DRUG INTERACTIONS

1. Valproic Acid

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.

If administration of VABOMERE is necessary, then supplemental anti-convulsant therapy should be considered 

2.Probenecid

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

U.S. FDA APPROVED  DRUGS DURING 2017

ADVERSE REACTIONS

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

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

• Hypersensitivity reactions were reported with the use of VABOMERE. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Discontinue infusion if signs of acute hypersensitivity occur. 

• Seizures and other adverse Central Nervous System experiences have been reported during treatment with meropenem, a component of VABOMERE. 

• Clostridium difficile-associated diarrhea has been reported with nearly all systemic antibacterial agents, including VABOMERE. Evaluate patients if diarrhea occurs. 

• Co-administration of meropenem with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. 

 PATIENT COUNSELING INFORMATION

Serious Allergic Reactions-                                                                                      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 VABOMERE (meropenem and vaborbactam), penicillins, cephalosporins, other beta-lactams, or other allergens [see Warnings and Precautions 

Seizures-                                                                                                                   Patients receiving VABOMERE 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 VABOMERE is well tolerated, patients should not operate machinery or motorized vehicles

Potentially Serious Diarrhea-                                                                                Counsel patients that diarrhea is a common problem caused by antibacterial drugs including VABOMERE, 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.

Interaction with Valproic Acid-                                                                              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 coadministration with VABOMERE.

If treatment with VABOMERE is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed].

Antibacterial Resistance-                                                                                       Counsel patients that antibacterial drugs, including VABOMERE, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).

When VABOMERE 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 VABOMERE or other antibacterial drugs in the future.].

Manufactured by:Facta Farmaceutici, S.p.A. Teramo, 64100, Italy

Marketed by: The Medicines Company Parsippany, NJ 07054

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                       VABOMERE is an antibacterial drug 

2. Pharmacodynamics-                                                                                            Similar to other beta-lactam antibacterial drugs, the percentage of time of a dosing interval that unbound plasma concentration of meropenem exceeds the meropenem-vaborbactam minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection.

3. Pharmacokinetics-

Pharmacokinetic (PK) Parameters The mean PK parameters of meropenem and vaborbactam in healthy adults with normal renal function after single and multiple 3-hour infusions of VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams) administered every 8 hours were ascertained, and the PK parameters of meropenem and vaborbactam were similar for single and multiple dose administration of VABOMERE. 

 Distribution-                                                                                                                  The plasma protein binding of meropenem is approximately 2%. The plasma protein binding of vaborbactam is approximately 33%. The steady-state volumes of distribution of meropenem and vaborbactam in patients were 20.2 L and 18.6 L, respectively.

Elimination-                                                                                                                    The clearance of meropenem in healthy subjects following multiple doses is 15.1 L/h and for vaborbactam is 10.9 L/h. The t1/2 is 1.22 hours and 1.68 hours for meropenem and vaborbactam, respectively.

Metabolism-                                                                                                                       A minor pathway of meropenem elimination is hydrolysis of the beta-lactam ring (meropenem open lactam), which accounts for 22% of a dose eliminated via the urine. Vaborbactam does not undergo metabolism.

Excretion-                                                                                                                     Both meropenem and vaborbactam are primarily excreted via the kidneys. Approximately 40–60% of a meropenem dose is excreted unchanged within 24-48 hours with a further 22% recovered as the microbiologically inactive hydrolysis product.

The mean renal clearance for meropenem was 7.8 L/h. The mean non-renal clearance for meropenem was 7.3 L/h which comprises both fecal elimination (~2% of dose) and degradation due to hydrolysis. For vaborbactam, 75 to 95% of the dose was excreted unchanged in the urine over a 24 to 48 hour period.

The mean renal clearance for vaborbactam was 8.9 L/h. The mean non-renal clearance for vaborbactam was 2.0 L/h indicating nearly complete elimination of vaborbactam by the renal route. 

 Specific Populations-

Patients with Renal Impairment-                                                                           Following a single dose of VABOMERE, pharmacokinetic studies with meropenem and vaborbactam in subjects with renal impairment have shown that meropenem AUC0-inf ratios to subjects with normal renal function are 1.28, 2.07, and 4.63 for subjects with mild (eGFR of 60 to 89 mL/min/1.73m2 ), moderate (eGFR of 30 to 59 mL/min/1.73m2 ), and severe (eGFR <30 mL/min/1.73m2 ) renal impairment, respectively; vaborbactam AUC0-inf ratios to subjects with normal renal function are 1.18, 2.31, and 7.8 for subjects with mild, moderate, and severe renal impairment, respectively 

Hemodialysis removed 38% of the meropenem dose and 53% of the vaborbactam dose. Vaborbactam exposure was high in subjects with ESRD (eGFR <15 ml/min/1.73 m2 ). 

. Patients with Hepatic Impairment-                                                                                A pharmacokinetic study conducted with an intravenous formulation of meropenem in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.

Vaborbactam does not undergo hepatic metabolism. Therefore, the systemic clearance of meropenem and vaborbactam is not expected to be affected by hepatic impairment.

Geriatric Patients-                                                                                                            In elderly patients with renal impairment, plasma clearances of meropenem and vaborbactam were reduced, correlating with age-associated reduction in renal function 

 Male and Female Patients-                                                                              Meropenem and vaborbactam Cmax and AUC were similar between males and females using a population pharmacokinetic analysis.

Racial or Ethnic Groups-                                                                                                No significant difference in mean meropenem or vaborbactam clearance was observed across race groups using a population pharmacokinetic analysis.

 USE IN SPECIFIC POPULATIONS

1. 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.

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.

2.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.

3.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.

4.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.

5. 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 VABOMERE is recommended in patients with renal impairment (eGFR less than 50 mL/min/ 1.73m2 ).

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 

OVERDOSAGE

In the event of overdose, discontinue VABOMERE and institute general supportive treatment.

Meropenem and vaborbactam can be removed by hemodialysis. In subjects with end-stage renal disease (ESRD) administered meropenem 1 gram and vaborbactam 1 gram, the mean total recovery in dialysate following a hemodialysis session was 38% and 53% of the administered dose of meropenem and vaborbactam, respectively.

No clinical information is available on the use of hemodialysis to treat VABOMERE overdosage.

11 DESCRIPTION VABOMERE (meropenem and vaborbactam) for injection is a combination product that contains meropenem, a synthetic penem antibacterial drug and vaborbactam, a cyclic boronic acid beta-lactamase inhibitor, for intravenous