic, amorphous compound with a molecular weight of 380.43. It is very soluble in water and in methanol. Its empirical formula is C 16 H 25 N 2 O 5 SNa, and its structural formula is: Imipenem and Cilastatin for Injection, USP (I.V.) is buffered to provide solutions in the pH range of 6.5 to 8.5. There is no significant change in pH when solutions are prepared and used as directed. [see How Supplied/ Storage and Handling ( 16.1 ).]

Each

Imipenem and Cilastatin for Injection, USP (I.V.) 250 mg/250 mg vial contains imipenem USP 250 mg (anhydrous equivalent) and cilastatin sodium USP equivalent to 250 mg cilastatin and each 500 mg/500 mg vial contains imipenem USP 500 mg (anhydrous equivalent) and cilastatin sodium USP equivalent to 500 mg cilastatin. In addition, the 250 mg/250 mg vial contains 10 mg of sodium bicarbonate and the 500 mg/500 mg vial contains 20 mg of sodium bicarbonate. The sodium content of the 250 mg/250 mg vial is 18.8 mg (0.8 mEq) and the sodium content for the 500 mg/500 mg vial is 37.5 mg (1.6 mEq). Solutions of Imipenem and Cilastatin for Injection, USP (I.V.) range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

Imipenem Structural Formula Cilastatin Sodium

Structural Formula

AND USAGE Imipenem and Cilastatin for Injection, USP for intravenous use is a combination of imipenem, a penem antibacterial, and cilastatin, a renal dehydropeptidase inhibitor, indicated for the treatment of the following serious infections caused by designated susceptible bacteria: Lower respiratory tract infections. ( 1.1 ) Urinary tract infections. ( 1.2 ) Intra-abdominal infections. ( 1.3 ) Gynecologic infections. ( 1.4 ) Bacterial septicemia. ( 1.5 ) Bone and joint infections. ( 1.6 ) Skin and skin structure infections. ( 1.7 ) Endocarditis. ( 1.8 ) Limitations of Use : Imipenem and Cilastatin for Injection, USP (I.V.) is not indicated in patients with meningitis because safety and efficacy have not been established ( 1.9 ). Imipenem and Cilastatin for Injection, USP (I.V.) is not recommended in pediatric patients with CNS infections because of the risk of seizures ( 1.9 ). Imipenem and Cilastatin for Injection, USP (I.V.) is not recommended in pediatric patients weighing less than 30 kg with impaired renal function ( 1.9 ). Usage : To reduce the development of drug resistant bacteria and maintain the effectiveness of Imipenem and Cilastatin for Injection, USP (I.V.) and other antibacterial drugs, Imipenem and Cilastatin for Injection, USP (I.V.) should be used only to treat infections that are proven or strongly suspected to be caused by bacteria ( 1.10 ).

1.1 Lower Respiratory Tract Infections Imipenem and Cilastatin for Injection, USP (I.V.) for intravenous use is indicated for the treatment of lower respiratory tract infections caused by susceptible strains of Staphylococcus aureus (penicillinase-producing isolates), Acinetobacter species, Enterobacter species, Escherichia coli , Haemophilus influenzae , Haemophilus parainfluenzae , Klebsiella species, Serratia marcescens .

1.2 Urinary Tract Infections (complicated and uncomplicated) Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of urinary tract infections (complicated and uncomplicated) caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii , Proteus vulgaris , Providencia rettgeri , Pseudomonas aeruginosa .

1.3 Intra-Abdominal Infections Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of intra-abdominal infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Citrobacter species, Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii , Proteus species, Pseudomonas aeruginosa , Bifidobacterium species, Clostridium species, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, Bacteroides species including B. fragilis , Fusobacterium species.

1.4 Gynecologic Infections Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of gynecologic infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Streptococcus agalactiae (Group B streptococci), Enterobacter species, Escherichia coli , Gardnerella vaginalis , Klebsiella species, Proteus species, Bifidobacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, Bacteroides species including B. fragilis .

