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1、NDA 50 706 S 022 Page 3 MERREM I V meropenem for injection FOR INTRAVENOUS USE ONLY To reduce the development of drug resistant bacteria and maintain the effectiveness of MERREM I V meropenem for injection and other antibacterial drugs MERREM I V should be used only to treat or prevent infections th
2、at are proven or strongly suspected to be caused by bacteria DESCRIPTION MERREM I V meropenem for injection is a sterile pyrogen free synthetic broad spectrum carbapenem antibiotic for intravenous administration It is 4R 5S 6S 3 3S 5S 5 Dimethylcarbamoyl 3 pyrrolidinyl thio 6 1R 1 hydroxyethyl 4 met
3、hyl 7 oxo 1 azabicyclo 3 2 0 hept 2 ene 2 carboxylic acid trihydrate Its empirical formula is C17H25N3O5S 3H2O with a molecular weight of 437 52 Its structural formula is MERREM I V is a white to pale yellow crystalline powder The solution varies from colorless to yellow depending on the concentrati
4、on 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 constituted as instructed see DOSAGE AND ADMINIST
5、RATION PREPARATION OF SOLUTION each 1 g MERREM I V vial will deliver 1 g of meropenem and 90 2 mg of sodium as sodium carbonate 3 92 mEq Each 500 mg MERREM I V vial will deliver 500 mg meropenem and 45 1 mg of sodium as sodium carbonate 1 96 mEq CLINICAL PHARMACOLOGY At the end of a 30 minute intrav
6、enous infusion of a single dose of MERREM I V in normal volunteers mean peak plasma concentrations are approximately 23 g mL range 14 26 for the 500 mg dose and 49 g mL range 39 58 for the 1 g dose A 5 minute intravenous bolus injection of MERREM I V in normal volunteers results in mean peak plasma
7、concentrations of approximately 45 g mL range 18 65 for the 500 mg dose and 112 g mL range 83 140 for the 1 g dose Following intravenous doses of 500 mg mean plasma concentrations of meropenem usually decline to approximately 1 g mL at 6 hours after administration In subjects with normal renal funct
8、ion the elimination half life of MERREM I V is approximately 1 hour Approximately 70 of the intravenously administered dose is recovered as unchanged meropenem in the urine over 12 hours after which little further urinary excretion is detectable Urinary NDA 50 706 S 022 Page 4 concentrations of mero
9、penem in excess of 10 g mL are maintained for up to 5 hours after a 500 mg dose No accumulation of meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in volunteers with normal renal function Plasma protein binding of mero
10、penem is approximately 2 There is one metabolite that is microbiologically inactive Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria After a single intravenous
11、dose of MERREM I V the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour 0 5 to 1 5 hours after the start of infusion except where indicated in the tissues and fluids listed in the table below Table 1 Meropenem Concentrations in Selected Tissues Highest Concentratio
12、ns Reported Tissue I V Dose g Number of Samples Mean g mL or g g Range g mL or g g Endometrium 0 5 7 4 2 1 7 10 2 Myometrium 0 5 15 3 8 0 4 8 1 Ovary 0 5 8 2 8 0 8 4 8 Cervix 0 5 2 7 0 5 4 8 5 Fallopian tube 0 5 9 1 7 0 3 3 4 Skin 0 5 22 3 3 0 5 12 6 Interstitial fluid 0 5 9 5 5 3 2 8 6 Skin 1 0 10
13、5 3 1 3 16 7 Interstitial fluid 1 0 5 26 3 20 9 37 4 Colon 1 0 2 2 6 2 5 2 7 Bile 1 0 7 14 6 3 h 4 0 25 7 Gall bladder 1 0 1 3 9 Peritoneal fluid 1 0 9 30 2 7 4 54 6 Lung 1 0 2 4 8 2 h 1 4 8 2 Bronchial mucosa 1 0 7 4 5 1 3 11 1 Muscle 1 0 2 6 1 2 h 5 3 6 9 Fascia 1 0 9 8 8 1 5 20 Heart valves 1 0 7
14、 9 7 6 4 12 1 Myocardium 1 0 10 15 5 5 2 25 5 CSF inflamed 20 mg kg 40 mg kg 8 5 1 1 2 h 3 3 3 h 0 2 2 8 0 9 6 5 CSF uninflamed 1 0 4 0 2 2 h 0 1 0 3 at 1 hour unless otherwise noted obtained from blister fluid in pediatric patients of age 5 months to 8 years in pediatric patients of age 1 month to
15、15 years The pharmacokinetics of MERREM I V in pediatric patients 2 years of age or older are essentially 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 are linear over the dose rang
16、e from 10 to 40 mg kg NDA 50 706 S 022 Page 5 Pharmacokinetic studies with MERREM I V in patients with renal insufficiency have shown that the plasma clearance of meropenem correlates with creatinine clearance Dosage adjustments are necessary in subjects with renal impairment See DOSAGE AND ADMINISTRATION Use in Adults with Renal Impairment A pharmacokinetic study with MERREM I V in elderly patients with renal insufficiency has shown a reduction in plasma clearance of meropenem that correlates w
