Recarbrio
(cilastatin / imipenem / relebactam)Dosage & Administration
| Estimated Creatinine Clearance (mL/min) * | Recommended Dose of RECARBRIO (imipenem/cilastatin/relebactam) (mg) administered by IV infusion over 30 minutes every 6 hours |
|---|---|
| 60 to 89 | 1 gram (imipenem 400 mg, cilastatin 400 mg, and relebactam 200 mg |
| 30 to 59 | 0.75 grams (imipenem 300 mg, cilastatin 300 mg, and relebactam 150 mg |
| 15 to 29 | 0.5 grams (imipenem 200 mg, cilastatin 200 mg, and relebactam 100 mg |
| End Stage Renal Disease on Hemodialysis | 0.5 grams (imipenem 200 mg, cilastatin 200 mg, and relebactam 100 mg |
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Recarbrio Prescribing Information
Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)
RECARBRIO™ is indicated for the treatment of patients 18 years of age and older with 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.
Complicated Urinary Tract Infections (cUTI), including Pyelonephritis
RECARBRIO is indicated in patients 18 years of age and older 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)].
Complicated Intra-abdominal Infections (cIAI)
RECARBRIO is indicated in patients 18 years of age and older 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)].
Usage
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 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.
Recommended Dosage in Adults
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 patients 18 years of age and older with creatinine clearance (CLcr) of 90 mL/min or greater. A dose reduction is recommended for patients with CLcr less than 90 mL/min [see Dosage and Administration (2.2)]. The severity and location of infection, as well as clinical response should guide the duration of therapy. The recommended duration of treatment with RECARBRIO is 4 days to 14 days.
Dosage Adjustments in Patients with Renal Impairment
Dosage adjustment is recommended in patients with renal impairment. Patients who have a CLcr less than 90 mL/min require dosage reduction of RECARBRIO . For patients with fluctuating renal function, CLcr should be monitored.
| Estimated CLcr (mL/min) * | Recommended Dosage of RECARBRIO (imipenem/cilastatin and relebactam) (mg) † | Dosing Interval |
|---|---|---|
| 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 (2.4)]. | ||
| ||
| 60 to 89 | 1 gram (imipenem 400 mg, cilastatin 400 mg, and relebactam 200 mg) | Every 6 hours |
| 30 to 59 | 0.75 grams (imipenem 300 mg, cilastatin 300 mg, and relebactam 150 mg) | Every 6 hours |
| 15 to 29 | 0.5 grams (imipenem 200 mg, cilastatin 200 mg, and relebactam 100 mg) | Every 6 hours |
| End Stage Renal Disease (ESRD) on Hemodialysis ‡ | 0.5 grams (imipenem 200 mg, cilastatin 200 mg, and relebactam 100 mg) | Every 6 hours |
Patients with CLcr less than 15 mL/min should not receive RECARBRIO unless hemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of RECARBRIO for patients undergoing peritoneal dialysis.
Imipenem, cilastatin, and relebactam are cleared from the circulation during hemodialysis. For patients maintained on hemodialysis, administer RECARBRIO after hemodialysis and at intervals timed from the end of that hemodialysis session.
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. The volume of this prepared RECARBRIO solution to be administered to patients is determined based on renal function [see Dosage and Administration (2.4)].
Preparation of RECARBRIO Solution for Intravenous Administration in Patients with Renal Impairment
For patients with renal impairment, prepare a reduced dose of RECARBRIO (1 gram, 0.75 grams, or 0.5 grams) [see Dosage and Administration (2.2)] by preparing a 100 mL solution containing 1.25 grams (as described above in Section 2.3) then withdrawing and discarding the excess according to Table 2.
| Creatinine Clearance (mL/min) | Dosage of RECARBRIO (imipenem/cilastatin/relebactam) | 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 | 1 gram (imipenem 400 mg, cilastatin 400 mg, and relebactam 200 mg) | 20 mL | 80 mL |
| 30 to 59 | 0.75 grams (imipenem 300 mg, cilastatin 300 mg, and relebactam 150 mg) | 40 mL | 60 mL |
| 15 to 29 or ESRD on hemodialysis | 0.5 grams (imipenem 200 mg, cilastatin 200 mg, and relebactam 100 mg) | 60 mL | 40 mL |
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.
RECARBRIO (imipenem, cilastatin, and relebactam) for injection, 1.25 grams is supplied as a white to light yellow sterile powder for constitution in a single-dose glass vial containing imipenem 500 mg (equivalent to 530 mg imipenem monohydrate), cilastatin 500 mg (equivalent to 531 mg cilastatin sodium), and relebactam 250 mg (equivalent to 263 mg relebactam monohydrate).
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.
Lactation
Risk Summary
There are insufficient data on the presence of imipenem/cilastatin and relebactam in human milk, and no data on the effects on the breastfed child, or the effects on milk production. Relebactam is present in the milk of lactating rats (see Data).
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for RECARBRIO and any potential adverse effects on the breastfed child from RECARBRIO or from the underlying maternal condition.
Data
Relebactam administered intravenously to lactating rats at a dose of 450 mg/kg/day (GD 6 to LD 14), was excreted into the milk with concentrations of approximately 5% that of maternal plasma concentrations.
Pediatric Use
The safety and efficacy of RECARBRIO in patients younger than 18 years of age have not been established.
Geriatric Use
Of the 266 patients treated with RECARBRIO in Trial 1, 113 (42.5%) were 65 years of age or older, including 55 (20.7%) patients 75 years of age and older. Of the 216 patients treated with imipenem/cilastatin plus relebactam 250 mg in Trials 2 and 3, 67 (31.0%) were 65 years of age or older, including 25 (11.6%) patients 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
RECARBRIO is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Renal Impairment
Reduce RECARBRIO dosage in patients with a CLcr less than 90 mL/min [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of RECARBRIO.
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)].
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.
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)].
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.
Development of Drug-resistant Bacteria
Prescribing RECARBRIO in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.