Imipenem/ cilastatin/ relebactam

Imipenem/ cilastatin/ relebactam is a combination medication that contains three active ingredients: imipenem, cilastatin, and relebactam. Each component has a different mechanism of action that works together to provide a broad spectrum of antibacterial activity against a range of Gram-negative and Gram-positive bacteria.

Imipenem is a carbapenem antibiotic that inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs) and disrupting the formation of peptidoglycan, a key component of the bacterial cell wall. This results in bacterial cell death.

Cilastatin is a renal dehydropeptidase inhibitor that prevents the degradation of imipenem in the kidneys, increasing the half-life of imipenem and allowing for longer dosing intervals.

Relebactam is a beta-lactamase inhibitor that binds to and inhibits beta-lactamase enzymes, which are produced by some bacteria to break down and inactivate beta-lactam antibiotics. By inhibiting beta-lactamase, relebactam enhances the activity of imipenem against beta-lactamase-producing bacteria.

In summary, the combination of imipenem, cilastatin, and relebactam works synergistically to provide a potent and broad-spectrum antibiotic activity against a range of bacterial infections.

For the recommended dose of 1.25 grams every 6 hours administered by intravenous infusion over 30 minutes, the Cmax of imipenem, cilastatin, and relebactam are approximately 89 mcg/mL, 78 mcg/mL, and 62 mcg/mL, respectively. The Tmax for all three components is achieved at the end of infusion.

The onset of action for Imipenem/ cilastatin/ relebactam is immediate after infusion, with peak activity reached within a few hours after administration. The duration of action varies depending on the severity of the infection and the patient's response to treatment. In general, the recommended duration of therapy is 4 to 14 days, depending on the indication and clinical response.

Imipenem/ cilastatin/ relebactam is a combination antibiotic medication that has several benefits in the treatment of bacterial infections. Some of the benefits include:

1. Broad-spectrum coverage: Imipenem/ cilastatin/ relebactam has a broad spectrum of coverage, meaning it can effectively treat a wide range of bacterial infections.
2. Resistance to beta-lactamases: Relebactam, one of the components of this medication, is a beta-lactamase inhibitor that helps to prevent the breakdown of imipenem and cilastatin by bacterial enzymes. This allows the medication to remain effective against bacteria that produce beta-lactamases, which can cause resistance to other antibiotics.
3. Improved outcomes: Clinical studies have shown that Imipenem/ cilastatin/ relebactam can improve outcomes for patients with certain types of infections, including complicated urinary tract infections and complicated intra-abdominal infections.
4. Well-tolerated: This medication is generally well-tolerated by patients, with few serious side effects reported in clinical trials.

• Complicated intra-abdominal infections
• Hospital-acquired or ventilator-associated pneumonia
• Complicated urinary tract infections (including pyelonephritis or UTI with systemic signs/symptoms)

Intra-Abdominal Infection, Complicated:

• For complicated intra-abdominal infections, Imipenem/ cilastatin/ relebactam should be administered intravenously at a dosage of 1.25 g every 6 hours.
• The duration of therapy is typically 4 to 7 days after source control has been achieved through surgical or percutaneous intervention, as recommended by SIS (Mazuski 2017) and SIS/IDSA (Solomkin 2010).
• For infections managed without surgical or percutaneous intervention, a longer duration of therapy may be necessary .

Pneumonia, Hospital Acquired or Ventilator Associated:

• For hospital-acquired or ventilator-associated pneumonia, Imipenem/ cilastatin/ relebactam should be administered intravenously at a dosage of 1.25 g every 6 hours.
• The duration of therapy may vary depending on the severity of the infection and the patient's response to therapy.
• Typically, treatment is given for 7 days, but a longer course may be necessary for severe or complicated infections.

Urinary Tract Infection, Complicated:

• For complicated urinary tract infections such as pyelonephritis or those with systemic signs/symptoms, Imipenem/ cilastatin/ relebactam should be administered intravenously at a dosage of 1.25 g every 6 hours.
• Once symptoms improve, switch to an appropriate oral regimen if culture and susceptibility results allow.
• The total duration of therapy ranges from 5 to 14 days and depends on clinical response and the antimicrobial chosen to complete the regimen.

• 500mg/500mg/250mg per vial (ie, 1.25g/vial) powder for injection

• For patients with a creatinine clearance (CrCl) of 90 mL/minute or greater, no dosage adjustment is needed.
• For patients with a CrCl of 60 to 89 mL/minute, the recommended dosage is 1 g every 6 hours.
• For patients with a CrCl of 30 to 59 mL/minute, the recommended dosage is 750 mg every 6 hours.
• For patients with a CrCl of 15 to 29 mL/minute, the recommended dosage is 500 mg every 6 hours.
• Imipenem/ cilastatin/ relebactam should not be administered to patients with a CrCl less than 15 mL/minute unless hemodialysis is initiated within 48 hours.
• For patients with end-stage renal disease receiving hemodialysis, the recommended dosage is 500 mg every 6 hours, to be administered after hemodialysis and at intervals timed from the end of that hemodialysis session.
• The use of Imipenem/ cilastatin/ relebactam is not recommended for patients receiving peritoneal dialysis due to insufficient data.

