MERREM

AstraZeneca Pharmaceuticals LP
AstraZeneca PLC

HIGHLIGHTS OF PRESCRIBING INFORMATION MERREM I.V. (meropenem for Injection)Initial U.S. Approval: 1996 To reduce the development of drug-resistant bacteria and maintain the effectiveness of MERREM I.V. and other antibacterial drugs, MERREM I.V. should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. RECENT MAJOR CHANGESDosage and Administration, Adult Patients (2.1)Dosage and Administration, Use in Pediatric Patients (≥ 3 Months only) (2.3)Stability and storage (2.6)INDICATIONS AND USAGEMERREM I.V. is a penem antibacterial indicated as single agent therapy for the treatment of: •Complicated skin and skin structure infections (adult patients and pediatric patients ≥ 3 months only). (1.1) •Complicated intra-abdominal infections (adult patients and pediatric patients ≥ 3 months only). (1.2) •Bacterial meningitis (pediatric patients ≥ 3 months only). (1.3) DOSAGE AND ADMINISTRATION •500 mg every 8 hours by intravenous infusion over 15 to 30 minutes for skin and skin structure infections for adult patients. When treating infections caused by Pseudomonas aeruginosa, a dose of 1g every 8 hours is recommended. (2.1) •1 g every 8 hours by intravenous infusion over 15 to 30 minutes for intra-abdominal infections for adult patients. (2.1) •1 g every 8 hours by intravenous bolus injection (5 to 20 mL) over 3 to 5 minutes for adult patients. (2.1) •Dosage should be reduced in adult patients with renal impairment. (2.2) Recommended MERREM I.V. Dosage Schedule for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval > 50 Recommended dose (500 mg cSSSI and 1 g Intra-abdominal) Every 8 hours 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hours

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 MERREM INDICATIONS AND USAGE
  • 1.1 Skin and Skin Structure Infections (Adult Patients and Pediatric Patients ≥ 3 Months only)
  • 1.2 Intra-abdominal Infections (Adult Patients and Pediatric Patients ≥ 3 Months only)
  • 1.3 Bacterial Meningitis (Pediatric Patients ≥ 3 Months only)
• 2 MERREM DOSAGE AND ADMINISTRATION
  • 2.1 Adult Patients
  • 2.2 Use in Adult Patients with Renal Impairment
  • 2.3 Use in Pediatric Patients (≥ 3 Months only)
  • 2.4 Preparation of Solution
  • 2.5 Compatibility
  • 2.6 Stability and Storage
• 3 DOSAGE FORMS AND STRENGTHS
• 4 MERREM CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hypersensitivity Reactions
  • 5.2 Seizure Potential
  • 5.3 Interaction with Valproic Acid
  • 5.4 –associated Diarrhea
  • 5.5 Development of Drug-Resistant Bacteria
  • 5.6 Overgrowth of Nonsusceptible Organisms
  • 5.7 Laboratory Tests
  • 5.8 Patients with Renal Impairment
  • 5.9 Dialysis
• 6 MERREM ADVERSE REACTIONS
  • 6.1 Adverse Reactions from Clinical Trials
  • 6.2 Post-Marketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Probenecid
  • 7.2 Valproic Acid
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Patients with Renal Impairment
• 10 OVERDOSAGE
• 11 MERREM DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Complicated Skin and Skin Structure Infections
  • 14.2 Complicated Intra-Abdominal Infections
  • 14.3 Bacterial Meningitis
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• Package/Label Display Panel – 500 mg
• Package/Label Display Panel – 1 g

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of MERREM I.V. and other antibacterial drugs, MERREM I.V. should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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

1.1 Skin and Skin Structure Infections (Adult Patients and Pediatric Patients ≥ 3 Months only)

MERREM I.V. is indicated as a single agent therapy for the treatment of complicated skin and skin structure infections due to Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (vancomycin-resistant isolates), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species.

1.2 Intra-abdominal Infections (Adult Patients and Pediatric Patients ≥ 3 Months only)

MERREM I.V. is indicated as a single agent therapy for the treatment of complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species.

1.3 Bacterial Meningitis (Pediatric Patients ≥ 3 Months only)

MERREM I.V. is indicated as a single agent therapy for the treatment of bacterial meningitis caused by Streptococcus pneumoniae‡, Haemophilus influenza, and Neisseria meningitidis.

‡ The efficacy of meropenem as monotherapy in the treatment of meningitis caused by penicillin nonsusceptible isolates of Streptococcus pneumoniae has not been established.

