meropenem 500 MG Injection
Generic Name: MEROPENEM
Brand Name: MEROPENEM
- Substance Name(s):
- MEROPENEM
DRUG INTERACTIONS
7 Co-administration of Meropenem for Injection with probenecid inhibits renal excretion of meropenem. (7.1) Co-administration of Meropenem for Injection with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. (5.3, 7.2) 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 Meropenem for Injection is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.3) ].
OVERDOSAGE
10 In mice and rats, large intravenous doses of meropenem (2200 mg/kg to 4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities. Intentional overdosing of Meropenem for Injection 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 grams 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. Consider symptomatic treatments. 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.
DESCRIPTION
11 Meropenem for Injection is a sterile, pyrogen-free, synthetic, broad-spectrum, carbapenem antibacterial 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-carboxilic acid trihydrate. Its empirical formula is C17H25N3O5S∙3H2O with a molecular weight of 437.52. Its structural formula is: Meropenem for Injection 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, each 1 gram Meropenem for Injection vial will deliver 1 gram of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). Each 500 mg Meropenem for Injection vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq) [see Dosage and Administration (2.4) ]. Chemical Structure
CLINICAL STUDIES
14 14.1 Complicated Skin and Skin Structure Infections Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial. The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours. The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure). The trial was conducted in the United States, South Africa, Canada, and Brazil. At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention. The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin. Two hundred and sixty one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable. The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm. The following table provides the results for the overall as well as subgroup comparisons in clinically evaluable population. Success RatePercent of satisfactory clinical response at follow-up evaluation. Population Meropenem for Injection nn=number of patients with satisfactory response./NN=number of patients in the clinically evaluable population or respective subgroup within treatment groups. (%) Imipenem-cilastatin n/N (%) Total 225/261 (86) 238/287 (83) Diabetes mellitus 83/97 (86) 76/105 (72) No diabetes mellitus 142/164 (87) 162/182 (89) Less than 65 years of age 190/218 (87) 205/241 (85) 65 years of age or older 35/43 (81) 33/46 (72) Men 130/148 (88) 137/172 (80) Women 95/113 (84) 101/115 (88) The following clinical efficacy rates were obtained, per organism. The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set). MICROORGANISMSPatients may have more than one pretreatment pathogen. Meropenem for Injection nn=number of patients with satisfactory response./NN=number of patients in the clinically evaluable population or subgroup within treatment groups. (%)%= Percent of satisfactory clinical response at follow-up evaluation. Imipenem-cilastatin n/N (%) Gram-positive aerobes Staphylococcus aureus, methicillin susceptible 82/88 (93) 84/100 (84) Streptococcus pyogenes (Group A) 26/29 (90) 28/32 (88) Streptococcus agalactiae (Group B) 12/17 (71) 16/19 (84) Enterococcus faecalis 9/12 (75) 14/20 (70) Streptococcus viridans Group, nos 11/12 (92) 5/6 (83) Gram-negative aerobes Escherichia coli 12/15 (80) 15/21 (71) Pseudomonas aeruginosa 11/15 (73) 13/15 (87) Proteus mirabilis 11/13 (85) 6/7 (86) Anaerobes Bacteroides fragilis 10/11 (91) 9/10 (90) Peptostreptococcus species 10/13 (77) 14/16 (88) The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (meropenem, 2.5% and imipenem-cilastatin, 2.7%). 14.2 Complicated Intra-Abdominal Infections One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial). Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the following presumptive microbiologic eradication/clinical cure rates and statistical findings were obtained: Treatment Arm No. evaluable/No. enrolled (%) Microbiologic Eradication Rate Clinical Cure Rate Outcome meropenem 146/516 (28%) 98/146 (67%) 101/146 (69%) imipenem 65/220 (30%) 40/65 (62%) 42/65 (65%) Meropenem equivalent to control cefotaxime/metronidazole 26/85 (30%) 22/26 (85%) 22/26 (85%) Meropenem not equivalent to control clindamycin/tobramycin 50/212 (24%) 38/50 (76%) 38/50 (76%) Meropenem equivalent to control The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm. Currently there is no additional information available to further interpret this observation. 14.3 Bacterial Meningitis Four hundred forty-six patients (397 pediatric patients 3 months to less than 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n=225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n=187) or ceftriaxone (n=34), at the approved dosing regimens. A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture. Patients were defined as clinically not cured if any one of the following three criteria were met: At the 5-7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of greater than60 decibels in one or both ears, or blindness. During therapy the patient’s clinical status necessitated the addition of other antibacterial drugs. Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse. Using the definition, the following efficacy rates were obtained, per organism. The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses. MICROORGANISMS Meropenem for Injection COMPARATOR S. pneumoniae 17/24 (71) 19/30 (63) H. influenzae (+)(+) β-lactamase-producing 8/10 (80) 6/6 (100) H. influenzae (-/NT)(-/NT) non-β-lactamase-producing or not tested 44/59 (75) 44/60 (73) N. meningitidis 30/35 (86) 35/39 (90) Total (including others) 102/131 (78) 108/140 (77) Sequelae were the most common reason patients were assessed as clinically not cured. Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa). The adverse events seen were comparable between the two treatment groups both in type and frequency. The meropenem group did have a statistically higher number of patients with transient elevation of liver enzymes [see Adverse Reactions (6.1) ]. Rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents. In the Meropenem for Injection 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. With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy. The following table shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients. Degree of Hearing Loss (in one or both ears) Meropenem n = 128 Comparator n = 135 No loss 61% 56% 20-40 decibels 20% 24% Greater than 40-60 decibels 8% 7% Greater than 60 decibels 9% 10%
HOW SUPPLIED
16 /STORAGE AND HANDLING Meropenem for Injection is supplied in 20 mL and 30 mL injection vials containing sufficient meropenem to deliver 500 mg or 1 gram for intravenous administration, respectively. The dry powder should be stored at controlled room temperature 20º-25ºC (68º-77ºF) [see USP]. 500 mg Injection Vial (NDC 0781-3000-94) and packaged in cartons of 10 vials (NDC 0781-3000-95) and cartons of 25 vials (NDC 0781-3000-96). 1 gram Injection Vial (NDC 0781-3098-94) and packaged in cartons of 10 vials (NDC 0781-3098-95) and cartons of 25 vials (NDC 0781-3098-96).
GERIATRIC USE
8.5 Geriatric Use Of the total number of subjects in clinical studies of Meropenem for Injection, 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 Meropenem for Injection 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) ].
DOSAGE FORMS AND STRENGTHS
3 Single use clear glass vials containing 500 mg or 1 gram (as the trihydrate blend with anhydrous sodium carbonate for constitution) of sterile meropenem powder. 500 mg Injection Vial (3) 1 gram Injection Vial (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Meropenem is an antibacterial drug [see Clinical Pharmacology (12.4) ].
INDICATIONS AND USAGE
1 To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection and other antibacterial drugs, Meropenem for Injection 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. Meropenem for Injection 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. For information regarding use in pediatric patients see [ Indications and Usage (1.1), (1.2),(1.3); Dosage and Administration (2.3), Adverse Reactions (6.1) , and Clinical Pharmacology (12.3) ]. Meropenem for Injection 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 of age and older only). (1.1) Complicated intra-abdominal infections (adult and pediatric patients). (1.2) Bacterial meningitis (pediatric patients 3 months of age and older only). (1.3) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection and other antibacterial drugs, Meropenem for Injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. 1.1 Skin and Skin Structure Infections (Adult Patients and Pediatric Patients 3 Months of age and older only) Meropenem for Injection 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-susceptible isolates only), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species. 1.2 Intra-abdominal Infections (Adult and Pediatric Patients) Meropenem for Injection 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 of age and older only) Meropenem for Injection is indicated as a single agent therapy for the treatment of bacterial meningitis caused by Streptococcus pneumoniaeThe efficacy of meropenem as monotherapy in the treatment of meningitis caused by penicillin nonsusceptible isolates of Streptococcus pneumoniae has not been established., Haemophilus influenzae, and Neisseria meningitidis. Meropenem for Injection has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of Meropenem for Injection have been established for pediatric patients 3 months of age and older with complicated skin and skin structure infections and bacterial meningitis, and for pediatric patients of all ages with complicated intra-abdominal infections. Skin and Skin Structure Infections Use of Meropenem for Injection in pediatric patients 3 months of age and older with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study in 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 (14.1) ]. Intra-abdominal Infections Use of Meropenem for Injection in pediatric patients 3 months of age and older with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. Use of Meropenem for Injection in pediatric patients less than 3 months of age with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from a pediatric pharmacokinetic and safety study [see Indications and Usage (1.2) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.2) ]. Bacterial Meningitis Use of Meropenem for Injection in pediatric patients 3 months of age and older with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population [see Indications and Usage (1.3) , Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.3) ].
PREGNANCY
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 gram 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 gram 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.
