Meropenem

5 WARNINGS AND PRECAUTIONS Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams. (5.1) Severe cutaneous adverse reactions have been reported in patients receiving meropenem for injection. (5.2) Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue meropenem for injection and initiate appropriate therapy. (5.3) Seizures and other adverse CNS experiences have been reported during treatment. (5.4) 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. (5.5, 7.2) Clostridioides difficile -associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported. Evaluate if diarrhea occurs. (5.6) In patients with renal dysfunction, thrombocytopenia has been observed (5.9) 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 about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to meropenem for injection occurs, discontinue the drug immediately. 5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving meropenem for injection [see Adverse Reactions (6.2)] . If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered. 5.3 Rhabdomyolysis Rhabdomyolysis has been reported with the use of meropenem [see Adverse Reactions (6.2)] . If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue meropenem for injection and initiate appropriate therapy. 5.4 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 meropenem-treated patients with seizures had pre-existing contributing factors. Among these included a prior history of seizures or CNS abnormality and concomitant medications with seizure potential. 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 meropenem for injection to determine whether it should be decreased or discontinued. 5.5 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of meropenem for injection is necessary, consider supplemental anti-convulsant therapy [see Drug Interactions (7.2)] . 5.6 Clostridioides difficile - associated Diarrhea Clostridioides 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. 5.7 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. 5.8 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. 5.9 Thrombocytopenia In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)] . 5.10 Potential for Neuromotor Impairment Alert patients receiving meropenem for injection 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 meropenem for injection is well tolerated, advise patients not to 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)] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] Rhabdomyolysi s [see Warnings and Precautions (5.3)] Seizure Potential [see Warnings and Precautions (5.4)] Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.5)] Clostridioides difficile – Associated Diarrhea [see Warnings and Precautions (5.6)] Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.7)] Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.8)] Thrombocytopenia [see Warnings and Precautions (5.9)] Potential for Neuromotor Impairment [see Warnings and Precautions (5.10)] Most common adverse reactions (incidence ≥ 1%) are diarrhea, rash (mostly diaper area moniliasis), oral moniliasis, and glossitis (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Steriscience at 1-888-278-1784 or www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. Adverse Reactions in Pediatric Patients with Bacterial Meningitis Meropenem for injection was studied in 321 pediatric patients (3 months to less than 17 years of age) with bacterial meningitis at a dosage of 40 mg/kg every 8 hours. The most common adverse reactions and their rates of occurrence were as follows: Diarrhea 4.7% Rash (mostly diaper area moniliasis) 3.1% Oral Moniliasis 1.9% Glossitis 1% In these studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem for injection and those who received comparator agents (either cefotaxime or ceftriaxone). In the meropenem for injection-treated group, 12/15 patients with seizures had late onset seizures (seizures that occurred on day 3 or later) versus 7/20 patients in the comparator arm. The meropenem for injection group had a statistically higher number of patients than the comparator with transient elevation of liver enzymes. Adverse Reactions from Studies of Meropenem for Injection in Other Serious Bacterial Infections (not bacterial meningitis) The following adverse reactions occurred in studies of 2,904 immunocompetent adult patients who received meropenem for injection (500 mg or 1 gram every 8 hours) for the treatment of other serious bacterial infections (not bacterial meningitis). This meropenem for injection product is indicated only for the treatment of bacterial meningitis caused by certain organisms in pediatric patients 3 months of age and older [see Indications and Usage (1.1)] . Many patients in these studies were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with meropenem for injection. Deaths in 5 patients were assessed as possibly related to meropenem for injection; 36 (1.2%) patients had meropenem for injection discontinued because of adverse events. Local Adverse Reactions Local adverse reactions that were reported with meropenem for injection 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%), and edema at the injection site (0.2%). Systemic Adverse Reactions Systemic adverse reactions that occurred in greater than 1% of the meropenem for injection-treated 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 occurred in less than or equal to 1% but greater than 0.1% of the meropenem for injection-treated patients are listed below within each body system in order of decreasing frequency: Bleeding Event s : 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 Laboratory Abnormalities Laboratory abnormalities that occurred in greater than 0.2% of the meropenem for injection-treated 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 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of meropenem, including meropenem for injection. 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 under the Clinical Trials Experience subsection [see Adverse Reactions (6.1)] and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. Blood and Lymphatic System Disorders : agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia. Immune System Disorders: angioedema. Skin and Subcutaneous Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme and acute generalized exanthematous pustulosis. Musculoskeletal Disorders: rhabdomyolysis

<table width="100%"><tbody><tr><td> Diarrhea</td><td> 4.7%</td></tr><tr><td> Rash (mostly diaper area moniliasis)</td><td> 3.1%</td></tr><tr><td> Oral Moniliasis</td><td> 1.9%</td></tr><tr><td> Glossitis</td><td> 1%</td></tr></tbody></table>