Cilastatin 250 mg, Imipenem 250 mg Dry-powder injectables

Imipenem and cilastatin for injection is a combination of imipenem and cilastatin. Imipenem is a penem antibacterial drug [see Clinical Pharmacology (12.4)]. Cilastatin is a renal dehydropeptidase inhibitor that limits the renal metabolism of imipenem.

Intravenous infusion of imipenem and cilastatin for injection over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from 21 to 58 mcg/mL for the 500 mg dose, and from 41 to 83 mcg/mL for the 1000 mg dose. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 mcg/mL or less in 4 to 6 hours. Peak plasma levels of cilastatin following a 20-minute intravenous infusion of imipenem and cilastatin for injection range from 31 to 49 mcg/mL for the 500 mg dose, and from 56 to 88 mcg/mL for the 1000 mg dose.

Distribution — The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%.

Imipenem has been shown to penetrate into human tissues, including vitreous humor, aqueous humor, lung, peritoneal fluid, CSF, bone, interstitial fluid, skin, and fascia. As there are no adequate and well-controlled studies of imipenem treatment in these additional body sites, the clinical significance of these tissue concentration data is unknown.

After a 1 gram dose of imipenem and cilastatin for injection, the following average levels of imipenem were measured (usually at 1 hour post dose except where indicated) in the tissues and fluids listed in Table 9:

Metabolism — Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase I, resulting in relatively low levels in urine. Cilastatin, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem so that when imipenem and cilastatin sodium are given concomitantly, adequate antibacterial levels of imipenem are achieved in the urine.

Elimination — The plasma half-life of each component is approximately 1 hour. Approximately 70% of the administered imipenem is recovered in the urine within 10 hours after which no further urinary excretion is detectable. Urine concentrations of imipenem in excess of 10 mcg/mL can be maintained for up to 8 hours with imipenem and cilastatin for injection at the 500 mg dose. Approximately 70% of the cilastatin sodium dose is recovered in the urine within 10 hours of administration of imipenem and cilastatin for injection. Imipenem and cilastatin for injection is hemodialyzable [see Overdosage (10)].

No accumulation of imipenem/cilastatin in plasma or urine is observed with regimens administered as frequently as every 6 hours in patients with normal renal function.

Geriatric Patients — In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of imipenem 500 mg and cilastatin 500 mg administered intravenously over 20 minutes are consistent with those expected in subjects with slight renal impairment for which no dosage alteration is considered necessary. The mean plasma half-lives of imipenem and cilastatin are 91 ± 7 minutes and 69 ± 15 minutes, respectively. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem/cilastatin is observed.

Pediatric Patients — Doses of 25 mg/kg/dose in patients 3 months to <3 years of age, and 15 mg/kg/dose in patients 3 to 12 years of age were associated with mean trough plasma concentrations of imipenem of 1.1±0.4 mcg/mL and 0.6±0.2 mcg/mL following multiple 60-minute infusions, respectively; trough urinary concentrations of imipenem were in excess of 10 mcg/mL for both doses. These doses have provided adequate plasma and urine concentrations for the treatment of non-CNS infections.

In a dose-ranging study of smaller premature infants (670 to 1,890 g) in the first week of life, a dose of 20 mg/kg q12h by 15 to 30 minutes infusion was associated with mean peak and trough plasma imipenem concentrations of 43 mcg/mL and 1.7 mcg/mL after multiple doses, respectively. However, moderate accumulation of cilastatin in neonates may occur following multiple doses of imipenem and cilastatin for injection. The safety of this accumulation is unknown.