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, USP. ( 5.2 ) Seizures and other adverse CNS experiences have been reported during treatment. ( 5.3 ) Co-administration of Meropenem for Injection, USP with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. ( 5.4 , 7.2 ) Clostridium difficile- associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported. Evaluate if diarrhea occurs. ( 5.5 ) 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, USP, 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, USP 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, USP [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 If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered. 5.3 Seizure Potential Seizures and other adverse CNS experiences have been reported during treatment with Meropenem for Injection, USP. 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 adult patients with creatinine clearance of 50 mL/min or less [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 re-examine the dosage of Meropenem for Injection, USP to determine whether it should be decreased or discontinued. 5.4 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, USP is necessary, consider supplemental anti-convulsant therapy [see Drug Interactions (7.2) ]. 5.5 Clostridium difficile –associated Diarrhea Clostridium difficile- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Meropenem for Injection, USP, 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. 5.6 Development of Drug-Resistant Bacteria Prescribing Meropenem for Injection, USP 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. 5.7 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. 5.8 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) , Use in Specific Populations (8.5) and (8.6) , and Clinical Pharmacology (12.3) ]. 5.9 Potential for Neuromotor Impairment Alert patients receiving Meropenem for Injection, USP 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, USP 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) ] Seizure Potential [see Warnings and Precautions (5.3) ] Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.4) ] Clostridium difficile – associated Diarrhea [see Warnings and Precautions (5.5) ] Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.6) ] Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.7) ] Thrombocytopenia [see Warnings and Precautions (5.8) ] Potential for Neuromotor Impairment [see Warnings and Precautions (5.9) ] Most common adverse reactions (2% or less) are: headache, nausea, constipation, diarrhea, anemia, vomiting, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xellia Pharmaceuticals USA, LLC at safety@xellia.com or 1-833-295-6953, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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, USP (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, USP. The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Meropenem for Injection, USP. Local Adverse Reactions Local adverse events that were reported with Meropenem for Injection, USP 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 events that were reported with Meropenem for Injection, USP 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 Meropenem for Injection, USP 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 [see Warnings and Precautions (5.3) and (5.9) ] 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 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 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 (7.0%), 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 Impairment: For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported with Meropenem for Injection, USP, increased in patients with moderately severe renal impairment (creatinine clearance 10 to 26 mL/min) [see Dosage and Administration (2.2) , Warnings and Precautions (5.9) , Use in Specific Populations (8.5) and (8.6) and Clinical Pharmacology (12.3) ]. Pediatric Patients: Systemic and Local Adverse Reactions Pediatric Patients with Serious Bacterial Infections (excluding Bacterial Meningitis): Meropenem for Injection, USP 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 Meropenem for Injection, USP and their rates of occurrence as follows: Diarrhea 3.5% Rash 1.6% Nausea and Vomiting 0.8% Pediatric Patients with Bacterial Meningitis: Meropenem for Injection, USP 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 Meropenem for Injection, USP 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, USP 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): Meropenem for Injection, USP 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 Meropenem for Injection, USP. 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% Adverse Laboratory Changes in Pediatric Patients: 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, USP. 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. 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.

<table width="50%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="left" valign="top"/><tbody><tr><td>Inflammation at the injection site</td><td>2.4%</td></tr><tr><td>Injection site reaction</td><td>0.9%</td></tr><tr><td>Phlebitis/thrombophlebitis</td><td>0.8%</td></tr><tr><td>Pain at the injection site</td><td>0.4%</td></tr><tr><td>Edema at the injection site</td><td>0.2%</td></tr></tbody></table>

<table width="50%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="left" valign="top"/><tbody><tr><td>Diarrhea</td><td>3.5%</td></tr><tr><td>Rash</td><td>1.6%</td></tr><tr><td>Nausea and Vomiting</td><td>0.8%</td></tr></tbody></table>

<table width="50%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="left" valign="top"/><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>1.0%</td></tr></tbody></table>