FDA label 5a42b3b2-cc35-4ef2-8b8b-0a6cb9e6f522

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 I.V. 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 I.V., 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 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 Meropenem for Injection 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. 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 I.V. 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 I.V. is necessary, supplemental anticonvulsant 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 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 antibacterial drugs 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 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 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 I.V. possesses the characteristic low toxicity of the beta-lactam group of antibiotics 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 I.V. in patients on hemodialysis or peritoneal dialysis. 5.10 Potential for Neuromotor Impairment Patients receiving Meropenem for Injection 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 Meropenem for Injection 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 difficil e – 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) ] Most common adverse reactions (2% or less) are: headache, nausea, constipation, diarrhea, anemia, vomiting, and rash ( 6.1 )To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch for voluntary reporting of adverse reactions. 6.1 Adverse Reactions 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 Meropenem for Injection I.V. (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 Meropenem for Injection I.V. The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Meropenem for Injection I.V. Local Adverse Reactions Local adverse reactions that were reported irrespective of the relationship to therapy with Meropenem for Injection I.V. 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 Reactions Systemic adverse reactions that were reported irrespective of the relationship to Meropenem for Injection 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 Meropenem for Injection 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 Meropenem for Injection 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 Meropenem for Injection I.V., increased in patients with moderately severe renal impairment (creatinine clearance greater than 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 greater than 5% of the patients were: headache (7.8%), nausea (7.8%), constipation (7%), diarrhea (7%), 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. Pediatric Patients Clinical Adverse Reactions Meropenem for Injection I.V. 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 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 Meropenem for Injection I.V. and their rates of occurrence as follows: Diarrhea 3.5% Rash 1.6% Nausea and Vomiting 0.8% Meropenem for Injection I.V. 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 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 Meropenem for Injection I.V. 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 Meropenem for Injection 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. Meropenem for Injection I.V. 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 reactions 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 reactions to Meropenem for Injection I.V. The clinical adverse reactions seen in these patients that were reported (regardless of investigator assessment of causality) and their rates of occurrence are as follows: Convulsion 5.0% Hyperbilirubinemia (conjugated) 4.5% Vomiting 2.5% Adverse Laboratory Changes Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of Meropenem for Injection 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.