Recarbrio Drug Information

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. 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%).

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. 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.

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 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.

Relebactam In an embryofetal development study in pregnant mice, relebactam administered subcutaneously in doses of 80, 200, and 450 mg/kg/day during the period of organogenesis (GD 6 to 17) was not associated with maternal toxicity at doses up to 450 mg/kg/day. 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 embryofetal development studies in rats and rabbits, intravenous relebactam was administered to rats in doses of 50, 150, and 450 mg/kg/day and rabbits in doses of 35, 275, and 450 mg/kg/day. In these studies, relebactam administered during the period of organogenesis to pregnant rats (GD 6 to 20) and rabbits (GD 7 to 20) was not associated with maternal or embryofetal toxicity at doses up to 450 mg/kg/day corresponding to plasma AUC exposures of approximately 7 and 24 times, respectively, 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.

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.

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.