RECARBRIO (Page 2 of 7)

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.

Table 2: Preparation of Reduced RECARBRIO Doses for Intravenous Administration in Patients with Renal Impairment
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

2.5 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.

2.6 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

2.7 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.

3 DOSAGE FORMS AND STRENGTHS

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).

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta lactams. Before initiating therapy with RECARBRIO, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta lactams, and other allergens. If a hypersensitivity reaction to RECARBRIO occurs, discontinue the therapy immediately.

RECARBRIO is contraindicated in patients with a history of severe hypersensitivity to any component of RECARBRIO [see Contraindications (4)].

5.2 Seizures and Other Central Nervous System (CNS) Adverse Reactions

CNS adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with imipenem/cilastatin, a component of RECARBRIO, especially when recommended dosages of imipenem were exceeded. These have been reported most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function.

Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether RECARBRIO should be discontinued.

5.3 Increased Seizure Potential Due to Interaction with Valproic Acid

Concomitant use of RECARBRIO, with valproic acid or divalproex sodium may increase the risk of breakthrough seizures. Avoid concomitant use of RECARBRIO with valproic acid or divalproex sodium or consider alternative antibacterial drugs other than carbapenems [see Drug Interactions (7.2)].

5.4 Clostridioides difficile -Associated Diarrhea (CDAD)

Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including RECARBRIO, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 Development of Drug-resistant Bacteria

Prescribing RECARBRIO in the absence of a proven or strongly 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.

6 ADVERSE REACTIONS

The following serious adverse reactions are described in greater detail in the Warnings and Precautions section.

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.

Overview of the Safety Evaluation of RECARBRIO

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 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 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 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 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 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 3 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 3: Adverse Reactions Occurring in Greater Than or Equal to 4% of HABP/VABP Patients Receiving RECARBRIO in Trial 1
Adverse Reaction RECARBRIO *(N=266) N (%) Piperacillin/Tazobactam (N=269)N (%)
*
RECARBRIO, IV every 6 hours.
Piperacillin 4000 mg and Tazobactam 500 mg (4.5 grams), IV every 6 hours.
Hypokalemia includes hypokalemia and blood potassium decreased.
§
Hyponatremia includes hyponatremia and blood sodium decreased.
Rash includes rash, rash erythematous, and rash generalized.
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 21 (7.9%) 26 (9.7%)
Hyponatremia § 17 (6.4%) 3 (1.1%)
Skin and subcutaneous tissue disorders
Rash 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 4 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 4: Adverse Reactions Occurring in Greater Than or Equal to 1% of cUTI and cIAI Patients Receiving Imipenem/Cilastatin plus Relebactam 250 mg or Imipenem/Cilastatin in Trials 2 and 3
Adverse Reaction Imipenem/Cilastatin and Relebactam 250 mg *(N=216)N (%) IMI + Placebo (N=214)N (%)
*
Imipenem/Cilastatin (500 mg/500 mg) + Relebactam (250 mg), IV every 6 hours.
Imipenem/Cilastatin (500 mg/500 mg) + Placebo, IV every 6 hours.
Anemia includes anemia and hemoglobin decreased.
§
Infusion site reactions include infusion site phlebitis, infusion site erythema, and infusion site pain.
Central nervous system adverse reactions include agitation, apathy, confusional states, delirium, disorientation, slow speech, and somnolence.
#
Hypertension includes hypertension and blood pressure increased.
Blood and lymphatic system disorders
Anemia 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 § 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 2 (1%) 5 (2%)
Vascular disorders
Hypertension # 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.

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