Before initiating therapy with Imipenem/ cilastatin/ relebactam, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta lactams, and other allergens. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta lactams. If a hypersensitivity reaction to Imipenem/ cilastatin/ relebactam occurs, discontinue the therapy immediately. Imipenem/ cilastatin/ relebactam is contraindicated in patients with a history of severe hypersensitivity to any component of Imipenem/ cilastatin/ relebactam.

CNS adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with imipenem/cilastatin, a component of Imipenem/ cilastatin/ relebactam. 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 Imipenem/ cilastatin/ relebactam should be discontinued.

Concomitant use of Imipenem/ cilastatin/ relebactam, with valproic acid or divalproex sodium may increase the risk of breakthrough seizures. Avoid concomitant use of Imipenem/ cilastatin/ relebactam with valproic acid or divalproex sodium or consider alternative antibacterial drugs other than carbapenems.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including imipenem/cilastatin plus relebactam. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued.

Prescribing Imipenem/ cilastatin/ relebactam 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.

The available information on the presence of imipenem/cilastatin and relebactam in human milk is insufficient to determine their potential effects on the breastfed child or milk production. Although relebactam has been found in the milk of lactating rats, the effects of this on human infants are unknown. Therefore, it is important to consider both the benefits of breastfeeding and the mother's clinical need for Imipenem/ cilastatin/ relebactam, as well as any potential risks to the breastfed child.

According to available data, lactating rats given intravenous doses of 450 mg/kg/day of relebactam from gestational day 6 to lactation day 14 showed concentrations of the drug in their milk that were approximately 5% of the concentrations found in maternal plasma.

The potential risks to pregnancy and fetal development should be communicated to pregnant women considering treatment with Imipenem/ cilastatin/ relebactam, imipenem, cilastatin, or relebactam. This is due to the observed embryonic loss in monkeys treated with imipenem/cilastatin and fetal abnormalities in mice treated with relebactam. However, there is currently insufficient human data to establish any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Animal studies with imipenem and cilastatin, administered parenterally during organogenesis to mice, rats, rabbits, and cynomolgus monkeys, showed no evidence of drug-induced fetal malformations. However, an increase in embryonic loss was observed in cynomolgus monkeys administered imipenem/cilastatin at doses similar to the maximum recommended human dose (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 MRHD in humans showed no adverse effects on pregnancy or embryofetal development. In an embryofetal study, parental administration of relebactam to pregnant mice during organogenesis was associated with an increased percent litter incidence of total skeletal malformations at a plasma exposure approximately 6 times the human exposure at the MRHD. However, relebactam administered to rats during gestation through lactation was not associated with any fetal toxicity, developmental delays, or impaired reproduction in first generation offspring at plasma exposures equivalent to 8 times the human exposure at the MRHD.

• Diarrhea
• Nausea
• Headache
• Elevated liver enzymes
• Rash
• Elevated creatinine
• Hypersensitivity reactions (such as rash, itching, or shortness of breath)

• Clostridioides difficile infection (CDI)
• Seizures
• Decreased white blood cell count (leukopenia)
• Decreased platelet count (thrombocytopenia)
• Increased blood eosinophil count (eosinophilia)
• Increased prothrombin time (PT)
• Prolonged activated partial thromboplastin time (aPTT)

• Stevens-Johnson syndrome (SJS)
• Toxic epidermal necrolysis (TEN)
• Anaphylaxis
• Angioedema
• Hepatic failure
• Renal failure
• Pancytopenia

Ganciclovir

• In patients who received ganciclovir concomitantly with imipenem/cilastatin, a component of Imipenem/ cilastatin/ relebactam, generalized seizures have been reported. Therefore, the use of ganciclovir with Imipenem/ cilastatin/ relebactam should be avoided unless the potential benefits outweigh the risks.

Valproic Acid

• According to case reports in the literature, the concomitant use of carbapenems, including imipenem/cilastatin (components of Imipenem/ cilastatin/ relebactam), with valproic acid or divalproex sodium may decrease valproic acid concentrations. This decrease in valproic acid concentrations may increase the risk of breakthrough seizures [see Warnings and Precautions (5.3)]. 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.
• To avoid such risks, it is recommended to consider alternative antibacterials other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. Additionally, it is advised to avoid concomitant use of Imipenem/ cilastatin/ relebactam with valproic acid or divalproex sodium.