NUSRING MOTHERS
8.3 Nursing Mothers Meropenem has been reported to be excreted in human milk. Caution should be exercised when Meropenem for Injection is administered to a nursing woman.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams. (5.1) Seizures and other adverse CNS experiences have been reported during treatment. (5.2) Co-administration of Meropenem for Injection with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. (5.3, 7.2) Clostridium difficile-associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported. Evaluate if diarrhea occurs. (5.4) In patients with renal dysfunction, thrombocytopenia has been observed. (5.8) 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 Meropenem for Injection, it is important to inquire aboutprevious hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to Meropenem for Injection 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 Meropenem for Injection 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 meropenemtreated 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. 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 the dosage of Meropenem for Injection re-examined to determine whether it should be decreased or the antibacterial drug 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 Meropenem for Injection is necessary, supplemental anti-convulsant therapy should be considered [see Drug Interactions (7.2) ]. 5.4 Clostridium difficile-associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Meropenem for Injection, 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. 5.5 Development of Drug-Resistant Bacteria Prescribing Meropenem for Injection 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 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. 5.7 Laboratory Tests While Meropenem for Injection possesses the characteristic low toxicity of the beta-lactam group of antibacterial drugs, 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 Meropenem for Injection in patients on hemodialysis or peritoneal dialysis. 5.10 Potential for Neuromotor Impairment Patients receiving Meropenem for Injection 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 Meropenem for Injection is well tolerated, patients should not operate machinery or motorized vehicles [see Adverse Reactions (6.1) ].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Counsel patients that antibacterial drugs including Meropenem for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Meropenem for Injection is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, take the medication exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Meropenem for Injection or other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.4) ]. Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with Meropenem for Injection. If treatment with Meropenem for Injection is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed [see Warnings and Precautions (5.3) ]. Patients receiving Meropenem for Injection 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 Meropenem for Injection is well tolerated, patients should not operate machinery or motorized vehicles [see Warnings and Precautions (5.10) ].
DOSAGE AND ADMINISTRATION
2 500 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 1 gram every 8 hours is recommended. (2.1) 1 gram every 8 hours by intravenous infusion over 15 minutes to 30 minutes for intra-abdominal infections for adult patients. (2.1) 1 gram every 8 hours by intravenous bolus injection (5 mL to 20 mL) over 3 minutes to 5 minutes for adult patients. (2.1) Dosage should be reduced in adult patients with renal impairment. (2.2) Recommended Meropenem for Injection 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 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hours Less than10 One-half recommended dose Every 24 hours Pediatric patients 3 months of age and older Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function (2.3) 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 structure20 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 (2.3). 10 500 mg Every 8 hours Intra-abdominal 20 1 gram Every 8 hours Meningitis 40 2 grams Every 8 hours Pediatric patients less than 3 months of age Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients Less than 3 Months of Age with Complicated Intra-Abdominal Infections and Normal Renal Function (2.3) Age Group Dose (mg/kg) Dosing Interval – Intravenous infusion is to be given over 30 minutes. – There is no experience in pediatric patients with renal impairment. GA: gestational age and PNA: postnatal 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 2.1 Adult Patients The recommended dose of Meropenem for Injection 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 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)5 may be used to estimate creatinine clearance. Males: Creatinine Clearance (mL/min) = Weight (kg) × (140 – age) 72 × serum creatinine (mg/dL) Females: 0.85 × above value Recommended Meropenem for Injection 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 Greater than 25-50 Recommended dose Every 12 hours 10-25 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 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 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 (complicated skin and skin structure, intra-abdominal or meningitis). (See dosing table below.) Pediatric patients weighing over 50 kg should be administered Meropenem for Injection at a dose of 500 mg every 8 hours for complicated skin and skin structure infections, 1 gram every 8 hours for intra-abdominal infections and 2 grams every 8 hours for meningitis. Meropenem for Injection should be given as intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes-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. Recommended Meropenem for Injection 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 10 500 mg Every 8 hours Intra-abdominal 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 complicated skin and skin structure infections 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 intra-abdominal infections, the Meropenem for Injection dose is based on gestational age (GA) and postnatal age (PNA). (See dosing table below). Meropenem for Injection should be given as intravenous infusion over 30 minutes. Recommended Meropenem for Injection 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 of Solution For Intravenous Bolus Administration Constitute injection vials (500 mg and 1 gram) with sterile Water for Injection (see table below). Shake to dissolve and let stand until clear. 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 Infusion vials (500 mg and 1 gram) may be directly constituted with a compatible infusion fluid. Alternatively, an injection vial may be 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) ]. WARNING: Do not use flexible container in series connections. 2.5 Compatibility Compatibility of Meropenem for Injection with other drugs has not been established. Meropenem for Injection 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 should be used. However, constituted solutions of Meropenem for Injection maintain satisfactory potency under the conditions described below. Solutions of intravenous Meropenem for Injection should not be frozen. Intravenous Bolus Administration Meropenem for Injection vials constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of Meropenem for Injection) 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 concentrations ranging from 1 mg/mL to 20 mg/mL) 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 concentrations ranging from 1 mg/mL 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.