1.5 Bacterial Septicemia Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of bacterial septicemia caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Enterobacter species, Escherichia coli , Klebsiella species, Pseudomonas aeruginosa , Serratia species, Bacteroides species including B. fragilis .

1.6 Bone and Joint Infections Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of bone and joint infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Enterobacter species, Pseudomonas aeruginosa .

1.7 Skin and Skin Structure Infections Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of skin and skin structure infections caused by susceptible strains of Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii , Proteus vulgaris , Providencia rettgeri , Pseudomonas aeruginosa , Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis , Fusobacterium species.

1.8 Endocarditis Imipenem and Cilastatin for Injection, USP (I.V.) is indicated for the treatment of endocarditis caused by susceptible strains of Staphylococcus aureus (penicillinase-producing isolates).

1.9 Limitations of Use Imipenem and Cilastatin for Injection, USP (I.V.) is not indicated in patients with meningitis because safety and efficacy have not been established. Imipenem and Cilastatin for Injection, USP (I.V.) is not recommended in pediatric patients with CNS infections because of the risk of seizures <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ), and Use in Specific Populations ( 8.4 )]</span> . Imipenem and Cilastatin for Injection, USP (I.V.) is not recommended in pediatric patients less than 30 kg with impaired renal function, as no data are available <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 ), and Dosage and Administration ( 2.2 )]</span> . Periodic assessment of organ system functions, including renal, hepatic and hematopoietic, is advisable during prolonged therapy.

1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Imipenem and Cilastatin for Injection, USP (I.V.) and other antibacterial drugs, Imipenem and Cilastatin for Injection, USP (I.V.) should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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 ) <span class="opacity-50 text-xs">[see Indications and Usage (1.4) and Use in Specific Populations (8.4) ]</span>. RECARBRIO is not recommended for pediatric patients weighing less than 30 kg with renal impairment <span class="opacity-50 text-xs">[see Dosage and administration (2.4) and Use in Specific Populations (8.4) ]</span> .

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 recommended dosage of RECARBRIO in adult patients with renal impairment is shown in Table 2 .

Table

2: Recommended Dosage of RECARBRIO in Adult Patients with Renal Impairment Creatinine Clearance (CLcr) ([mL/min)] CLcr calculated using the Cockcroft-Gault formula for adult patients. Dose RECARBRIO is provided as a single vial in a fixed-dose combination; the dose for each component will be adjusted equally during preparation [see Dosage and Administration (2.5) ] .

Dosing Frequency Infusion Duration

60 to 89 RECARBRIO 1 gram Provides 400 mg imipenem, 400 mg cilastatin, and 200 mg relebactam Every 6 hours 30 minutes 30 to 59 RECARBRIO 0.75 grams Provides 300 mg imipenem, 300 mg cilastatin, and 150 mg relebactam Every 6 hours 30 minutes 15 to 29 not receiving hemodialysis RECARBRIO 0.5 grams Provides 200 mg imipenem, 200 mg cilastatin, and 100 mg relebactam Every 6 hours 30 minutes Receiving hemodialysis Administration should be timed to follow hemodialysis and at intervals timed from the end of that hemodialysis session. RECARBRIO 0.5 grams Every 6 hours 30 minutes Less than 15 not receiving hemodialysis Not recommended Do not administer RECARBRIO to adult patients with CLcr less than 15 mL/min unless hemodialysis is instituted within 48 hours after dose administration. Imipenem, cilastatin, and relebactam are cleared from the circulation during hemodialysis. For adult patients maintained on hemodialysis, administer the recommended dose of RECARBRIO after hemodialysis and at intervals timed from the end of that hemodialysis session. There is inadequate information to recommend dosage of RECARBRIO for adults undergoing peritoneal dialysis.

2.4 Recommended Dosage in Pediatric Patients Weighing at Least 30 kg with Renal Impairment Pediatric patients weighing at least 30 kg who have an estimated glomerular filtration rate (eGFR) less than 90 mL/min/1.73m 2 require dosage reduction of RECARBRIO. The recommended dosage of RECARBRIO in pediatric patients weighing at least 30 kg with renal impairment is shown in Table 3 . There is insufficient information to recommend a dosage of RECARBRIO for pediatric patients weighing less than 30 kg with any degree of renal impairment.