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

For information regarding use in pediatric patients (3 months of age and older) [see Indications and Usage (1.1) , (1.2) or (1.3); Dosage and Administration (2.3) , and Adverse Reactions (6.1) ].

2 DOSAGE AND ADMINISTRATION

2.1 Adult Patients

The recommended dose of MERREM I.V. is 500 mg given every 8 hours for skin and skin structure infections and 1 g given every 8 hours for intra-abdominal infections. When treating complicated skin and skin structure infections caused by P.aeruginosa, a dose of 1g every 8 hours is recommended.

MERREM I.V. should be administered by intravenous infusion over approximately 15 to 30 minutes. Doses of 1 g may also be administered as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 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)⁵ 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

Recommended MERREM I.V. Dosage Schedule for Adult Patients With Renal Impairment

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

2.3 Use in Pediatric Patients (≥ 3 Months only)

For pediatric patients from 3 months of age and older, the MERREM I.V. dose is 10, 20 or 40 mg/kg every 8 hours (maximum dose is 2 g every 8 hours), depending on the type of infection (complicated skin and skin structure, intra-abdominal or meningitis). (See dosing table below.) Pediatric patients weighing over 50 kg should be administered MERREM I.V. at a dose of 500 mg every 8 hours for complicated skin and skin structure infections, 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 limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 g) bolus dose.

Recommended MERREM I.V. Dosage Schedule for Pediatric Patients with Normal Renal Function

When treating complicated skin and skin structure infections caused by P. aeruginosa, a dose of 20 mg/kg (or 1 g for pediatric patients weighing over 50 kg) every 8 hours is recommended.

There is no experience in pediatric patients with renal impairment.

2.4 Preparation of Solution

For Intravenous Bolus Administration

Constitute injection vials (500 mg and 1 g) with sterile Water for Injection. (See table below.) Shake to dissolve and let stand until clear.

For Infusion

Infusion vials (500 mg and 1 g) may be directly constituted with a compatible infusion fluid. Alternatively, an injection vial may be constituted, then the resulting solution added to an I.V. container and further diluted with an appropriate infusion fluid [see Dosage and Administration (2.5) and (2.6)].

WARNING: Do not use flexible container in series connections.

2.5 Compatibility

Compatibility of MERREM I.V. with other drugs has not been established. MERREM I.V. should not be mixed with or physically added to solutions containing other drugs.

2.6 Stability and Storage

Freshly prepared solutions of MERREM I.V. should be used. However, constituted solutions of MERREM I.V. maintain satisfactory potency under the conditions described below. Solutions of intravenous MERREM I.V. should not be frozen.

MERREM I.V. injection vials constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of MERREM I.V.) may be stored for up to 3 hours at up to 25^oC (77^oF) or for 13 hours at up to 5^°C (41°F).

Solutions prepared for infusion (MERREM I.V. concentrations ranging from 1 to 20 mg/mL) constituted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25^oC (77^oF) or 15 hours at up to 5^oC (41^oF).

Solutions prepared for infusion (MERREM I.V. concentrations ranging from 1 to 20 mg/mL) constituted with Dextrose Injection 5% should be used immediately.

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

3 DOSAGE FORMS AND STRENGTHS

Single use clear glass vials containing 500 mg or 1 g (as the trihydrate blend with anhydrous sodium carbonate for constitution) of sterile meropenem powder.

4 CONTRAINDICATIONS

MERREM I.V. 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 β-lactams.

5 WARNINGS AND PRECAUTIONS

5.1 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 MERREM I.V., careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other β-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.

5.2 Seizure Potential

Seizures and other adverse CNS experiences have been reported during treatment with MERREM I.V. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function [see Adverse Reactions (6.1) and Drug Interactions (7.2) ].

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (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. Dosage adjustment is recommended in patients with advanced age and/or reduced renal function [see Dosage and Administration (2.2) ].

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

5.3 Interaction with Valproic Acid

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. The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of MERREM I.V. is necessary, supplemental anti-convulsant therapy should be considered [see Drug Interactions (7.2) ].

5.4 –associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MERREM I.V., 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 Development of Drug-Resistant Bacteria

Prescribing MERREM I.V. 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.

5.6 Overgrowth of Nonsusceptible Organisms

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.

5.7 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.

5.8 Patients with Renal Impairment

In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [see Dosage and Administration (2.2) , Adverse Reactions (6.1) , Use In Specific Populations (8.5) and (8.6), and Clinical Pharmacology (12.3) ].

5.9 Dialysis

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

Patients receiving MERREM I.V. on an outpatient basis may develop adverse events such as seizures, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that MERREM I.V. is well tolerated, patients should not operate machinery or motorized vehicles [see Adverse Reactions (6.1) ].

