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Meropenem and Vaborbactam

Class: Carbapenems
Chemical Name: (4R,5S,6S)-3-[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;trihydrate
Molecular Formula: C17H31N3O8SC12H16BNO5S
CAS Number: 119478-56-7
Brands: Vabomere

Introduction

The fixed combination of meropenem and vaborbactam is a carbapenem β-lactam antibiotic.1

Uses for Meropenem and Vaborbactam

Meropenem and vaborbactam has the following uses:

Meropenem and vaborbactam is a fixed combination of meropenem (a penem antibacterial) and vaborbactam (a beta-lactamase inhibitor) and is indicated for the treatment of patients 18 years and older with complicated urinary tract infections (cUTI), including pyelonephritis, caused by Enterobacter cloacae species complex, Escherichia coli, and Klebsiella pneumoniae.1

To reduce the development of drug-resistant bacteria and maintain the effectiveness of meropenem and vaborbactam and other antibacterial drugs, meropenem and vaborbactam should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.1

Meropenem and Vaborbactam Dosage and Administration

General

Meropenem and vaborbactam is available in the following dosage form(s) and strength(s):

Single-dose vials containing sterile powder for reconstitution labeled as containing 2 grams of meropenem and vaborbactam (i.e., meropenem 1 gram [equivalent to 1.14 grams of meropenem trihydrate] and vaborbactam 1 gram).1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Dosage of the fixed combination of meropenem and vaborbactam is expressed in terms of the total of the meropenem and vaborbactam content.1

  • Administer meropenem and vaborbactam 4 grams (meropenem 2 grams and vaborbactam 2 grams) every 8 hours by intravenous infusion over 3 hours for up to 14 days, in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m 2.1

  • Dosage adjustment is recommended in patients with renal impairment who have an eGFR less than 50 mL/min/ 1.73m 2.1 (See Table 1.)

As calculated using the Modification of Diet in Renal Disease (MDRD) formula.

All doses of meropenem and vaborbactam are administered intravenously over 3 hours.

Doses adjusted for renal impairment should be administered after a hemodialysis session.

The total duration of treatment is for up to 14 days.

Table 1: Meropenem and Vaborbactam Dosage for Adults with Renal Impairment1

eGFR (mL/min /1.73m 2)

Recommended Dosage Regimen for Meropenem and Vaborbactam,,

Dosing Interval

30 to 49

Meropenem and vaborbactam 2 grams (meropenem 1 gram and vaborbactam 1 gram)

Every 8 hours

15 to 29

Meropenem and vaborbactam 2 grams (meropenem 1 gram and vaborbactam 1 gram)

Every 12 hours

Less than 15

Meropenem and vaborbactam 1 gram (meropenem 0.5 grams and vaborbactam 0.5 grams)

Every 12 hours

  • See Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution.1

  • See Full Prescribing Information for drug compatibilities.1

Cautions for Meropenem and Vaborbactam

Contraindications

Known hypersensitivity to the components of meropenem and vaborbactam or anaphylactic reactions to beta-lactams.1

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions were reported in patients treated with meropenem and vaborbactam in the clinical trials. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving therapy with beta-lactam antibacterial drugs. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another beta-lactam antibacterial drug.1

Before initiating therapy with meropenem and vaborbactam, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactam antibacterial drugs, and other allergens. If an allergic reaction to meropenem and vaborbactam occurs, discontinue the drug immediately.1

Seizure Potential

Seizures and other adverse central nervous system (CNS) experiences have been reported during treatment with meropenem, which is a component of meropenem and vaborbactam. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function.1

Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Continue anti-convulsant therapy in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, place on anti-convulsant therapy if not already instituted, and reexamine the dosage of meropenem and vaborbactam to determine whether it should be decreased or discontinued.1

Clostridium difficile-associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem and vaborbactam, 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.1

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing isolates 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.1

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.1

Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid

The concomitant use of meropenem and vaborbactam and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction.1

Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of meropenem and vaborbactam is necessary, consider supplemental anticonvulsant therapy.1

Thrombocytopenia

In patients with renal impairment, thrombocytopenia has been observed in patients treated with meropenem, but no clinical bleeding has been reported.1

Potential for Neuromotor Impairment

Alert patients receiving meropenem and vaborbactam on an outpatient basis regarding adverse reactions such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that meropenem and vaborbactam is well tolerated, advise patients not to operate machinery or motorized vehicles.1

Development of Drug-resistant Bacteria

Prescribing meropenem and vaborbactam in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of drug-resistant bacteria.1

Overgrowth of Nonsusceptible Organisms

As with other antibacterial drugs, prolonged use of meropenem and vaborbactam may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken.1

Specific Populations

Pregnancy

Fetal malformations were observed in vaborbactam-treated rabbits, therefore advise pregnant women of the potential risks to the fetus. There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem and vaborbactam, meropenem, or vaborbactam in pregnant women.1