Table

3.

Recommended

Dosage of RECARBRIO in Pediatric Patients Weighing at Least 30 kg with Renal Impairment eGFR (mL/min/1.73 m 2 ) Calculated using a GFR estimating equation validated in pediatric patients weighing at least 30 kg.

Recommended

Dose RECARBRIO is provided as a single vial in a fixed-dose combination; the dose for each component will be adjusted equally during preparation [see Dosage and Administration (2.5) ] .

Dosing Frequency Infusion Duration

60 to 89 RECARBRIO 1 gram Provides 400 mg imipenem, 400 mg cilastatin, and 200 mg relebactam Every 6 hours 30 minutes 30 to 59 RECARBRIO 0.75 grams Provides 300 mg imipenem, 300 mg cilastatin, and 150 mg relebactam Every 6 hours 30 minutes 15 to 29 not receiving hemodialysis RECARBRIO 0.5 grams Provides 200 mg imipenem, 200 mg cilastatin, and 100 mg relebactam Every 6 hours 30 minutes Receiving hemodialysis Administration should be timed to follow hemodialysis and at intervals timed from the end of that hemodialysis session. RECARBRIO 0.5 grams Every 6 hours 30 minutes Less than 15 not receiving hemodialysis Not recommended 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. Imipenem, cilastatin, and relebactam are cleared from the circulation during hemodialysis. For pediatric patients weighing at least 30 kg maintained on hemodialysis, administer the recommended dose of RECARBRIO after hemodialysis and at intervals timed from the end of that hemodialysis session. There is inadequate information to recommend a dosage of RECARBRIO for pediatric patients undergoing peritoneal dialysis.

2.5 Preparation of RECARBRIO Solution for Intravenous Administration RECARBRIO is supplied as a dry powder in a single-dose vial that must be constituted and further diluted using aseptic technique prior to intravenous infusion. To prepare the infusion solution, contents of the vial must be constituted with the appropriate diluent as instructed below. A list of appropriate diluents is as follows: 0.9% Sodium Chloride Injection, USP 5% Dextrose Injection, USP 5% Dextrose Injection, USP + 0.9% Sodium Chloride Injection, USP 5% Dextrose Injection, USP + 0.45% Sodium Chloride Injection, USP 5% Dextrose Injection, USP + 0.225% Sodium Chloride Injection, USP RECARBRIO has low aqueous solubility. To ensure complete dissolution of RECARBRIO it is important to adhere to the following instructions: Step 1) For diluents available in 100 mL prefilled infusion bags, proceed to step 2. For diluents not available in 100 mL prefilled infusion bags, aseptically withdraw 100 mL of the desired diluent and transfer it to an empty infusion bag, then proceed to step 2.

Step

2)

Withdraw

20 mL (as two 10 mL aliquots) of diluent from the appropriate infusion bag and constitute the vial with one 10 mL aliquot of the diluent. The constituted suspension is for intravenous infusion only after dilution in an appropriate infusion solution.

Step

3) After constitution, shake vial well and transfer resulting suspension into the remaining 80 mL of the infusion bag.

Step

4) Add the second 10 mL aliquot of infusion diluent to the vial and shake well to ensure complete transfer of vial contents; repeat transfer of the resulting suspension to the infusion solution before administering. Agitate the resulting mixture until clear. Constituted solutions of RECARBRIO range from colorless to yellow. Variations of color within this range do not affect the potency of the product. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if discoloration or visible particles are observed. The above instructions for preparation of RECARBRIO solution for intravenous administration must be followed for all patients, irrespective of the intended patient’s renal function, age or weight. The volume of this prepared RECARBRIO solution to be administered in adult and pediatric (weighing at least 30 kg) patients is determined based on estimated renal function [see Dosage and Administration (2.6) ] . The volume of the prepared RECARBRIO solution to be administered to pediatric patients weighing 2 kg to less than 30 kg with normal renal function is calculated based on patient weight using the formula below [see Dosage and Administration (2.2) ]: To achieve the appropriate infusion volume, withdraw and discard the excess (100 mL minus the infusion volume) from the prepared 100 mL solution. The remaining volume is the appropriate infusion volume. Figure

