MEROPENEM

2 DOSAGE AND ADMINISTRATION 500 mg every 8 hours by intravenous infusion over 15 to 30 minutes for complicated skin and skin structure infections (cSSSI) for adult patients. When treating infections caused by Pseudomonas aeruginosa , a dose of 1 gram every 8 hours is recommended.

1 ) 1 gram every 8 hours by intravenous infusion over 15 minutes to 30 minutes for intra-abdominal infections for adult patients. 1 ) 1 gram every 8 hours by intravenous bolus injection (5 mL to 20 mL) over 3 minutes to 5 minutes for adult patients.

1 ) Dosage should be reduced in adult patients with renal impairment. 3 ) Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval - Intravenous infusion is to be given over approximately 15 minutes to 30 minutes. - Intravenous bolus injection (5 mL to 20 mL) is to be given over approximately 3 minutes to 5 minutes.

- There is no experience in pediatric patients with renal impairment. Complicated skin and skin structure 20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended when treating complicated skin and skin structure infections caused by P.

aeruginosa. 3 ) Age Group Dose (mg/kg) Dose Interval - Intravenous infusion is to be given over 30 minutes. - There is no experience in pediatric patients with renal impairment. 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 Use in Adult Patients with Renal Impairment Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less.

) When only serum creatinine is available, the following formula (Cockcroft and Gault equation) 1 may be used to estimate creatinine clearance. 85 × above value Table 1: Recommended Meropenem 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.

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 There is no experience in pediatric patients with renal impairment.

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 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 There is no experience in pediatric patients with renal impairment.

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.

6) ]. Do not use flexible container in series connections. 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.

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).

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.

9) ] Most common adverse reactions (2% or less) are: headache, nausea, constipation, diarrhea, anemia, vomiting, and rash. gov/medwatch . 1 Adverse Reactions from Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Patients During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with Meropenem for Injection, USP (500 mg or 1 gram every 8 hours). 2%) patients had meropenem discontinued because of adverse events.

Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with Meropenem for Injection, USP.

The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Meropenem for Injection, USP. 2%). 2%). 2% of the patients were as follows: Hepatic: increased alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and bilirubin Hematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased white blood cell (WBC), shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia Renal: increased creatinine and increased blood urea nitrogen (BUN) Urinalysis: presence of red blood cells Complicated Skin and Skin Structure Infections In a study of complicated skin and skin structure infections, the adverse reactions were similar to those listed above.

1%). Adverse events with an incidence of greater than 1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia. 3) ].

Pediatric Patients:

Systemic and Local Adverse Reactions Pediatric Patients with Serious Bacterial Infections (excluding Bacterial Meningitis): Meropenem for Injection, USP was studied in 515 pediatric patients (3 months to less than 13 years of age) with serious bacterial infections (excluding meningitis, see next section) at dosages of 10 mg/kg to 20 mg/kg every 8 hours.

8% Pediatric Patients with Bacterial Meningitis: Meropenem for Injection, USP was studied in 321 pediatric patients (3 months to less than 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. 0% In the meningitis studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents (either cefotaxime or ceftriaxone).

In the Meropenem for Injection, USP treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm. The meropenem group had a statistically higher number of patients with transient elevation of liver enzymes.

Pediatric Patients (Neonates and Infants less than 3 months of Age):

Meropenem for Injection, USP was studied in 200 neonates and infants less than 3 months of age. The study was open-label, uncontrolled, 98% of the infants received concomitant medications, and the majority of adverse events were reported in neonates less than 32 weeks gestational age and critically ill at baseline, making it difficult to assess the relationship of the adverse events to Meropenem for Injection, USP.

5% Adverse Laboratory Changes in Pediatric Patients: Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies. 2 Post marketing Experience The following adverse reactions have been identified during post-approval use of Meropenem for Injection, USP.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Worldwide post-marketing adverse reactions not otherwise listed in the Adverse Reactions from Clinical Trials section of this prescribing information and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity.

Blood and Lymphatic System Disorders : agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia. Immune System Disorders : angioedema.

Skin and Subcutaneous Disorders :

Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme and acute generalized exanthematous pustulosis.

5 WARNINGS AND PRECAUTIONS Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams. 1 ) Severe cutaneous adverse reactions have been reported in patients receiving Meropenem for Injection, USP.

2 ) Seizures and other adverse CNS experiences have been reported during treatment. 3 ) Co-administration of Meropenem for Injection, USP with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures.

2 ) Clostridium difficile- associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported. Evaluate if diarrhea occurs. 5 ) In patients with renal dysfunction, thrombocytopenia has been observed. 1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams.

These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam.

Before initiating therapy with Meropenem for Injection, USP, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to Meropenem for Injection, USP occurs, discontinue the drug immediately.

2) ] . If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered. 3 Seizure Potential Seizures and other adverse CNS experiences have been reported during treatment with Meropenem for Injection, USP.

2) ]. 7% (based on 20 patients with this adverse event). All meropenem-treated patients with seizures had pre-existing contributing factors. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential.

2) ]. Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Continue anti-convulsant therapy in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, placed on anti-convulsant therapy if not already instituted, and re-examine the dosage of Meropenem for Injection, USP to determine whether it should be decreased or discontinued.

4 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations.

The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction.

Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. 2) ]. 5 Clostridium difficile –associated Diarrhea Clostridium difficile- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Meropenem for Injection, USP, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C.

difficile, and surgical evaluation should be instituted as clinically indicated. 6 Development of Drug-Resistant Bacteria Prescribing Meropenem for Injection, USP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

7 Overgrowth of Nonsusceptible Organisms As with other broad-spectrum antibacterial drugs, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken.

3) ]. 9 Potential for Neuromotor Impairment Alert patients receiving Meropenem for Injection, USP on an outpatient basis regarding adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment.

1) ].

4 CONTRAINDICATIONS Meropenem for Injection, USP is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta (β)-lactams.

Known hypersensitivity to product components or anaphylactic reactions to β-lactams. ( 4 )