Malformations (supernumerary lung lobes, interventricular septal defect) were observed in offspring from pregnant rabbits administered intravenous vaborbactam during the period of organogenesis at doses approximately equivalent to or above the maximum recommended human dose (MRHD) based on plasma AUC comparison. The clinical relevance of the malformations is uncertain. No similar malformations or fetal toxicity were observed in offspring from pregnant rats administered intravenous vaborbactam during organogenesis or from late pregnancy and through lactation at a dose equivalent to approximately 1.6 times the MRHD based on body surface area comparison.1

No fetal toxicity or malformations were observed in pregnant rats and cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 1.6 and 1.2 times the MRHD based on body surface area comparison, respectively. In rats administered intravenous meropenem in late pregnancy and during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 1.6 times the MRHD based on body surface area comparison.1

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.1

Animal Data for Meropenem: Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day and in cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of body surface area comparisons, approximately 1.6 times and 1.2 times higher, respectively, than the MRHD of 2 grams every 8 hours). These studies revealed no evidence of harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (equivalent to approximately 0.4 times the MRHD of 2 grams every 8 hours based on body surface area comparison) and above in rats. In a published study, meropenem administered to pregnant rats from Gestation Day 6 to Gestation Day 17, was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 1.2 times the MRHD based on body surface area comparison). In a peri-postnatal study in rats described in the published literature, intravenous meropenem was administered to dams from Gestation Day 17 until Postpartum Day 21. There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. Second generation offspring showed no meropenem-related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 1.6 times the MRHD based on body surface area comparisons).1

Animal Data for Vaborbactam: In a rat embryo-fetal toxicology study, intravenous administration of vaborbactam during Gestation Days 6–17 showed no evidence of maternal or embryofetal toxicity at doses up to 1000 mg/kg, which is equivalent to approximately 1.6 times the MRHD based on body surface area comparisons. In the rabbit, intravenous administration of vaborbactam during Gestation Days 7–19 at doses up to 1000 mg/kg/day (approximately 5 times the MRHD based on AUC exposure comparison) was not associated with maternal toxicity or fetal weight loss. A low incidence of malformations occurred in the 300 mg/kg/day mid-dose group (two fetuses from different litters with interventricular septal defects, one fetus with a fused right lung lobe and one fetus with a supernumerary lung lobe), and in the 1000 mg/kg/day high-dose group (two fetuses from different litters with supernumerary lobes). The NOAEL was considered to be 100 mg/kg/day which is equivalent to 0.3 times the MRHD based on plasma AUC exposure comparison and 6-times the MRHD based on maximum plasma concentration (C max) comparison. The clinical relevance of the malformations is uncertain. Vaborbactam C max values may have influenced malformations in the rabbit study, and the recommended 3-hour infusion time for clinical administration of vaborbactam is associated with lower plasma C max values than the 30-minute infusions in rabbits. In a peri-postnatal study in rats, vaborbactam administered intravenously to pregnant dams from Gestation Day 6 to Lactation Day 20 caused no adverse effects on the dams, or in first and second generation offspring. The NOAEL was considered to be 1000 mg/kg/day (equivalent to approximately 1.6 times the MRHD based on body surface area comparison).1

Lactation

Meropenem has been reported to be excreted in human milk. It is unknown whether vaborbactam is excreted in human milk. No information is available on the effects of meropenem and vaborbactam on the breast-fed child or on milk production.1

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for meropenem and vaborbactam and any potential adverse effects on the breast-fed child from meropenem and vaborbactam or from the underlying maternal condition.1

Pediatric Use

The safety and effectiveness of meropenem and vaborbactam in pediatric patients (younger than 18 years of age) has not been established. Studies of meropenem and vaborbactam have not been conducted in patients younger than 18 years of age.1

Geriatric Use

Of the 272 patients treated with meropenem and vaborbactam in the Phase 3 cUTI trial, 48 (18%) patients were 65 years of age and older, while 39 (14%) patients were 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.1

Meropenem, a component of meropenem and vaborbactam, is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. 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.1

Population pharmacokinetic (PK) analysis found no clinically relevant change in pharmacokinetic parameters in elderly patients. No dosage adjustment based on age is required. Dosage adjustment for elderly patients should be based on renal function.1

Renal Impairment

Pharmacokinetic studies conducted with meropenem and vaborbactam in subjects with renal impairment have shown that the plasma exposures of both meropenem and vaborbactam increased with decreasing renal function. Dosage adjustment for meropenem and vaborbactam is recommended in patients with renal impairment (eGFR less than 50 mL/min/1.73m 2).1