2.6 Preparation of RECARBRIO Solution for Intravenous Administration in Adult and Pediatric Patients Weighing at Least 30 kg with Renal Impairment Prepare a reduced dose of RECARBRIO (1 gram, 0.75 grams, or 0.5 grams) <span class="opacity-50 text-xs">[see Dosage and Administration (2.3 , 2.4) ]</span> by preparing a 100 mL solution containing 1.25 grams as described above <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> then withdrawing and discarding the excess according to Table 4 .

Table

4: Preparation of Reduced RECARBRIO Doses for Intravenous Administration in Adult and Pediatric Patients Weighing at Least 30 kg with Renal Impairment Estimated Renal Function Creatinine Clearance (mL/min) Calculated using the Cockcroft-Gault formula for adult patients Or Estimated Glomerular Filtration Rate eGFR (mL/min/1.73 m 2 ) Calculated using a GFR estimating equation validated in pediatric patients weighing at least 30 kg Dose After preparation as instructed above, remove from the 100 mL prepared bag the volume indicated below and discard Resulting volume that provides the indicated reduced dose 60 to 89 RECARBRIO 1 gram Provides 400 mg imipenem, 400 mg cilastatin, and 200 mg relebactam 20 mL 80 mL 30 to 59 RECARBRIO 0.75 grams Provides 300 mg imipenem, 300 mg cilastatin, and 150 mg relebactam 40 mL 60 mL 15 to 29 not receiving hemodialysis RECARBRIO 0.5 grams Provides 200 mg imipenem, 200 mg cilastatin, and 100 mg relebactam 60 mL 40 mL Receiving hemodialysis RECARBRIO 0.5 grams 60 mL 40 mL

2.7 Storage of Constituted Solution RECARBRIO, as supplied in single-dose glass vials upon constitution with the appropriate diluent and following further dilution in the infusion bag, maintains satisfactory potency for at least 2 hours at room temperature (up to 30°C) or for at least 24 hours under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze solutions of RECARBRIO.

2.8 Compatible Injectable Drug Products Compatible Drug Products The physical compatibility of RECARBRIO with selected injectable drug products was evaluated in two commonly available diluents. Compatible drugs with the corresponding compatible diluent (i.e., 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP) are listed below. RECARBRIO should not be co-administered through the same intravenous line (or cannula), with other drug products not listed below, as no compatibility data are available. Refer to the respective prescribing information of the co-administered drug(s) to confirm compatibility of simultaneous co-administration. List of Compatible Injectable Drugs for use with 5% Dextrose USP or 0.9% Sodium Chloride USP Injection as Diluents dexmedetomidine dopamine epinephrine fentanyl heparin midazolam norepinephrine phenylephrine

2.9 Incompatible Injectable Drug Products RECARBRIO for injection for intravenous infusion is physically incompatible with propofol in 5% Dextrose USP or 0.9% Sodium Chloride USP.

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 )

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 discretion of the investigator. The mean age was 56 years, 40% of patients were 65 years of age and older, 16% were 75 years of age and older, 50% were female, and approximately 18% had moderate to severe renal impairment.

Clinical Trial

Experience in Adult Patients with cIAI Trial 3 included 233 adult patients treated with imipenem/cilastatin plus relebactam (116 subjects with imipenem 500 mg/cilastatin 500 mg and relebactam 125 mg and 117 subjects with imipenem 500 mg/cilastatin 500 mg plus relebactam 250 mg), and 114 patients treated with imipenem 500 mg/cilastatin 500 mg, administered intravenously over 30 minutes every 6 hours for 4 to 14 days, at the discretion of the investigator. The mean age was 49 years, 23% of the patients were 65 years of age and older, 9.8% were 75 years of age and older, and 42% were female.

