Meropenem (Page 5 of 8)

11 DESCRIPTION

Meropenem for Injection, USP is a sterile, pyrogen-free, synthetic, carbapenem antibacterial for intravenous administration. It 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. Its empirical formula is C17 H25 N3 O5 S•3H2 O with a molecular weight of 437.52. Its structural formula is:

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Meropenem for Injection, USP is a white to pale yellow crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether.

When re-constituted as instructed, each 1 gram Meropenem for Injection, USP vial will deliver 1 gram of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). Each 500 mg Meropenem for Injection, USP vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq) [see Dosage and Administration (2.4)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


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

12.2 Pharmacodynamics

The percentage of time of a dosing interval that unbound plasma concentration of meropenem exceeds the meropenem minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection.

12.3 Pharmacokinetics

Plasma Concentrations
At the end of a 30-minute intravenous infusion of a single dose of Meropenem for Injection, USP in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14 to 26) for the 500 mg dose and 49 mcg/mL (range 39 to 58) for the 1 gram dose. A 5-minute intravenous bolus injection of Meropenem for Injection, USP in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18 to 65) for the 500 mg dose and 112 mcg/mL (range 83 to 140) for the 1 gram dose.

Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration.

No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 gram administered every 6 hours in healthy volunteers with normal renal function.

Distribution
The plasma protein binding of meropenem is approximately 2%.

After a single intravenous dose of Meropenem for Injection, USP, the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 hours to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in Table 5 below.Table 5: Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported)

Tissue Intravenous Dose (gram) Number of Samples Mean [mcg/mL or mcg/(gram)]1 Range [mcg/mL or mcg/(gram)]
Endometrium 0.5 7 4.2 1.7 to 10.2
Myometrium 0.5 15 3.8 0.4 to 8.1
Ovary 0.5 8 2.8 0.8 to 4.8
Cervix 0.5 2 7 5.4 to 8.5
Fallopian tube 0.5 9 1.7 0.3 to 3.4
Skin 0.5 22 3.3 0.5 to 12.6
Interstitial fluid 2 0.5 9 5.5 3.2 to 8.6
Skin 1 10 5.3 1.3 to 16.7
Interstitial fluid 2 1 5 26.3 20.9 to 37.4
Colon 1 2 2.6 2.5 to 2.7
Bile 1 7 14.6 (3 hours) 4 to 25.7
Gall bladder 1 1 3.9
Peritoneal fluid 1 9 30.2 7.4 to 54.6
Lung 1 2 4.8 (2 hours) 1.4 to 8.2
Bronchial mucosa 1 7 4.5 1.3 to 11.1
Muscle 1 2 6.1 (2 hours) 5.3 to 6.9
Fascia 1 9 8.8 1.5 to 20
Heart valves 1 7 9.7 6.4 to 12.1
Myocardium 1 10 15.5 5.2 to 25.5
CSF (inflamed) 20 mg/kg 3 40 mg/kg 4 85 1.1 (2 hours)3.3 (3 hours) 0.2 to 2.80.9 to 6.5
CSF (uninflamed) 1 4 0.2 (2 hours) 0.1 to 0.3
  1. at 1 hour unless otherwise noted
  2. obtained from blister fluid
  3. in pediatric patients of age 5 months to 8 years
  4. in pediatric patients of age 1 month to 15 years

Elimination
In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour.
Metabolism
There is one metabolite of meropenem that is microbiologically inactive.

Excretion
Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50% to 75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion.

Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose.

Specific Populations
Patients with Renal Impairment
Pharmacokinetic studies with Meropenem for Injection, USP in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6) ].

Meropenem for Injection, USP is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage [see Overdosage (10)].

Patients with Hepatic Impairment
A pharmacokinetic study with Meropenem for Injection, USP in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.

Geriatric Patients
A pharmacokinetic study with Meropenem for Injection, USP in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.

Pediatric Patients
The pharmacokinetics of meropenem for injection, USP, in pediatric patients 2 years of age or older, are similar to those in adults. The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years.

The pharmacokinetics of meropenem in patients less than 3 months of age receiving combination antibacterial drug therapy are given below.

Table 6: Meropenem Pharmacokinetic Parameters in Patients Less Than 3 Months of Age*

GA less than 32 weeks PNA less than 2 weeks (20 mg/kg every 12 hours) GA less than 32 weeks PNA 2 weeks or older (20 mg/kg every 8 hours) GA 32 weeks or older PNA less than 2 weeks (20 mg/kg every 8 hours) GA 32 weeks or older PNA 2 weeks or older (30 mg/kg every 8 hours) Overall
CL (L/h/kg) 0.089 0.122 0.135 0.202 0.119
V (L/kg) 0.489 0.467 0.463 0.451 0.468
AUC 0-24 (mcg-h/mL) 448 491 445 444 467
C max (mcg/mL) 44.3 46.5 44.9 61 46.9
C min (mcg/mL) 5.36 6.65 4.84 2.1 5.65
T1/2 (h) 3.82 2.68 2.33 1.58 2.68
*Values are derived from a population pharmacokinetic analysis of sparse data

Drug InteractionsProbenecid 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 (7.1)].

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