• Diarrhea
• Nausea
• Vomiting
• Headache
• Rash
• Abdominal pain
• Elevated liver enzymes
• Decreased appetite
• Anemia
• Increased risk of fungal or bacterial infections
• Allergic reactions such as hives, itching, and swelling
• Difficulty breathing
• Chest pain
• Rapid or irregular heartbeat
• Seizures or convulsions
• Confusion or hallucinations

The potential risks to pregnancy and fetal development should be communicated to pregnant women considering treatment with Imipenem/ cilastatin/ relebactam, imipenem, cilastatin, or relebactam. This is due to the observed embryonic loss in monkeys treated with imipenem/cilastatin and fetal abnormalities in mice treated with relebactam. However, there is currently insufficient human data to establish any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Animal studies with imipenem and cilastatin, administered parenterally during organogenesis to mice, rats, rabbits, and cynomolgus monkeys, showed no evidence of drug-induced fetal malformations. However, an increase in embryonic loss was observed in cynomolgus monkeys administered imipenem/cilastatin at doses similar to the maximum recommended human dose (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 MRHD in humans showed no adverse effects on pregnancy or embryofetal development. In an embryofetal study, parental administration of relebactam to pregnant mice during organogenesis was associated with an increased percent litter incidence of total skeletal malformations at a plasma exposure approximately 6 times the human exposure at the MRHD. However, relebactam administered to rats during gestation through lactation was not associated with any fetal toxicity, developmental delays, or impaired reproduction in first generation offspring at plasma exposures equivalent to 8 times the human exposure at the MRHD.

The available information on the presence of imipenem/cilastatin and relebactam in human milk is insufficient to determine their potential effects on the breastfed child or milk production. Although relebactam has been found in the milk of lactating rats, the effects of this on human infants are unknown. Therefore, it is important to consider both the benefits of breastfeeding and the mother's clinical need for Imipenem/ cilastatin/ relebactam, as well as any potential risks to the breastfed child.

According to available data, lactating rats given intravenous doses of 450 mg/kg/day of relebactam from gestational day 6 to lactation day 14 showed concentrations of the drug in their milk that were approximately 5% of the concentrations found in maternal plasma.

In Trials 1 and 2, a total of 216 patients were administered imipenem/cilastatin plus relebactam 250 mg, out of which 67 patients (31.0%) were aged 65 years or older. Among these elderly patients, 25 (11.6%) were 75 years of age or older.

It should be noted that Imipenem/ cilastatin/ relebactam is largely eliminated from the body through the kidney, and patients with impaired renal function may be at an increased risk of experiencing adverse effects. Since elderly patients are more likely to have impaired renal function, the dosage of the drug should be carefully selected and renal function should be monitored. There is no need for a dosage adjustment based on age alone, but any necessary adjustments for elderly patients should be based on their renal function.

Pharmacokinetics of Imipenem/ cilastatin/ relebactam Combination:

• Steady-state pharmacokinetic parameters in patients with active bacterial infection with CLcr 90 mL/min or greater
• Pharmacokinetic parameters similar for single- and multiple-dose administration due to minimal accumulation

Distribution:

• Imipenem and cilastatin bind to human plasma proteins approximately 20% and 40%, respectively, while binding of relebactam is approximately 22% and is independent of concentration at a range of 5 to 50 μM
• Steady-state volume of distribution of imipenem, cilastatin, and relebactam is 24.3 L, 13.8 L, and 19.0 L, respectively, in subjects following multiple doses infused over 30 minutes every 6 hours

Elimination:

• Imipenem and relebactam are eliminated from the body by the kidneys with a mean half-life of 1 (± 0.5) hour and 1.2 (± 0.7) hours, respectively

Metabolism:

• Imipenem is metabolized in the kidneys by dehydropeptidase when administered alone, while cilastatin, an inhibitor of this enzyme, prevents renal metabolism
• Relebactam is minimally metabolized with unchanged relebactam being the only drug-related component detected in human plasma

Excretion:

• Imipenem, cilastatin, and relebactam are mainly excreted by the kidneys
• Following multiple-dose administration, approximately 63% of the administered imipenem dose, and 77% of the administered cilastatin dose are recovered as unchanged parent drugs in the urine, while greater than 90% of the administered relebactam dose was excreted unchanged in human urine.
• Therapeutic Benefits of Imipenem/ cilastatin/ relebactam Combination

The therapeutic benefits of the Imipenem/ cilastatin/ relebactam combination include:

1. Enhanced efficacy against Gram-negative pathogens, including those resistant to carbapenems alone.
2. Broader spectrum of activity against resistant bacteria, including those that produce extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemase (KPC), and metallo-β-lactamases (MBLs).
3. Improved clinical outcomes for patients with complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs), and hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP).
4. Reduced emergence of resistance due to the combination of three different mechanisms of action.
5. Well-tolerated and safe, with a similar adverse event profile to imipenem/cilastatin alone.