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 MERREM IV 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 postmarketing 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.
MERREM IV 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.
The following are discussed in greater detail in other sections of labeling:
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 PatientsDuring clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with MERREM IV (500 mg or 1 gram 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 IV.
The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with MERREM IV.
Local Adverse ReactionsLocal adverse events that were reported with MERREM IV were as follows:
| Inflammation at the injection site | 2.4% |
| Injection site reaction | 0.9% |
| Phlebitis/thrombophlebitis | 0.8% |
| Pain at the injection site | 0.4% |
| Edema at the injection site | 0.2% |
Systemic adverse events that were reported with MERREM IV 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 events that were reported with MERREM IV 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%).
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
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 ChangesAdverse laboratory changes that were reported and occurring in greater than 0.2% 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 InfectionsIn 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 greater than 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 greater than 1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia.
Patients With Renal ImpairmentFor patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported with MERREM IV, increased in patients with moderately severe renal impairment (creatinine clearance 10 to 26 mL/min).
Pediatric Patients Systemic and Local Adverse ReactionsPediatric Patients with Serious Bacterial Infections (excluding Bacterial Meningitis):
MERREM IV 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. The types of systemic and local 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 IV and their rates of occurrence as follows:
| Diarrhea | 3.5% |
| Rash | 1.6% |
| Nausea and Vomiting | 0.8% |
Pediatric Patients with Bacterial Meningitis:
MERREM IV 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. The types of systemic and local adverse events seen in these patients are similar to the adults, with the most common adverse reactions reported as possibly, probably, or definitely related to MERREM IV and their rates of occurrence as follows:
| Diarrhea | 4.7% |
| Rash (mostly diaper area moniliasis) | 3.1% |
| Oral Moniliasis | 1.9% |
| Glossitis | 1.0% |
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 MERREM IV 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):
MERREM IV 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 MERREM IV.
The adverse reactions seen in these patients that were reported and their rates of occurrence are as follows:
| Convulsion | 5.0% |
| Hyperbilirubinemia (conjugated) | 4.5% |
| Vomiting | 2.5% |
Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies.
Post Marketing ExperienceThe following adverse reactions have been identified during post-approval use of MERREM IV. 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 and drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
Skin and Subcutaneous Disorders: toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.
MERREM IV is indicated for the treatment of complicated skin and skin structure infections (cSSSI) 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.
Complicated Intra-Abdominal Infections (Adult And Pediatric Patients)MERREM IV is indicated 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.
Bacterial Meningitis (Pediatric Patients 3 Months Of Age And Older Only)MERREM IV is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae.
MERREM IV has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.
UsageTo reduce the development of drug-resistant bacteria and maintain the effectiveness of MERREM IV and other antibacterial drugs, MERREM IV 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.
There are no adequate and well-controlled studies with meropenem 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.
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 higher, respectively, than 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.
Single dose clear glass vials of MERREM IV containing 500 mg or 1 gram (as the trihydrate blended with anhydrous sodium carbonate for re-constitution) of sterile meropenem powder.
Storage And HandlingMERREM IV 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 20°25°C (68°-77°F).
500 mg Injection Vial (NDC 0310-0325-20)
1 gram Injection Vial (NDC 0310-0321-30)
REFERENCES
5. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16:31-41.
Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850. Revised: Jan 2018
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS Hypersensitivity ReactionsSerious 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 IV, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to MERREM IV occurs, discontinue the drug immediately.
Seizure PotentialSeizures and other adverse CNS experiences have been reported during treatment with MERREM IV 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.
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 adult patients with creatinine clearance of 50 mL/min or less.
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 reexamine the dosage of MERREM IV to determine whether it should be decreased or discontinued.
Risk Of Breakthrough Seizures Due To Drug Interaction With Valproic AcidThe 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. If administration of MERREM IV is necessary, consider supplemental anti-convulsant therapy.
Clostridium Difficile–Associated DiarrheaClostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MERREM IV, 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.
Development Of Drug-Resistant BacteriaPrescribing MERREM IV 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.
Overgrowth Of Nonsusceptible OrganismsAs 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.
ThrombocytopeniaIn patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported.
Potential For Neuromotor ImpairmentAlert patients receiving MERREM IV 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. Until it is reasonably well established that MERREM IV is well tolerated, advise patients not to operate machinery or motorized vehicles.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisCarcinogenesis studies have not been performed.
MutagenesisGenetic 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 FertilityReproductive 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 gram every 8 hours). There was no reproductive toxicity seen.
Use In Specific Populations Pregnancy Pregnancy Category BThere are no adequate and well-controlled studies with meropenem 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.
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 higher, respectively, than 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.
Nursing MothersMeropenem has been reported to be excreted in human milk. Caution should be exercised when MERREM IV is administered to a nursing woman.
Pediatric UseThe safety and effectiveness of MERREM IV 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 InfectionsUse of MERREM IV 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.
Intra-Abdominal InfectionsUse of MERREM IV 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 MERREM IV 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.
Bacterial MeningitisUse of MERREM IV 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.
Geriatric UseOf the total number of subjects in clinical studies of MERREM IV, 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 IV in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.
Patients With Renal ImpairmentDosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less.
The recommended dose of MERREM IV 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.
MERREM IV 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.
Use In Adult Patients With Renal ImpairmentDosage 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: | (weight in kg) x (140 – age) |
| (72) x serum creatinine (mg/100 mL) | |
| Females: | (0.85) x (above value) |
Table 1: Recommended MERREM IV 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 than 10 | One-half recommended dose | Every 24 hours |
There is inadequate information regarding the use of MERREM IV in patients on hemodialysis or peritoneal dialysis.
Use In Pediatric Patients Pediatric Patients 3 Months Of Age And OlderTable 2: Recommended MERREM IV Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function
| Type of Infection | Dose (mg/kg) | Up to a Maximum Dose | Dosing Interval |
| Complicated skin and skin structure infections | 10 | 500 mg | Every 8 hours |
| Complicated intra-abdominal infections | 20 | 1 gram | Every 8 hours |
| Meningitis | 40 | 2 grams | Every 8 hours |
| There is no experience in pediatric patients with renal impairment. When treating cSSSI caused by P. aeruginosa, a dose of 20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended. |
For pediatric patients (with normal renal function) less than 3 months of age, with complicated intra-abdominal infections, the MERREM IV dose is based on gestational age (GA) and postnatal age (PNA). See dosing table 3 below. MERREM IV should be given as intravenous infusion over 30 minutes.
Table 3: Recommended MERREM IV 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. |
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
Compatibility of MERREM IV with other drugs has not been established. MERREM IV should not be mixed with or physically added to solutions containing other drugs.
Stability And StorageFreshly prepared solutions of MERREM IV should be used. However, re-constituted solutions of MERREM IV maintain satisfactory potency under the conditions described below. Solutions of intravenous MERREM IV should not be frozen.
Intravenous Bolus AdministrationMERREM IV injection vials re-constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of MERREM IV) 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 AdministrationSolutions prepared for infusion (MERREM IV concentrations ranging from 1 mg/mL to 20 mg/mL) re-constituted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25°C (77°F) or 15 hours at up to 5°C (41°F).
Solutions prepared for infusion (MERREM IV concentrations ranging from 1 mg/mL to 20 mg/mL) re-constituted with Dextrose Injection 5% should be used immediately.
Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38%. Co-administration of probenecid with meropenem is not recommended.
