MEROPENEM ANHYDROUS: 144 Adverse Event Reports & Safety Profile

Meropenem for Injection, USP contains meropenem a synthetic carbapenem antibacterial. Meropenem 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]hept2-ene-2-carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S•3H2O with a molecular weight of 437.52. Its structural formula is: 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. Meropenem for Injection, USP is a white to slight yellow crystalline powder for intravenous administration. Each vial contains meropenem equivalent to 2 grams and 416 mg of sodium bicarbonate, anhydrous. When re-constituted as instructed Meropenem for Injection, USP will deliver 2 grams of meropenem (on anhydrous basis) and approximately 180 mg of sodium as sodium carbonate (7.8 mEq) [see Dosage and Administration (2.2)] . The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Structure

AND USAGE

1.1 Bacterial Meningitis (Pediatric Patients 3 Months of Age and Older Only) Meropenem for Injection is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae , in pediatric patients 3 months of age and older. Meropenem for injection has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.

1.2 Usage 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 a penem antibacterial indicated for the treatment of bacterial meningitis in pediatric patients 3 months of age and older only. (1.1) 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. (1.2)

AND ADMINISTRATION Pediatric patients 3 months of age and older with bacterial meningitis (2.1)

Recommended

Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Bacterial Meningitis and Normal Renal Function (2.1) Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Bacterial Meningitis 40 2 grams Every 8 hours Intravenous infusion is to be given over approximately 15 minutes to 30 minutes. There is no experience with the use of Meropenem for Injection in pediatric patients with renal impairment.

2.1 Recommended Dosage in Pediatric Patients 3 Months of Age and Older with Bacterial Meningitis For pediatric patients 3 months of age and older with bacterial meningitis, the Meropenem for Injection recommended dosage is 40 mg/kg every 8 hours (maximum dosage is 2 grams every 8 hours). For pediatric patients weighing over 50 kg administer Meropenem for Injection at a dosage of 2 grams every 8 hours for bacterial meningitis. Administer diluted Meropenem for Injection as an intravenous infusion over approximately 15 minutes to 30 minutes <span class="opacity-50 text-xs">[see Dosage and Administration (2.2)]</span> . There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) intravenous bolus injection. There is no experience with the use of Meropenem for Injection in pediatric patients with renal impairment <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> .

2.2 Preparation and Administration of Meropenem for Injection Preparation instructions for Intravenous Infusion (Reconstitution and Dilution)

Reconstitute

Meropenem for Injection vial (2 grams) with Sterile Water for Injection according to the instructions in Table 1 below. Shake well to dissolve and let stand until clear.

Table

1: 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) 2 grams 40 mL 40 mL 50 mg/mL Add the resulting reconstituted solution to an intravenous container and further dilute with an appropriate infusion fluid [see Dosage and Administration (2.3) and (2.4)] . Discard unused portion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstituted, the solution varies from colorless to yellow depending on the concentration. Do not use flexible container in series connections.

Administration

Instructions for Meropenem Intravenous Infusion Solution After reconstitution and dilution of Meropenem for Injection, administer the appropriate dose of diluted Meropenem solution as an intravenous infusion over approximately 15 minutes to 30 minutes [see Dosage and Administration (2.1)] .

2.3 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.

2.4 Stability and Storage Reconstituted Solution with Sterile Water for Injection Use the reconstituted solution with Sterile Water for Injection immediately. However, re-constituted solutions of Meropenem for Injection maintain satisfactory potency under the conditions described below. Do not freeze reconstituted solutions of Meropenem for Injection.

Reconstituted Solution

Diluted with Sodium Chloride Injection, 0.9 % Solutions prepared for infusion (meropenem concentrations ranging from 1 mg/mL to 20 mg/mL) reconstituted with Water for Injection and further diluted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25°C (77°F) or 2 hours at up to 5°C (41°F).

Reconstituted Solution

Diluted with Dextrose Injection, 5 % Immediately use solutions (meropenem concentrations ranging from 1 mg/mL to 20 mg/mL) reconstituted with Water for Injection and subsequently diluted with Dextrose Injection 5%.

Meropenem for injection 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. Known hypersensitivity to product components or other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta (β)lactams. (4)

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> 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

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) and Drug Interactions (7.2)]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.2)]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> .

INTERACTIONS Co-administration of meropenem for injection with probenecid inhibits renal excretion of meropenem and therefore Meropenem for Injection is not recommended. (7.1) The concomitant use of Meropenem for Injection and valproic acid or divalproex sodium is generally not recommended. Antibacterial drugs other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium (5.4, 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4)]</span> .