13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:

Carcinogenesis studies have not been performed.

Mutagenesis:

Genetic toxicity studies were performed with meropenem using the bacterial reverse mutation test, the Chinese hamster ovary HGPRT assay, cultured human lymphocytes cytogenic assay, and the mouse micronucleus test. There was no evidence of mutagenic potential found in any of these tests.

Impairment of Fertility:

In fertility studies, intravenous meropenem was administered to male rats beginning 11 weeks before mating and throughout mating and to female rats from 2 weeks before mating through Gestation Day 7 at doses of 240, 500, and 1000 mg/kg/day. There was no evidence of impaired fertility at doses up to 1000 mg/kg/day (on the basis of body surface area comparison, approximately 3.2 times to the MRHD of 1 gram every 8 hours).

2 DOSAGE AND ADMINISTRATION

2.1 Adult Patients

The recommended dose of Meropenem for Injection, USP is 500 mg given every 8 hours for skin and skin structure infections and 1 gram given every 8 hours for intra-abdominal infections. When treating complicated skin and skin structure infections caused by P. aeruginosa, a dose of 1 gram every 8 hours is recommended.

Meropenem for Injection, USP should be administered by intravenous infusion over approximately 15 minutes to 30 minutes. Doses of 1 gram may also be administered as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes.

2.2 Use in Adult Patients with Renal Impairment

Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. (See dosing table below.)

When only serum creatinine is available, the following formula (Cockcroft and Gault equation) 1 may be used to estimate creatinine clearance.

Males: Creatinine Clearance (mL/min) =

Weight (kg) x (140 - age)

72 x serum creatinine (mg/dL)

Females: 0.85 x above value

Table 1:RecommendedMeropenem for Injection, USP Dosage Schedule for Adult Patients with Renal Impairment

Creatinine Clearance (mL/min)	Dose (dependent on type of infection)	Dosing Interval
Greater than 50	Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal)	Every 8 hours
26 to 50	Recommended dose	Every 12 hours
10 to 25	One-half recommended dose	Every 12 hours
Less than 10	One-half recommended dose	Every 24 hours

There is inadequate information regarding the use of Meropenem for Injection, USP in patients on hemodialysis or peritoneal dialysis.

2.3 Use in Pediatric Patients

Pediatric Patients 3 Months of Age and Older

• For pediatric patients 3 months of age and older, the Meropenem for Injection, USP dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every 8 hours (maximum dose is 2 grams every 8 hours), depending on the type of infection (cSSSI, cIAI, intra-abdominal infection or meningitis). See dosing table 2 below.
• For pediatric patients weighing over 50 kg administer Meropenem for Injection, USP at a dose of 500 mg every 8 hours for cSSSI, 1 gram every 8 hours for cIAI and 2 grams every 8 hours for meningitis.
• Administer Meropenem for Injection, USP as an intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes.
• There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) bolus dose.

Table 2: Recommended****Meropenem for Injection, USP Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function

Type of Infection	Dose (mg/kg)	Up to a Maximum Dose	Dosing Interval
Complicated skin and skin structure infections	10	500 mg	Every 8 hours
Complicated intra-abdominal infections	20	1 gram	Every 8 hours
Meningitis	40	2 grams	Every 8 hours
There is no experience in pediatric patients with renal impairment.

When treating cSSSI caused by P. aeruginosa, a dose of 20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended.

Pediatric Patients Less Than 3 Months of Age

For pediatric patients (with normal renal function) less than 3 months of age, with complicated intra-abdominal infections, the Meropenem for Injection, USP dose is based on gestational age (GA) and postnatal age (PNA). See dosing table 3 below. Meropenem for Injection, USP should be given as intravenous infusion over 30 minutes.

Table 3: Recommended Meropenem for Injection, USP Dosage Schedule for Pediatric Patients Less than****3 Months of Age with Complicated Intra- abdominal Infections and Normal Renal Function

Age Group	Dose (mg/kg)	Dose Interval
Infants less than 32 weeks GA and PNA less than 2 weeks	20	Every 12 hours
Infants less than 32 weeks GA and PNA 2 weeks and older	20	Every 8 hours
Infants 32 weeks and older GA and PNA less than 2 weeks	20	Every 8 hours
Infants 32 weeks and older GA and PNA 2 weeks and older	30	Every 8 hours
There is no experience in pediatric patients with renal impairment.

2.4 Preparation and Administration of Meropenem for Injection, USP

Important Administration Instructions

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

For Intravenous Bolus Administration

Re-constitute injection vials (500 mg and 1 gram) with Sterile Water for Injection (see table 4 below). Shake to dissolve and let stand until clear.

Table 4: Volume of Sterile Water for Injection for Reconstitution of Injection Vials

Vial Size	Amount of Diluent Added (mL)	Approximate Withdrawable Volume (mL)	Approximate Average Concentration (mg/mL)
500 mg	10	10	50
1 gram	20	20	50

For Infusion

• Injection vials (500 mg and 1 gram) may be directly re-constituted with a compatible infusion fluid.
• Alternatively, an injection vial may be re-constituted, then the resulting solution added to an intravenous container and further diluted with an appropriate infusion fluid [see Dosage and Administration (2.5) and (2.6)].
• Do not use flexible container in series connections.

2.5 Compatibility

Compatibility of Meropenem for Injection, USP with other drugs has not been established. Meropenem for Injection, USP should not be mixed with or physically added to solutions containing other drugs.

2.6 Stability and Storage

Freshly prepared solutions of Meropenem for Injection, USP should be used. However, re-constituted solutions of Meropenem for Injection, USP maintain satisfactory potency under the conditions described below. Solutions of intravenous Meropenem for Injection, USP should not be frozen.

Intravenous Bolus Administration

Meropenem for Injection, USP vials re-constituted with Sterile Water for Injection for bolus administration (up to 50 mg/mL of Meropenem for Injection, USP) may be stored for up to 3 hours at up to 25°C (77°F) or for 13 hours at up to 5°C (41°F).

Intravenous Infusion Administration

Solutions prepared for infusion (Meropenem for Injection, USP concentrations ranging from 1 mg/mL to 20 mg/mL) re-constituted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25°C (77°F) or 15 hours at up to 5°C (41°F).

Solutions prepared for infusion (Meropenem for Injection, USP concentrations ranging from 1 mg/mL to 20 mg/mL) re-constituted with Dextrose Injection 5% should be used immediately.