6 ADVERSE REACTIONS

The following are discussed in greater detail in other sections of labeling:

• •Hypersensitivity Reactions [see Warnings and Precautions (5.1) ]
• •Seizure Potential [see Warnings and Precautions (5.2) ]
• •Interaction with Valproic Acid [see Warnings and Precautions (5.3) ]
• • Clostridium difficile – associated Diarrhea [see Warnings and Precautions (5.4) ]
• •Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.5) ]
• •Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.6) ]
• •Laboratory Tests [see Warnings and Precautions (5.7) ]
• •Patients with Renal Impairment [see Warnings and Precautions (5.8) ]
• •Dialysis [see Warnings and Precautions (5.9) ]
• •Potential for Neuromotor Impairment [see Warnings and Precautions (5.10) ]

6.1 Side Effects 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 MERREM I.V. (500 mg or 1000 mg every 8 hours). Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) 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 MERREM I.V.

The following adverse reaction frequencies were derived from the clinical trials in the 2904 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 reactions that were reported irrespective of the relationship to MERREM I.V. occurring in greater than 1.0% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%).

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

Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%), summing to 1.2%.

Body as a Whole: pain, abdominal pain, chest pain, fever, back pain, abdominal enlargement, chills, pelvic pain

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

Digestive System: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure, dyspepsia, intestinal obstruction

Hemic/Lymphatic: anemia, hypochromic anemia, hypervolemia

Metabolic/Nutritional: peripheral edema, hypoxia

Nervous System: insomnia, agitation/delirium, confusion, dizziness, seizure, nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, asthenia [see Warnings and Precautions (5.2) and (5.10)].

Respiratory: respiratory disorder, dyspnea, pleural effusion, asthma, cough increased, lung edema

Skin and Appendages: urticaria, sweating, skin ulcer

Urogenital System: dysuria, kidney failure, vaginal moniliasis, urinary incontinence

Adverse Laboratory Changes

Adverse laboratory changes that were reported irrespective of relationship to MERREM I.V. and 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, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased WBC, shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia

Renal: increased creatinine and increased BUN

NOTE: For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported irrespective of relationship to MERREM I.V., increased in patients with moderately severe renal impairment (creatinine clearance >10 to 26 mL/min) [see Dosage and Administration (2.2) , Warnings and Precautions (5.8) , Use in Specific Populations (8.5) and (8.6) and Clinical Pharmacology (12.3) ].

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. The most common adverse events occurring in >5% of the patients were: headache (7.8%), nausea (7.8%), constipation (7.0%), diarrhea (7.0%), anemia (5.5%), and pain (5.1%). Adverse events with an incidence of >1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia.

Pediatric Patients

Clinical Adverse Reactions

MERREM I.V. was studied in 515 pediatric patients (≥ 3 months to < 13 years of age) with serious bacterial infections (excluding meningitis, see next section) 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 321 pediatric patients (> 3 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 changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies.

There is no experience in pediatric patients with renal impairment.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of MERREM I.V. 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 section of this product label and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. Hematologic - agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia. Skin-toxic epidermal necrolysis, Stevens-Johnson Syndrome, angioedema, and erythema multiforme.

7 DRUG INTERACTIONS

7.1 Probenecid

Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Co-administration of probenecid with meropenem is not recommended.

7.2 Valproic Acid

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. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. If administration of MERREM I.V. is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.3) ].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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.

8.3 Nursing Mothers

Meropenem has been reported to be excreted in human milk. Caution should be exercised when MERREM I.V. is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of MERREM I.V. have been established for pediatric patients ≥ 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. Use of MERREM I.V. in pediatric patients with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study with adults and additional data from pediatric pharmacokinetics studies [see Indications and Usage (1.3) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.3) ].

8.5 Geriatric Use

Of the total number of subjects in clinical studies of MERREM I.V., approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. Additionally, in a study of 511 patients with complicated skin and skin structure infections, 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

A pharmacokinetic study with MERREM I.V. in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [see Clinical Pharmacology (12.3) ].

8.6 Patients with Renal Impairment

Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less [see Dosage and Administration (2.2) , Warnings and Precautions (5.8) , and Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

In mice and rats, large intravenous doses of meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities.

Intentional overdosing of MERREM I.V. is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function. The largest dose of meropenem administered in clinical trials has been 2 g given intravenously every 8 hours. At this dosage, no adverse pharmacological effects or increased safety risks have been observed.

Limited post-marketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should be considered. In individuals with normal renal function, rapid renal elimination takes place. Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage.

11 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. Its structural formula is: