Meropenem

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-methyl-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.

 MERREM I.V. 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 constituted as instructed (See DOSAGE AND ADMINISTRATION - 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).

MERREM I.V. in the Abbott ADD-Vantage^®† vial is intended for intravenous use only after dilution with the appropriate volume of diluent solution in the ADD-Vantage diluent container (See DOSAGE AND ADMINISTRATION - PREPARATION OF SOLUTION). MERREM I.V. in the ADD-Vantage vial is available in two strengths. Each 1 g ADD-Vantage vial of MERREM I.V. will deliver 90.2 mg of sodium as sodium carbonate (3.92 mEq), and each 500 mg ADD-Vantage vial will deliver 45.1 mg of sodium as sodium carbonate (1.96 mEq).

CLINICAL PHARMACOLOGY

At the end of a 30-minute intravenous infusion of a single dose of MERREM I.V. in normal volunteers, mean peak plasma concentrations are approximately 23 µg/mL (range 14-26) for the 500 mg dose and 49 µg/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 concentrations of approximately 45 µg/mL (range 18-65) for the 500 mg dose and 112 µg/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 µg/mL at 6 hours after administration.

 In subjects with normal renal function, 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 concentrations of meropenem in excess of 10 µg/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 meropenem is approximately 2%.

 There is one metabolite which 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 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.

The pharmacokinetics of MERREM I.V. in pediatric patients 2 years of age or older is 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 range from 10 to 40 mg/kg.

Pharmacokinetics 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 with age-associated reduction in creatinine clearance.

Meropenem I.V. is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage. (See OVERDOSAGE.)

A pharmacokinetic study with MERREM I.V. in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.

INDICATIONS

MERREM I.V. is indicated as single agent therapy for the treatment of the following infections when caused by susceptible strains of the designated microorganisms:

 Intra-abdominal Infections

Complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B thetaiotaomicron, and Peptostreptococcus species.

Bacterial Meningitis (pediatric patients ³3 months only)

Bacterial meningitis caused by Streptococcus pneumoniae,^‡Haemophilus influenzae (b-lactamase and non-b-lactamase-producing strains), and Neisseria meningitidis.
‡Penicillin-resistant strains have not been studied in clinical trials.

MERREM I.V. has been found to be effective in eliminating concurrent bacteremia in association with bacteria meningitis.

For information regarding use in pediatric patients (3 months of age and older) See PRECAUTIONS - Pediatrics, ADVERSE REACTIONS, and

DOSAGE AND ADMINISTRATION

Appropriate cultures should usually be performed before initiating antimicrobial treatment in order to isolate and identify the organisms causing infection and determine their susceptibility to MERREM I.V.

MERREM I.V. is useful as presumptive therapy in the indicated condition (ie, intra-abdominal infections) prior to the identification of the causative organisms because of its broad spectrum of bactericidal activity.

Antimicrobial therapy should be adjusted, if appropriate, once the results of culture(s) and antimicrobial susceptibility testing are known.

DOSAGE AND ADMINISTRATION

Adults: One gram (1 g) by intravenous administration every 8 hours. MERREM I.V. should be given by intravenous infusion, over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.

Use in Adults with Renal Impairment: Dosage should be reduced in patients with creatinine clearance less than 51 mL/min. (See dosing table below.)

When only serum creatinine is available, the following formula (Cockcroft and Gault equation)⁴ may be used to estimate creatinine clearance.

There is inadequate information regarding the use of MERREM I.V. in patients on hemodialysis.

There is no experience with peritoneal dialysis.

Use in Adults With Hepatic Insufficiency: No dosage adjustment is necessary in patients with impaired hepatic function.

Use in Elderly Patients: No dosage adjustment is required for elderly patients with creatinine clearance values above 50 mL/min.

Use in Pediatric Patients: For pediatric patients from 3 months of age and older, the MERREM I.V. dose is 20 or 40 mg/kg every 8 hours (maximum dose is 2 g every 8 hours), depending on the type of infection (intra-abdominal or meningitis). (See dosing table below.) Pediatric patients weighing over 50 kg should be administered MERREM I.V. at a dose of 1 g every 8 hours for intra-abdominal infections and 2 g every 8 hours for meningitis. MERREM I.V. should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.

There is no experience in pediatric patients with renal impairment.

HOW SUPPLIED

MERREM I.V. is supplied in 20 mL and 30 mL injection vials containing sufficient meropenem to deliver 500 mg or 1 g for intravenous administration, respectively. MERREM I.V. is supplied in 100 mL infusion vials containing sufficient meropenem to deliver 500 mg or 1 g for intravenous administration. The dry powder should be stored at controlled room temperature 20-25°C (68-77°F) [see USP].

 MERREM I.V. is also supplied as ADD-Vantage Vials containing sufficient meropenem to deliver 500 mg or 1 g for intravenous administration. 500 mg/20 mL Injection Vial (NDC 0310-0325-20) 500 mg/100 mL Infusion Vial (NDC 0310-0325-11) 1 g/30 mL Injection Vial (NDC 0310-0321-30) 1 g/100 mL Infusion Vial (NDC 0310-0321-11) 500 mg/15 mL ADD-Vantage (NDC 0310-0325-15) 1 g/15 mL ADD-Vantage (NDC 0310-0321-15)

SIDE EFFECTS

 Adult Patients

During the initial clinical investigations, 2038 immunocompetent adult patients were treated for infections outside the CNS with MERREM I.V. (500 mg or 1000 mg q 8 hours). Deaths in 3 patients were assessed as possibly related to meropenem; 28 (1.4%) 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 population, it was not possible to determine the relationship between observed adverse events and therapy with MERREM I.V.

The following adverse reaction frequencies were derived from the clinical trials in the 2038 patients treated with MERREM .I. V.

Local Adverse Reactions

Local adverse reactions that were reported irrespective of the relationship to therapy with MERREM I.V. were as follows:

Systemic Adverse Reactions

Systemic adverse clinical reactions that were reported irrespective of the relationship to MERREM I.V. occurring in greater than 1.0% of the patients were diarrhea (5.0%), nausea/vomiting (3.9%), headache (2.8%), rash (1.7%), pruritus (1.6%), apnea (1.2%), and constipation (1.2%).

Additional adverse systemic clinical reactions that were reported irrespective of relationship to therapy with MERREM I.V. and occurring in less than 1.0% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency:

Bleeding events [gastrointestinal hemorrhage, melena, epistaxis, and hemoperitoneum] occurred in 0.7% of meropenem patients.

Body as a Whole: pain, abdominal pain, chest pain, sepsis, shock, fever, abdominal enlargement, back pain, hepatic failure

Cardiovascular: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, syncope

Digestive: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus

Hemic & Lymphatic: anemia

Metabolic & Nutritional: peripheral edema, hypoxia

Nervous System: insomnia, agitation/delirium, confusion, dizziness, seizure (See PRECAUTIONS), nervousness, paresthesia, hallucinations, somnolence, anxiety, depression

Respiratory: respiratory disorder, dyspnea

Skin and Appendages: urticaria, sweating

Urogenital: dysuria, kidney failure

Adverse Laboratory Changes

Adverse laboratory changes that were reported irrespective of relationship to MERREM I.V. occurring in greater than 0.2% of the patients were as follows:

Hepatic: increased SGPT (ALT), SGOT (AST), alkaline phosphatase, LDH, and bilirubin

Hematologic: increased platelets, increased eosinophils, prolonged prothrombin time, prolonged partial thromboplastin time, decreased platelets, positive direct or indirect Coombs test, decreased hemoglobin, decreased hematocrit, decreased WBC, shortened prothrombin time, and shortened partial thromboplastin time

Renal: increased creatinine and increased BUN

NOTE: It is not known if the safety profile of MERREM I.V. is changed in patients with varying degrees of renal impairment.

Urinalysis: presence of urine red blood cells

Pediatric Patients

Clinical Adverse Reactions

MERREM I.V. was studied in 417 pediatric patients (³3 months to <13 years of age) with serious bacterial infections at dosages of 10 to 20 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to MERREM I.V. and their rates of occurrence as follows:

MERREM I.V. was studied in 198 pediatric patients (³3 months to <17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to MERREM I.V. and their rates of occurrence as follows:

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 MERREM I.V. 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.

Adverse Laboratory Changes

Laboratory abnormalities seen in the pediatric-aged patients in both the pediatric and the meningitis studies are similar to those reported in adult patients.

There is no experience in pediatric patients with renal impairment.

Postmarketing Experience

No postmarketing experience is available.

DRUG INTERACTIONS

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended.

Other than probenecid, no specific drug interaction studies were conducted.

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH ß-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 ß-LACTAM. BEFORE INITIATING THERAPY WITH MERREM I.V., CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER ß-LACTAMS, AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO MERREM I.V. OCCURS, DISCONTINUE THE DRUG IMMEDIATELY. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE, OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION. OTHER THERAPY MAY ALSO BE ADMINISTERED AS INDICATED.

Seizures and other CNS adverse experiences have been reported during treatment with MERREM I.V. (See

PRECAUTIONS

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including meropenem, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis."

After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate-to-severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

PRECAUTIONS

General

Seizures and other CNS adverse experiences have been reported during treatment with MERREM I.V. These adverse experiences have occurred most commonly in patients with CNS disorders (eg, brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function.

During the initial clinical investigations, 2038 immunocompetent adult patients were treated for infections outside the CNS with MERREM I.V. (500 mg or 1000 mg q 8 hours). Overall seizures, whether drug related or not, occurred in 0.5% of the meropenem-treated patients. All meropenem-treated patients with seizures had preexisting contributing factors. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Dosage adjustment is recommended in patients with advanced age and/or reduced renal function. (See DOSAGE AND ADMINISTRATION - Use in Adults with Renal Impairment.)

Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of MERREM I.V. reexamined to determine whether it should be decreased or the antibiotic discontinued.

In patients with renal dysfunction, thrombocytopenia has been observed but no clinical bleeding reported. (See DOSAGE AND ADMINISTRATION - Use in Adults with Renal Impairment.)

There is inadequate information regarding the use of MERREM I.V. in patients on hemodialysis.

As with other broad-spectrum antibiotics, 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.

Laboratory Tests

While MERREM I.V. possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Drug Interactions

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended.

Other than probenecid, no specific drug interaction studies were conducted.

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: Reproductive studies were performed with meropenem in rats at doses up to 1000 mg/kg/day, and cynomolgus monkeys at doses up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). There was no reproductive toxicity seen.

Pregnancy Category B

Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day, and cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). These studies revealed no evidence of impaired fertility or harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (on the basis of AUC comparisons, 0.4 times the human exposure at a dose of 1 g every 8 hours) and above in rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Pediatrics

The safety and effectiveness of MERREM I.V. have been established for pediatric patients ³ 3 months of age. Use of MERREM I.V. in pediatric patients with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population. Use of MERREM I.V. in pediatric patients with intra-abdominal infections is supported by evidence from adequate and well-controlled studies with adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. (See CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION.)

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when MERREM I.V. is administered to a nursing woman.