Serious Adverse

Reactions and Adverse Reactions Leading to Discontinuation in Adult Patients In Trial 1, serious adverse reactions occurred in 27% (71/266) of patients receiving RECARBRIO and 32% (86/269) of patients receiving piperacillin and tazobactam. Adverse reactions leading to death were reported in 15% (40/266) of patients receiving RECARBRIO and 21% (57/269) of patients receiving piperacillin and tazobactam. Adverse reactions leading to discontinuation occurred in 5.6% (15/266) of patients receiving imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg and 8.2% (22/269) of patients receiving piperacillin and tazobactam.

In Trials

2 and 3, serious adverse reactions occurred in 3.2% (7/216) of patients receiving imipenem 500 mg/cilastatin 500 mg plus relebactam 250 mg and 5.1% (11/214) of patients receiving imipenem 500 mg/cilastatin 500 mg. There were no deaths reported in patients receiving imipenem 500 mg/cilastatin 500 mg plus relebactam 250 mg or imipenem 500 mg/cilastatin 500 mg alone. Deaths were reported in 1.4% (3/215) of patients receiving imipenem 500 mg/cilastatin 500 mg plus relebactam 125 mg (not an approved dose). Adverse reactions leading to discontinuation occurred in 1.9% (4/216) of patients receiving imipenem 500 mg/cilastatin 500 mg plus relebactam 250 mg and 2.3% (5/214) of patients receiving imipenem 500 mg/cilastatin 500 mg.

Common Adverse

Reactions in Adult Patients In Trial 1, adverse reactions occurred during the protocol-specified follow-up period, which was IV therapy plus 14 days following completion of therapy, in 85% (226/266) of patients receiving RECARBRIO and 87% (233/269) of patients receiving piperacillin and tazobactam.

Table

5 lists the most common adverse reactions occurring in ≥4% of patients receiving imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg or piperacillin and tazobactam in Trial 1.

Table

5: Adverse Reactions Occurring in Greater Than or Equal to 4% of HABP/VABP Adult Patients Receiving RECARBRIO in Trial 1 Adverse Reaction RECARBRIO RECARBRIO, IV every 6 hours. (N=266) N (%)

Piperacillin/Tazobactam

Piperacillin 4000 mg and Tazobactam 500 mg (4.5 grams), IV every 6 hours. (N=269) N (%) Blood and lymphatic system disorders Anemia 28 (10.5%) 27 (10.0%) Gastrointestinal disorders Constipation 11 (4.1%) 3 (1.1%)

Diarrhea

21 (7.9%) 30 (11.2%) General disorders and administration site conditions Pyrexia 11 (4.1%) 20 (7.4%) Laboratory investigations Alanine aminotransferase increased 26 (9.8%) 19 (7.1%) Aspartate aminotransferase increased 31 (11.7%) 20 (7.4%) Metabolism and nutrition disorders Hypokalemia Hypokalemia includes hypokalemia and blood potassium decreased. 21 (7.9%) 26 (9.7%)

Hyponatremia

Hyponatremia includes hyponatremia and blood sodium decreased. 17 (6.4%) 3 (1.1%) Skin and subcutaneous tissue disorders Rash Rash includes rash, rash erythematous, and rash generalized. 11 (4.1%) 5 (1.9%)

Less Common Adverse Reactions

Reported in Trial 1 The following selected adverse reaction was reported in RECARBRIO-treated subjects at a rate of less than 4%: Blood and lymphatic system disorders: thrombocytopenia In Trials 2 and 3, adverse reactions occurred during the protocol specified follow-up period, which was IV therapy plus 14 days following completion of therapy, in 39% (85/216) of patients receiving imipenem 500 mg/cilastatin 500 mg plus relebactam 250 mg and 36% (77/214) of patients receiving imipenem 500 mg/cilastatin 500 mg.

Table

6 lists the most common adverse reactions occurring in ≥1% of patients receiving imipenem 500 mg/cilastatin 500 mg plus relebactam 250 mg or imipenem 500 mg/cilastatin 500 mg in Trials 2 and 3.

