RECARBRIO

(imipenem, cilastatin, and relebactam) for injection 1.25 g

Safety

Adverse reactions

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 hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), complicated urinary tract infections (cUTI), and complicated intra-abdominal infections (cIAI) (Trials 1, 2, and 3, respectively).

In the HABP/VABP trial (Trial 1), patients were treated with either RECARBRIO™ (imipenem, cilastatin, and relebactam) 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. The table below 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.

Adverse reactions occurring in greater than or equal to 4% of HABP/VABP patients receiving RECARBRIO in Trial 1

Adverse Reaction

RECARBRIOa

(N=266)

N (%)

Piperacillin/Tazobactamb

(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
Hypokalemiac 21 (7.9%) 26 (9.7%)
Hyponatremiad 17 (6.4%) 3 (1.1%)
Skin and subcutaneous tissue disorders
Rashe 11 (4.1%) 5 (1.9%)

aRECARBRIO, IV every 6 hours.

bPiperacillin 4000 mg and Tazobactam 500 mg (4.5 grams), IV every 6 hours.

cHypokalemia includes hypokalemia and blood potassium decreased.

dHyponatremia includes hyponatremia and blood sodium decreased.

eRash includes rash, rash erythematous, and rash generalized.

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. The table below 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.

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 mga

(N=216)

N (%)

IMI + Placebob

(N=214)

N (%)

Blood and lymphatic system disorders
Anemiac 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 reactionsd 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 reactionse 2 (1%) 5 (2%)
Vascular disorders
Hypertensionf 4 (2%) 6 (3%)

aImipenem/Cilastatin (500 mg/500 mg) + Relebactam (250 mg), IV every 6 hours.

bImipenem/Cilastatin (500 mg/500 mg) + Placebo, IV every 6 hours.

cAnemia includes anemia and hemoglobin decreased.

dInfusion site reactions include infusion site phlebitis, infusion site erythema, and infusion site pain.

eCentral nervous system adverse reactions include agitation, apathy, confusional states, delirium, disorientation, slow speech, and somnolence.

fHypertension includes hypertension and blood pressure increased.

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

Indications

RECARBRIO is indicated for the treatment of patients 18 years of age and older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), 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.

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.

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 the cUTI and cIAI indications is based on limited clinical safety and efficacy data for RECARBRIO.

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.

Selected Safety Information

  • Hypersensitivity Reactions: RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of RECARBRIO. 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.
  • 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 (eg, 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.
  • 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. 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.
  • 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.
  • Adverse Reactions: The most frequently reported adverse reactions occurring in ≥2% of cUTI and cIAI patients treated with RECARBRIO were diarrhea (6%), nausea (6%), headache (4%), vomiting (3%), alanine aminotransferase increased (3%), aspartate aminotransferase increased (3%), phlebitis/infusion site reactions (2%), pyrexia (2%), and hypertension (2%). The most frequently reported adverse reactions occurring in ≥5% of HABP/VABP patients treated with RECARBRIO were aspartate aminotransferase increased (11.7%), anemia (10.5%), alanine aminotransferase increased (9.8%), diarrhea (7.9%), hypokalemia (7.9%), and hyponatremia (6.4%).
US-TIX-0010609/20