For patients with changing renal function, monitor serum creatinine concentrations and eGFR at least daily and adjust the dosage of meropenem and vaborbactam accordingly. Meropenem and vaborbactam are removed by hemodialysis. Following a single dose of meropenem and vaborbactam, vaborbactam exposure was substantially greater when meropenem and vaborbactam was administered after hemodialysis than before hemodialysis.1

Common Adverse Effects

The most frequently reported adverse reactions occurring in ≥3% of patients treated with meropenem and vaborbactam were headache, phlebitis/infusion site reactions, and diarrhea.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing 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. If administration of meropenem and vaborbactam is necessary, then supplemental anti-convulsant therapy should be considered.1

Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Co-administration of probenecid with meropenem and vaborbactam is not recommended.1

Actions and Spectrum

Mechanism of Action

The meropenem component of meropenem and vaborbactam is a penem antibacterial drug. The bactericidal action of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets. Meropenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria, with the exception of carbapenem hydrolyzing beta-lactamases.1

The vaborbactam component of meropenem and vaborbactam is a non-suicidal beta-lactamase inhibitor that protects meropenem from degradation by certain serine beta-lactamases such as Klebsiella pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity. Vaborbactam does not decrease the activity of meropenem against meropenem-susceptible organisms.1

Spectrum

Meropenem and vaborbactam has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections.1

    Gram-negative Bacteria
  • Enterobacter cloacae species complex1

  • Escherichia coli1

  • Klebsiella pneumoniae1

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro MIC less than or equal to the susceptible breakpoint for meropenem and vaborbactam against isolates of a similar genus or organism group. However, the efficacy of meropenem and vaborbactam in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.1

    Gram-negative Bacteria
  • Citrobacter freundii1

  • Citrobacter koseri1

  • Enterobacter aerogenes1

  • Klebsiella oxytoca1

  • Morganella morganii1

  • Proteus mirabilis1

  • Providencia spp.1

  • Pseudomonas aeruginosa1

  • Serratia marcescens1

In vitro synergy studies have not demonstrated antagonism between meropenem and vaborbactam and levofloxacin, tigecycline, polymyxin, amikacin, vancomycin, azithromycin, daptomycin, or linezolid.1

Resistance

Mechanisms of beta-lactam resistance may include the production of beta-lactamases, modification of PBPs by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin. Meropenem and vaborbactam may not have activity against gram-negative bacteria that have porin mutations combined with overexpression of efflux pumps.1

Clinical isolates may produce multiple beta-lactamases, express varying levels of beta-lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.1

Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.1

Meropenem and vaborbactam demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: KPC, SME, TEM, SHV, CTX-M, CMY, and ACT.1

Meropenem and vaborbactam is not active against bacteria that produce metallo-beta lactamases or oxacillinases with carbapenemase activity.1

In the Phase 3 cUTI trial with meropenem and vaborbactam, some isolates of E. coli, K. pneumoniae, E. cloacae, C. freundii, P. mirabilis, and P. stuartii that produced beta-lactamases were susceptible to meropenem and vaborbactam (minimum inhibitory concentration ≤4 mcg /mL). These isolates produced one or more beta-lactamases of the following enzyme groups: OXA (non-carbapenemases), KPC, CTX-M, TEM, SHV, CMY, and ACT.1

Some beta-lactamases were also produced by an isolate of K. pneumoniae that was not susceptible to meropenem and vaborbactam (minimum inhibitory concentration ≥32 mcg/mL). This isolate produced beta-lactamases of the following enzyme groups: CTX-M, TEM, SHV, and OXA.1

No cross-resistance with other classes of antimicrobials has been identified. Some isolates resistant to carbapenems (including meropenem) and to cephalosporins may be susceptible to meropenem and vaborbactam.1

Advice to Patients

Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask patient about any previous hypersensitivity reactions to meropenem and vaborbactam, penicillins, cephalosporins, other beta-lactams, or other allergens.1

Patients receiving meropenem and vaborbactam on an outpatient basis must be alerted of adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that meropenem and vaborbactam is well tolerated, patients should not operate machinery or motorized vehicles.1

Counsel patients that diarrhea is a common problem caused by antibacterial drugs including, meropenem and vaborbactam, which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible.1

Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with meropenem and vaborbactam. If treatment with meropenem and vaborbactam is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed.1

Counsel patients that antibacterial drugs, including meropenem and vaborbactam, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When meropenem and vaborbactam is prescribed to treat a bacterial infection, tell patients that, although it is common to feel better early in the course of therapy, take the medication exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by meropenem and vaborbactam or other antibacterial drugs in the future.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Meropenem And Vaborbactam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For Injection, for IV infusion

2 g (1 g of meropenem and 1 g of vaborbactam)

Vabomere

The Medicines Company

AHFS Drug Information. © Copyright 2017, Selected Revisions October 9, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. The Medicines Company. Vabomere (meropenem and vaborbactam) INTRAVENOUS prescribing information. 2017 Aug.

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