Vabomere
(meropenem / vaborbactam)Dosage & Administration
| eGFR * (mL/min/ 1.73m2) | Recommended Dosage Regimen for VABOMERE (meropenem and vaborbactam) †, ‡, § | Dosing Interval |
|---|---|---|
| 30 to 49 | VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) | Every 8 hours |
| 15 to 29 | VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) | Every 12 hours |
| Less than 15 | VABOMERE 1 gram (meropenem 0.5 grams and vaborbactam 0.5 grams) | Every 12 hours |
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Vabomere Prescribing Information
. Complicated Urinary Tract Infections (cUTI), including Pyelonephritis
VABOMERE® is indicated for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex.
. Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of VABOMERE and other antibacterial drugs, VABOMERE 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
The recommended dosage of VABOMERE is 4 grams (meropenem 2 grams and vaborbactam 2 grams) administered every 8 hours by intravenous (IV) infusion over 3 hours in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) greater than or equal to 50 mL/min/1.73m2. The duration of treatment is for up to 14 days.
Dosage Adjustments in Patients with Renal Impairment
Dosage adjustment is recommended in patients with renal impairment who have an eGFR less than 50 mL/min/1.73m2. The recommended dosage of VABOMERE in patients with varying degrees of renal function is presented in Table 1. For patients with changing renal function, monitor serum creatinine concentrations and eGFR at least daily and adjust the dosage of VABOMERE accordingly [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Meropenem and vaborbactam are removed by hemodialysis [see Clinical Pharmacology (12.3)]. For patients maintained on hemodialysis, administer VABOMERE after a hemodialysis session.
| eGFR * (mL/min/ 1.73m2) | Recommended Dosage Regimen for VABOMERE (meropenem and vaborbactam) †, ‡, § | Dosing Interval |
|---|---|---|
| ||
| 30 to 49 | VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) | Every 8 hours |
| 15 to 29 | VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) | Every 12 hours |
| Less than 15 | VABOMERE 1 gram (meropenem 0.5 grams and vaborbactam 0.5 grams) | Every 12 hours |
Preparation and Administration of VABOMERE for Intravenous Infusion
Preparation
VABOMERE is supplied as a dry powder in a single-dose vial that must be constituted and further diluted prior to intravenous infusion as outlined below. VABOMERE does not contain preservatives. Aseptic technique must be used for constitution and dilution.
1. To prepare the required dose for intravenous infusion, constitute the appropriate number of vials, as determined from Table 2 below. Withdraw 20 mL of 0.9% Sodium Chloride Injection, USP, from an infusion bag and constitute each vial of VABOMERE.
2. Mix gently to dissolve. The constituted VABOMERE solution will have an approximate meropenem concentration of 0.05 gram/mL and an approximate vaborbactam concentration of 0.05 gram/mL. The final volume is approximately 21.3 mL. The constituted solution is not for direct injection.
3. The constituted solution must be diluted further, immediately, in a 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. The intravenous infusion of the diluted solution must be completed within 4 hours if stored at room temperature or 22 hours if stored refrigerated at 2°C to 8°C (36°F to 46°F).
4. To dilute the constituted solution, withdraw the full or partial constituted vial contents from each vial and add it back into the infusion bag in accordance with Table 2 below.
| VABOMERE Dose (meropenem and vaborbactam) | Number of Vials to Constitute for Further Dilution | Volume to Withdraw from Each Constituted Vial for Further Dilution | Volume of Infusion Bag | Final Infusion Concentration of VABOMERE |
|---|---|---|---|---|
| 4 grams (2 grams-2 grams) | 2 vials | Entire contents (approximately 21 mL) | 250 mL | 16 mg/mL |
| 500 mL | 8 mg/mL | |||
| 1,000 mL | 4 mg/mL | |||
| 2 grams (1 gram-1 gram) | 1 vial | Entire contents (approximately 21 mL) | 125 mL | 16 mg/mL |
| 250 mL | 8 mg/mL | |||
| 500 mL | 4 mg/mL | |||
| 1 gram (0.5 gram-0.5 gram) | 1 vial | 10.5 mL (discard unused portion) | 70 mL | 14.3 mg/mL |
| 125 mL | 8 mg/mL | |||
| 250 mL | 4 mg/mL |
5. Visually inspect the diluted VABOMERE solution for particulate matter and discoloration prior to administration (the color of the VABOMERE infusion solution for administration ranges from colorless to light yellow). Discard unused portion after use.