Table

6: Adverse Reactions Occurring in Greater Than or Equal to 1% of cUTI and cIAI Adult Patients Receiving Imipenem/Cilastatin plus Relebactam 250 mg or Imipenem/Cilastatin in Trials 2 and 3 Adverse Reaction Imipenem/Cilastatin and Relebactam 250 mg Imipenem/Cilastatin (500 mg/500 mg) + Relebactam (250 mg), IV every 6 hours. (N=216) N (%) IMI + Placebo Imipenem/Cilastatin (500 mg/500 mg) + Placebo, IV every 6 hours. (N=214) N (%) Blood and lymphatic system disorders Anemia Anemia includes anemia and hemoglobin decreased. 2 (1%) 4 (2%) Gastrointestinal disorders Diarrhea 12 (6%) 9 (4%)

Nausea

12 (6%) 12 (6%)

Vomiting

7 (3%) 4 (2%) General disorders and administration site conditions Phlebitis/Infusion site reactions Infusion site reactions include infusion site phlebitis, infusion site erythema, and infusion site pain. 5 (2%) 3 (1%)

Pyrexia

5 (2%) 3 (1%)

Laboratory Investigations

Alanine aminotransferase increased 7 (3%) 4 (2%) Aspartate aminotransferase increased 6 (3%) 3 (1%) Lipase increased 3 (1%) 4 (2%) Blood creatinine increased 1 (<1%) 3 (1%) Nervous system disorders Headache 9 (4%) 5 (2%) Central nervous system adverse reactions Central nervous system adverse reactions include agitation, apathy, confusional states, delirium, disorientation, slow speech, and somnolence. 2 (1%) 5 (2%) Vascular disorders Hypertension Hypertension includes hypertension and blood pressure increased. 4 (2%) 6 (3%)

Other Adverse Reactions

Associated with Imipenem/Cilastatin Adverse reactions reported with imipenem/cilastatin, a component of RECARBRIO, in clinical studies or during post-marketing experience are listed below. These adverse reactions are not listed above for patients treated with RECARBRIO in Trial 1 or imipenem 500 mg/cilastatin 500 mg plus relebactam 250 mg in Trials 2 and 3. Blood and Lymphatic System Disorders : agranulocytosis, increased eosinophils, hemolytic anemia Nervous System Disorders: seizure Hepatobiliary Disorders : hepatic failure, jaundice Laboratory Investigations : blood lactate dehydrogenase increased, Coombs test positive, eosinophil count increased.

Pediatric Patients Clinical Trial

Experience in Pediatric Patients with HABP/VABP, cUTI and cIAI RECARBRIO was evaluated in an open-label, randomized, active-controlled, multi-dose, phase 2/3 clinical trial (Trial 4) in pediatric patients from birth to less than 18 years of age with HABP/VABP, cUTI or cIAI [see Clinical Studies (14.3) ]. A total of 85 patients were treated with RECARBRIO and 28 were treated with a comparator agent (investigator's choice from a specified list of comparators). RECARBRIO was administered intravenously as a weight-based dose of 37.5 mg/kg (imipenem 15 mg/kg, cilastatin 15 mg/kg, and relebactam 7.5 mg/kg) every 6 hours or 8 hours, or a fixed-dose of 1.25 grams (imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg) every 6 hours.

In Trial

4, adverse reactions were comparable to those observed in adults. No patient died in either intervention group in the study through Day 28. The most common adverse reactions occurring in greater than 3% of pediatric patients receiving RECARBRIO were vomiting (15%), diarrhea (9%), nausea (7%), headache (6%), phlebitis/infusion site reactions (including phlebitis, infusion site phlebitis, infusion site extravasation, medical device site dermatitis; 5%), and rash (including rash, rash erythematous, rash maculopapular; 4%).

AND PRECAUTIONS Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. If an allergic reaction to Imipenem and Cilastatin for Injection (I.V.) occurs, discontinue the drug immediately ( 5.1 ).

