Recarbrio Drug Information

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 ). RECARBRIO is not recommended for pediatric patients weighing

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) 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. 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.

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.

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. 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. 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. 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: 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. Table 4: Preparation of Reduced RECARBRIO Doses for Intravenous Administration in Adult and Pediatric Patients Weighing at Least 30 kg with Renal Impairment

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.

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

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.

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).

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. 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. 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 s 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.

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. 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).

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.

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.

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. 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. Consider alternative antibacterials other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium.

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.

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 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 50) at 100 mg/kg/day, a dose approximately equivalent to the MRHD (based on body surface area comparison), at an infusion rate mimicking human clinical use was not associated with fetal malformations, but there was an increase in embryonic loss relative to controls. Imipenem/cilastatin administered to pregnant cynomolgus monkeys during organogenesis at 40 mg/kg/day by bolus intravenous injection caused significant maternal toxicity including death and embryofetal loss. However, although individual skeletal malformations appeared only as single occurrences in the high dose group, the percent litter incidence of total skeletal malformations (skull and vertebral) was increased in the high-dose group (21% litter incidence) compared to the concurrent control value (5.3% litter incidence).

The plasma relebactam exposure for the high dose associated with increased skeletal malformations was approximately 6 times greater than the human plasma exposure at the MRHD based on AUC comparison. Also, mice receiving the lowest administered dose of relebactam, 80 mg/kg/day, exhibited a higher percent litter incidence (15% litter incidence) of cleft palate (a rare malformation in mice) compared to the concurrent control value (0% litter incidence) and historical control values (up to 11% litter incidence). This finding did not increase in a dose-dependent manner with percent litter incidences of 0% and 5.3% in the mid- and high-dose groups respectively.

The plasma AUC exposure for the low dose of relebactam associated with increased cleft palate was approximately equivalent to the human plasma AUC at the MRHD. In a pre-postnatal development study, relebactam administered intravenously in doses of 65, 200, and 450 mg/kg/day to rats from GD 6 to lactation day (LD) 20 produced no maternal toxicity and did not impair the physical and behavioral development or reproduction in first generation offspring at doses up to 450 mg/kg/day corresponding to a plasma AUC exposure of approximately 8 times the plasma AUC exposure in humans at the MRHD. Studies in pregnant rats and rabbits showed that relebactam is transferred to the fetus through the placenta, with fetal plasma concentrations up to 5% to 6% of maternal concentrations observed on GD 20.

Pediatric Use The safety and effectiveness of RECARBRIO for the treatment of HABP/VABP, and for the treatment of cUTI and cIAI in patients who have limited or no alternative treatment options have been established in pediatric patients weighing at least 2 kg. Use of RECARBRIO in pediatric patients is supported by evidence from an adequate and well-controlled trial of RECARBRIO in adults with HABP/VABP, controlled trials in adults with cUTI and cIAI, and additional pharmacokinetic, safety, and efficacy data from pediatric trials. The safety profile of RECARBRIO in pediatric patients from the pediatric trials was comparable to that in adults treated with RECARBRIO.

RECARBRIO is not recommended in pediatric patients less than 37 weeks post-menstrual age (gestational age at birth plus post-natal age) or weighing less than 30 kg with renal impairment. The safety and effectiveness of RECARBRIO for the treatment of HABP/VABP, cUTI or cIAI have not been established in pediatric patients weighing less than 2 kg.

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

In the event of overdose, discontinue RECARBRIO, treat symptomatically, and institute general supportive treatment. Imipenem, cilastatin, and relebactam can be removed by hemodialysis. No clinical information is available on the use of hemodialysis to treat overdosage.