VABOMERE (Page 4 of 6)

10 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 administration.

Meropenem, present as a trihydrate, is a white to light yellow crystalline powder, with a molecular weight of 437.52. The chemical name for meropenem trihydrate is (4R ,5S ,6S)-3-[[(3S ,5S)-5-(dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, trihydrate. The empirical formula of meropenem trihydrate is C17 H25 N3 O5 S∙3H2 O and its chemical structure is:

Figure 1: Structure of Meropenem Trihydrate

Chemical Structure
(click image for full-size original)

Vaborbactam is a white to off-white powder, with a molecular weight of 297.14. The chemical name for vaborbactam is (3R ,6S)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-1,2-oxaborinane-6-acetic acid. Its empirical formula is C12 H16 BNO5 S and its chemical structure is:

Figure 2: Structure of Vaborbactam

Chemical Structure

VABOMERE is supplied as a white to light yellow sterile powder for constitution that contains meropenem trihydrate, vaborbactam, and sodium carbonate. Each 50 mL glass vial contains 1 gram of meropenem (equivalent to 1.14 grams of meropenem trihydrate), 1 gram of vaborbactam, and 0.575 gram of sodium carbonate. The total sodium content of the mixture is approximately 0.25 grams (10.9 mEq)/vial.

Each vial is constituted and further diluted with 0.9% Sodium Chloride Injection, USP. Both the constituted solution and the diluted solution for intravenous infusion should be a colorless to light yellow solution [see Dosage and Administration (2.3)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

VABOMERE is an antibacterial drug [see Microbiology (12.4)].

12.2 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. The ratio of the 24-hour unbound plasma vaborbactam AUC to meropenem-vaborbactam MIC is the index that best predicts efficacy of vaborbactam in combination with meropenem in animal and in vitro models of infection.

12.3 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 are summarized in Table 4.

The PK parameters of meropenem and vaborbactam were similar for single and multiple dose administration of VABOMERE.

Table 4: Pharmacokinetic Parameters (Mean [SD]) of Meropenem and Vaborbactam Following Administration of VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams) by 3-hour Infusion in Healthy Adult Subjects
Parameter Meropenem Vaborbactam
Single VABOMERE 4 gram * Dose(N=8) Multiple VABOMERE 4 gram * Doses Administered Every 8 hours for 7 Days (N=8) Single VABOMERE 4 gram * Dose(N=8) Multiple VABOMERE 4 gram * Doses Administered Every 8 hours for 7 Days (N=8)
Cmax = maximum observed concentration; CL = plasma clearance; AUC = area under the concentration time curve; T½ = half-life.
*
Meropenem 2 grams and vaborbactam 2 grams administered as a 3-hour infusion
AUC0-inf reported for single-dose administration; AUC0-8 reported for multiple-dose administration; AUC0 – 24 is 414 mg∙h/L for meropenem and 588 mg∙h/L for vaborbactam.
Cmax (mg/L) 46.0 (5.7) 43.4 (8.8) 50.7 (8.4) 55.6 (11.0)
CL (L/h) 14.6 (2.7) 15.1 (2.8) 12.3 (2.2) 10.9 (1.8)
AUC (mg∙h/L) 142.0 (28.0) 138.0 (27.7) 168.0 (32.2) 196.0 (36.7)
T1/2 (h) 1.50 (1.0) 1.22 (0.3) 1.99 (0.8) 1.68 (0.4)

The maximum plasma concentration (Cmax ) and area under the plasma drug concentration time curve (AUC) of meropenem and vaborbactam proportionally increased with dose across the dose range studied (1 gram to 2 grams for meropenem and 0.25 grams to 2 grams for vaborbactam) when administered as a single 3-hour intravenous infusion. There is no accumulation of meropenem or vaborbactam following multiple intravenous infusions administered every 8 hours for 7 days in subjects with normal renal function.

The mean population PK parameters of meropenem and vaborbactam in 295 patients (including 35 patients with reduced renal function) after 3-hour infusions of VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams) administered every 8 hours (or dose adjusted based on renal function) are summarized in Table 5.

Table 5: Population Pharmacokinetic Parameters (Mean [SD]) of Meropenem and Vaborbactam Following Administration of VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams) by 3-hour Infusion in Patients *
Parameter Meropenem Vaborbactam
*
Meropenem 2 grams and vaborbactam 2 grams administered as a 3-hour infusion.
Cmax (mg/L) 57.3 (23.0) 71.3 (28.6)
AUC0-24 , Day 1 (mg∙h/L) 637 (295) 821 (369)
AUC0-24 , steady-state (mg∙h/L) 650 (364) 835 (508)
CL (L/h) 10.5 (6.4) 7.95 (4.3)
T1/2 (h) 2.30 (2.5) 2.25 (2.1)

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 [see Dosing and Administration (2.2)]. 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). Vaborbactam exposure was higher when VABOMERE was administered after hemodialysis (AUC0-inf ratio to subjects with normal renal function of 37.5) than when VABOMERE was administered before hemodialysis (AUC0-inf ratio to subjects with normal renal function of 10.2) [see Use in Specific Populations (8.6) and Dosing and Administration (2.2)].

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 [see Dosage and Administration (2.2) and Use in Specific Populations (8.5)].

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.

Drug Interactions

No drug-drug interaction was observed between meropenem and vaborbactam in clinical studies with healthy subjects.

Based upon the in vitro and in vivo data available to date, there is a low potential for clinically significant drug interactions with vaborbactam.

Vaborbactam at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in vitro human liver microsomes. Vaborbactam showed no potential for in vitro induction of CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes. Studies evaluating the potential for meropenem to interact with CYP450 enzymes or active transport systems have not been conducted. However, carbapenems as a class have not shown the potential for inhibition or induction CYP450 enzymes and clinical experience suggests that such effects are unlikely.

Vaborbactam does not inhibit the following hepatic and renal transporters in vitro at clinically relevant concentrations: P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3 or BSEP. Vaborbactam was not a substrate of OAT1, OAT3, OCT2, P-gp, and BCRP.

Meropenem is a substrate of OAT1 and OAT3 and as such, probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38% [see Drug Interactions (7.2)].

Concomitant administration of meropenem and valproic acid has been associated with reductions in valproic acid concentrations with subsequent loss in seizure control [see Drug Interactions (7.1)].

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