Seizure

Potential: Seizures and other CNS adverse reactions, such as confusional states and myoclonic activity, have been reported during treatment with Imipenem and Cilastatin for Injection (I.V.). If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of Imipenem and Cilastatin for Injection (I.V.) re-examined to determine whether it should be decreased, or the antibacterial drug discontinued ( 5.2 ).

Increased Seizure Potential

Due to Interaction with Valproic Acid: Co-administration of Imipenem and Cilastatin for Injection (I.V.), to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. The concomitant use of Imipenem and Cilastatin for Injection (I.V.) and valproic acid/divalproex sodium is generally not recommended ( 5.3 , 7.3 ). Clostridioides difficile-Associated Diarrhea (CDAD): has been reported with use of Imipenem and Cilastatin for Injection (I.V.) and may range in severity from mild diarrhea to fatal colitis. 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. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another beta-lactam. Before initiating therapy with Imipenem and Cilastatin for Injection (I.V.), careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams and other allergens. If an allergic reaction to Imipenem and Cilastatin for Injection (I.V.) occurs, discontinue the drug immediately. Serious anaphylactic reactions require immediate emergency treatment as clinically indicated.

5.2 Seizure Potential Seizures and other CNS adverse experiences, such as confusional states and myoclonic activity, have been reported during treatment with Imipenem and Cilastatin for Injection (I.V.), especially when recommended dosages were exceeded <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 , 6.2 )]</span>. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> . However, there have been reports of CNS adverse experiences in patients who had no recognized or documented underlying CNS disorder or compromised renal function. Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of Imipenem and Cilastatin for Injection (I.V.) re-examined to determine whether it should be decreased, or the antibacterial drug discontinued.

5.3 Increased Seizure Potential Due to Interaction with Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including Imipenem and Cilastatin for Injection (I.V.), to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of Imipenem and Cilastatin for Injection (I.V.) and valproic acid/divalproex sodium is generally not recommended. Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of Imipenem and Cilastatin for Injection (I.V.) is necessary, supplemental anti-convulsant therapy should be considered <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span>. Close adherence to the recommended dosage and dosage schedules is urged, especially in patients with known factors that predispose to convulsive activity.

5.4 Clostridioides difficile -Associated Diarrhea (CDAD) Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Imipenem and Cilastatin for Injection (I.V.), 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 As with other antibacterial drugs, prolonged use of Imipenem and Cilastatin for Injection (I.V.) may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient&apos;s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Prescribing

Imipenem and Cilastatin for Injection (I.V.) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

INTERACTIONS Ganciclovir: Generalized seizures have been reported in patients who received ganciclovir. Do not co-administer unless benefit outweighs risk ( 7.1 ). Probenecid: Concomitant administration of Imipenem and Cilastatin for Injection (I.V.) and probenecid results in increases in the plasma level and half-life of imipenem. Concomitant administration is not recommended ( 7.2 ). Valproic acid/divalproex sodium: Concomitant use with Imipenem and Cilastatin for Injection (I.V.) is generally not recommended. Consider other antibacterial drugs to treat infections in patients whose seizures are well-controlled on valproic acid or divalproex sodium ( 5.3 , 7.3 ).

7.1 Ganciclovir Generalized seizures have been reported in patients who received ganciclovir and Imipenem and Cilastatin for Injection (I.V.). These drugs should not be used concomitantly with Imipenem and Cilastatin for Injection (I.V.) unless the potential benefits outweigh the risks.

7.2 Probenecid Concomitant administration of Imipenem and Cilastatin for Injection (I.V.) and probenecid results in increases in the plasma level and half-life of imipenem. Therefore, it is not recommended that probenecid be given concomitantly with Imipenem and Cilastatin for Injection (I.V.).

7.3 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including Imipenem and Cilastatin for Injection (I.V.), to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. 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&apos;s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>. The concomitant use of Imipenem and Cilastatin for Injection (I.V.) and valproic acid/divalproex sodium is generally not recommended. Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well-controlled on valproic acid or divalproex sodium.