Drug Compatibility
VABOMERE solution for administration by 3-hour infusion is only compatible with 0.9% Sodium Chloride Injection, USP.
Compatibility of VABOMERE solution for administration with other drugs has not been established.
VABOMERE 2 grams (meropenem and vaborbactam) for injection, is supplied as a white to light yellow sterile powder for constitution in single-dose, clear glass vials containing meropenem 1 gram (equivalent to 1.14 grams meropenem trihydrate) and vaborbactam 1 gram.
Pregnancy
Risk Summary
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 VABOMERE, meropenem, or vaborbactam in pregnant women.
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 [see Data].
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 [see Data].
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.
Data
Animal Data
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 study1, 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 literature1, 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).
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 (Cmax) comparison. The clinical relevance of the malformations is uncertain. Vaborbactam Cmax 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 Cmax 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).
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.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VABOMERE and any potential adverse effects on the breast-fed child from VABOMERE or from the underlying maternal condition.
Females and Males of Childbearing Potential
Use of VABOMERE may reduce the effectiveness of hormonal contraceptives. Advise patients taking hormonal contraceptives to use an effective alternative non-hormonal contraception or additional contraceptive method (e.g., barrier method of contraception) during treatment with VABOMERE [see Drug Interactions (7.4)].
Pediatric Use
The safety and effectiveness of VABOMERE in pediatric patients (younger than 18 years of age) has not been established. Studies of VABOMERE have not been conducted in patients younger than 18 years of age.
Geriatric Use
Of the 272 patients treated with VABOMERE 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.
Meropenem, a component of VABOMERE, 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.
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 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
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 [see Clinical Pharmacology (12.3)]. Dosage adjustment for VABOMERE is recommended in patients with renal impairment (eGFR less than 50 mL/min/1.73m2) [see Dosage and Administration (2.2)].
For patients with changing renal function, monitor serum creatinine concentrations and eGFR at least daily and adjust the dosage of VABOMERE accordingly. Meropenem and vaborbactam are removed by hemodialysis. Following a single dose of VABOMERE, vaborbactam exposure was substantially greater when VABOMERE was administered after hemodialysis than before hemodialysis [see Clinical Pharmacology (12.3)].
VABOMERE is contraindicated in patients with known hypersensitivity to any components of VABOMERE (meropenem and vaborbactam), or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactam antibacterial drugs [see Warnings and Precautions (5.1)].
Hypersensitivity Reactions
Hypersensitivity reactions were reported in patients treated with VABOMERE in the clinical trials [see Adverse Reactions (6.1)]. 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. Before initiating therapy with VABOMERE, 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 VABOMERE occurs, discontinue the drug immediately.
Seizure Potential
Seizures and other adverse Central Nervous System (CNS) experiences have been reported during treatment with meropenem, which is a component of VABOMERE. 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 [see Adverse Reactions (6.1) and Drug Interactions (7.1)].
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 VABOMERE to determine whether it should be decreased or discontinued.
Rhabdomyolysis
Rhabdomyolysis has been reported with the use of meropenem, a component of VABOMERE [see Adverse Reactions (6.2)]. If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue VABOMERE and initiate appropriate therapy.
Clostridioides difficile-associated Diarrhea
Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including VABOMERE, 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 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.
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.
Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid
The concomitant use of VABOMERE 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. 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 VABOMERE is necessary, consider supplemental anticonvulsant therapy [see Drug Interactions (7.1)].
Thrombocytopenia
In patients with renal impairment, thrombocytopenia has been observed in patients treated with meropenem, but no clinical bleeding has been reported [see Dosage and Administration (2.2), Adverse Reactions (6.1), Use in Specific Populations (8.5) and (8.6), and Clinical Pharmacology (12.3)].
Potential for Neuromotor Impairment
Alert patients receiving VABOMERE 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 VABOMERE is well tolerated, advise patients not to operate machinery or motorized vehicles [see Adverse Reactions (6.1)].
Development of Drug-Resistant Bacteria
Prescribing VABOMERE 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 [see Indications and Usage (1.2)].
Overgrowth of Non-susceptible Organisms
As with other antibacterial drugs, prolonged use of VABOMERE may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken.