These Highlights Do Not Include All The Information Needed To Use Meropenem For Injection Safely And Effectively. See Full Prescribing Information For Meropenem For Injection

Risk Summary

There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem in pregnant women.

No fetal toxicity or malformations were observed in pregnant rats and Cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 2.4 and 2.3 times the maximum recommended human dose (MRHD) based on body surface area comparison, respectively. In rats administered intravenous meropenem in late pregnancy and during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 3.2 times the MRHD based on body surface area comparison (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Meropenem administered to pregnant rats during organogenesis (Gestation Day 6 to Gestation Day 17) in intravenous doses of 240, 500, and 750 mg/kg/day was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 2.4 times the MRHD of 1 gram every 8 hours based on body surface area comparison). Meropenem administered intravenously to pregnant Cynomolgus monkeys during organogenesis from Day 20 to 50 after mating at doses of 120, 240, and 360 mg/kg/day did not produce maternal or fetal toxicity at the NOAEL dose of 360 mg/kg/day (approximately 2.3 times the MRHD based on body surface area comparison).

In a peri-postnatal study in rats described in the published literature ², intravenous meropenem was administered to dams from Gestation Day 17 until Lactation Day 21 at doses of 240, 500, and 1000 mg/kg/day. There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. Second generation offspring showed no meropenem-related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 3.2 times the MRHD based on body surface area comparisons).

Pediatric Patients 3 Months of Age and Older

• For pediatric patients 3 months of age and older, the meropenem for injection dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every 8 hours (maximum dose is 2 grams every 8 hours), depending on the type of infection (cSSSI, cIAI, intra-abdominal infection or meningitis). See dosing Table 2 below.
• For pediatric patients weighing over 50 kg administer meropenem for injection at a dose of 500 mg every 8 hours for cSSSI, 1 gram every 8 hours for cIAI and 2 grams every 8 hours for meningitis.
• Administer meropenem for injection as an intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes.
• There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) bolus dose.

Table 2: Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function

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.

Mechanism of Action

The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding-protein (PBP) targets. Meropenem binds to PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus.Bactericidal concentrations (defined as a 3 log ₁₀reduction in cell counts within 12 hours to 24 hours) are typically 1 to 2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed.

Meropenem does not have in vitroactivity against methicillin-resistant Staphylococcus aureus(MRSA) or methicillin-resistant Staphylococcus epidermidis(MRSE).

Meropenem for injection 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 20º to 25ºC (68º to 77ºF) [see USP].



500 mg Injection Vial (NDC 72572-415-01) and packaged in cartons of 10 vials (NDC 72572-415-10).



1 gram Injection Vial (NDC 72572-416-01) and packaged in cartons of 10 vials (NDC 72572-416-10).

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.

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 meropenem 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.

• Cockcroft DW, MH Gault, 1976, Prediction of creatinine clearance from serum creatinine, Nephron, 16:31-41.
• Kawamura S, AW Russell, SJ Freeman, and RA Siddall, 1992, Reproductive and Developmental Toxicity of Meropenem in Rats, Chemotherapy, 40:S238-250.

Risk Summary

Meropenem has been reported to be excreted in human milk. No information is available on the effects of meropenem on the breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for meropenem and any potential adverse effects on the breast-fed child from meropenem or from the underlying maternal conditions.

Meropenem for injection is a sterile, pyrogen-free, synthetic, carbapenem antibacterial for intravenous administration. It 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]hept-2-ene-2-carboxilic acid trihydrate. Its empirical formula is C ₁₇H ₂₅N ₃O ₅S∙3H ₂O with a molecular weight of 437.52. Its structural formula is:

Meropenem for injection is a white to pale yellow crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3.

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.

When re-constituted as instructed, each 1 gram meropenem for injection vial will deliver 1 gram of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). Each 500 mg meropenem for injection vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq) [ see Dosage and Administration (2.4) ].

Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem.  Co-administration of probenecid with meropenem is not recommended.

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.

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 vitroand 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 is necessary, then supplemental anti-convulsant therapy should be considered [ see Warnings and Precautions (5.4) ].

The safety and effectiveness of meropenem 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.

Of the total number of subjects in clinical studies of meropenem, 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 meropenem in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [ see Clinical Pharmacology (12.3) ].

The recommended dose of meropenem for injection 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.

Meropenem for injection 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.

Meropenem 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:

• 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) ]

• Co-administration of meropenem with probenecid inhibits renal excretion of meropenem and is therefore not recommended. ( 7.1)
• The concomitant use of meropenem 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)

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), (8.6) , Clinical Pharmacology (12.3) ].

The percentage of time of a dosing interval that unbound plasma concentration of meropenem exceeds the meropenem minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection.

Seizures and other adverse CNS experiences have been reported during treatment with meropenem. 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),  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 to determine whether it should be decreased or discontinued.

Meropenem for injection is a penem antibacterial indicated for the treatment of:

• Complicated skin and skin structure infections (adult patients and pediatric patients 3 months of age and older only).
  
  ( 1.1)
• Complicated intra-abdominal infections (adult and pediatric patients). ( 1.2)
• Bacterial meningitis (pediatric patients 3 months of age and older only). ( 1.3)

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.

Meropenem is an antibacterial drug [ see Microbiology (12.4) ].

Four hundred forty-six patients (397 pediatric patients 3 months to less than 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n=225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n=187) or ceftriaxone (n=34), at the approved dosing regimens. A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture.

Patients were defined as clinically not cured if any one of the following three criteria were met:

• At the 5 to 7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of greater than 60 decibels in one or both ears, or blindness.
• During therapy the patient's clinical status necessitated the addition of other antibacterial drugs.
• Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse.

Using the definition, the following efficacy rates were obtained, per organism (noted in Table 10). The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses.

Table 10: Efficacy rates by Pathogen in the Clinically Evaluable Population with Bacterial Meningitis

Sequelae were the most common reason patients were assessed as clinically not cured.

Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa).

With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy. The following Table 11shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients.

Table 11: Hearing Loss at Post-Therapy in the Evaluable Population Treated with Meropenem

Freshly prepared solutions of meropenem for injection should be used. However, re-constituted solutions of meropenem for injection maintain satisfactory potency under the conditions described below. Solutions of intravenous meropenem for injection should not be frozen.

• 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. ( 5.2)
• Seizures and other adverse CNS experiences have been reported during treatment. ( 5.3)
• Co-administration of meropenem 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)

• 500 mg every 8 hours by intravenous infusion over 15 to 30 minutes for complicated skin and skin structure infections (cSSSI) for adult patients. When treating infections caused by Pseudomonas aeruginosa, a dose of 1 gram every 8 hours is recommended. ( 2.1)
• 1 gram every 8 hours by intravenous infusion over 15 minutes to 30 minutes for intra-abdominal infections for adult patients. ( 2.1)
• 1 gram every 8 hours by intravenous bolus injection (5 mL to 20 mL) over 3 minutes to 5 minutes for adult patients.
  
  ( 2.1)
• Dosage should be reduced in adult patients with renal impairment. ( 2.2)

Pediatric patients 3 months of age and older

Pediatric patients less than 3 months of age

Single dose clear glass vials of meropenem for injection containing 500 mg or 1 gram (as the trihydrate blended with anhydrous sodium carbonate for re-constitution) of sterile meropenem powder.

The following adverse reactions have been identified during post-approval use of meropenem. 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.

• Renal Impairment: Dose adjustment is necessary, if creatinine clearance is 50 mL/min or less. ( 2.2, 8.6)

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, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to meropenem occurs, discontinue the drug immediately.

For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported with meropenem, 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),  (8.6),  Clinical Pharmacology (12.3) ].

• Counsel patients that antibacterial drugs including meropenem for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When meropenem for injection is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, take the medication exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by meropenem for injection or other antibacterial drugs in the future.
• Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible [ see Warnings and Precautions (5.5) ].
• Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with meropenem for injection. If treatment with meropenem for injection is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed [ see Warnings and Precautions (5.4) ].
• Patients receiving meropenem for injection on an outpatient basis must be alerted of 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, patients should not operate machinery or motorized vehicles [ see Warnings and Precautions (5.9) ].

Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less [ see Dosage and Administration (2.2) , Warnings and Precautions (5.8) , Clinical Pharmacology (12.3) ].

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 [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.

Alert patients receiving meropenem 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 is well tolerated, advise patients not to operate machinery or motorized vehicles [ see Adverse Reactions (6.1) ].

Prescribing meropenem 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.

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.

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.

One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial).

Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the presumptive microbiologic eradication/clinical cure rates and statistical findings are provided in Table 9:

Table 9: Presumptive Microbiologic Eradication and Clinical Cure Rates at Test-of-Cure Visit in the Evaluable Population with Complicated Intra-Abdominal Infection

The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm. Currently there is no additional information available to further interpret this observation.

NDC 72572-416-01

Meropenem for Injection, USP

1 g per vial

Meropenem Equivalent

For Intravenous Use Only

Rx only

Contents are Sterile

Each vial contains meropenem equivalent to 1 g of meropenem activity.

Sodium content is 90.2 mg (3.92 mEq).

Usual Dosage: See package insert.

For IV Preparation: Dilute with approved diluent and prepare as specified in the package insert.

Prior to Constitution: Store at 20 ^oC to 25 ^oC (68 ^oto 77 ^oF) [see USP Controlled Room Temperature]

After Constitution: See package insert.

Distr by Civica, Inc., Lehi, Utah 84043

Mfd by Savior Lifetec Corp., Taiwan, R.O.C

Rev: 07/2020

976143

NDC 72572-415-01

Meropenem for Injection, USP

500 mg per vial

Meropenem Equivalent

For Intravenous Use Only

Rx only

Contents are Sterile

Each vial contains meropenem equivalent to 500 mg of meropenem activity. Sodium content is 45.1 mg (1.96 mEq).

Usual Dosage: See package insert.

For IV Preparation: Dilute with approved diluent and prepare as specified in the package insert.

Prior to Constitution: Store at 20 ^oC to 25 ^oC (68 ^oto 77 ^oF) [see USP Controlled Room Temperature]

After Constitution: See package insert.

Distr by Civica, Inc., Lehi, Utah 84043

Mfd by Savior Lifetec Corp., Taiwan, R.O.C.

Rev: 07/2020

976142

NDC 72572-416-10

Rx only

Meropenem for Injection, USP

1 g per vial

Meropenem Equivalent

For Intravenous Use Only

Discard unused portion

10 x 1 g Single Dose Vials

CIVICA

Each vial contains meropenem equivalent to 1 g of meropenem activity.

Sodium content is 90.2 mg (3.92 mEq).

Usual Dosage: See package insert.

For IV Preparation: Dilute with approved diluent and prepare as specified in the package insert.

Prior to Constitution: Store at 20 ^oC to 25 ^oC (68 ^oto 77 ^oF) [see USP Controlled Room Temperature]

After Constitution: See package insert.

Distributed by Civica, Inc., Lehi, Utah 84043

Manufactured by Savior Lifetec Corporation

4F, No. 12 & 16 Chuangye Rd., Tainan City 74144, Taiwan, R.O.C.

Product of Taiwan

Rev: 07/2020

977134

NDC72572-415-10

Rx only

Meropenem for Injection, USP

500 mg per vial



Meropenem Equivalent

For Intravenous Use Only

Discard unused portion

10 x 500 mg Single Dose Vials

CIVICA

Each vial contains meropenem equivalent to 500 mg of meropenem activity.

Sodium content is 45.1 mg (1.96 mEq).

Usual Dosage: See package insert.

For IV Preparation: Dilute with approved diluent and prepare as specified in the package insert.

Prior to Constitution: Store at 20 ^oC to 25 ^oC (68 ^oto 77 ^oF) [see USP Controlled Room Temperature]

After Constitution: See package insert.

Distributed by Civica, Inc., Lehi, Utah 84043

Manufactured by Savior Lifetec Corporation

4F, No. 12 & 16 Chuangye Rd., Tainan City 74144, Taiwan, R.O.C.

Product of Taiwan

Rev: 07/2020

977134

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem, 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. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficilecause 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. difficilemay 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.

Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. (See dosing Tablebelow.)

When only serum creatinine is available, the following formula (Cockcroft and Gault equation) ¹may be used to estimate creatinine clearance.

Males: Creatinine Clearance (mL/min) =

Females: 0.85 × above value

Table 1: Recommended Meropenem for Injection Dosage Schedule for Adult Patients with Renal Impairment

There is inadequate information regarding the use of meropenem for injection in patients on hemodialysis or peritoneal dialysis.

Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial. The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours. The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure). The trial was conducted in the United States, South Africa, Canada, and Brazil. At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention. The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin. Two hundred and sixty one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable. The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm.

The success rates for the clinically evaluable population are provided in Table 7.

Table 7: Success Rates at Test-of-Cure Visit for Clinically Evaluable Population with Complicated Skin and Skin Structure Infections

The clinical efficacy rates by pathogen are provided in Table 8. The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set).

Table 8: Clinical Efficacy Rates by Pathogen for Clinically Evaluable Population

The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (meropenem, 2.5% and imipenem-cilastatin, 2.7%).

Meropenem for injection 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 Peptostreptococcusspecies .

Meropenem for injection is indicated for the treatment of bacterial meningitis caused by  Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae.

Meropenem for injection has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.

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 is necessary, consider supplemental anti-convulsant therapy [ see Drug Interactions (7.2) ].

Meropenem for injection 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 Peptostreptococcusspecies .

Risk Summary

There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem in pregnant women.

No fetal toxicity or malformations were observed in pregnant rats and Cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 2.4 and 2.3 times the maximum recommended human dose (MRHD) based on body surface area comparison, respectively. In rats administered intravenous meropenem in late pregnancy and during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 3.2 times the MRHD based on body surface area comparison (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Meropenem administered to pregnant rats during organogenesis (Gestation Day 6 to Gestation Day 17) in intravenous doses of 240, 500, and 750 mg/kg/day was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 2.4 times the MRHD of 1 gram every 8 hours based on body surface area comparison). Meropenem administered intravenously to pregnant Cynomolgus monkeys during organogenesis from Day 20 to 50 after mating at doses of 120, 240, and 360 mg/kg/day did not produce maternal or fetal toxicity at the NOAEL dose of 360 mg/kg/day (approximately 2.3 times the MRHD based on body surface area comparison).

In a peri-postnatal study in rats described in the published literature ², intravenous meropenem was administered to dams from Gestation Day 17 until Lactation Day 21 at doses of 240, 500, and 1000 mg/kg/day. There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. Second generation offspring showed no meropenem-related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 3.2 times the MRHD based on body surface area comparisons).

Pediatric Patients 3 Months of Age and Older

• For pediatric patients 3 months of age and older, the meropenem for injection dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every 8 hours (maximum dose is 2 grams every 8 hours), depending on the type of infection (cSSSI, cIAI, intra-abdominal infection or meningitis). See dosing Table 2 below.
• For pediatric patients weighing over 50 kg administer meropenem for injection at a dose of 500 mg every 8 hours for cSSSI, 1 gram every 8 hours for cIAI and 2 grams every 8 hours for meningitis.
• Administer meropenem for injection as an intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes.
• There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) bolus dose.

Table 2: Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function

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.

Mechanism of Action

The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding-protein (PBP) targets. Meropenem binds to PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus.Bactericidal concentrations (defined as a 3 log ₁₀reduction in cell counts within 12 hours to 24 hours) are typically 1 to 2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed.

Meropenem does not have in vitroactivity against methicillin-resistant Staphylococcus aureus(MRSA) or methicillin-resistant Staphylococcus epidermidis(MRSE).

Meropenem for injection 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 20º to 25ºC (68º to 77ºF) [see USP].



500 mg Injection Vial (NDC 72572-415-01) and packaged in cartons of 10 vials (NDC 72572-415-10).



1 gram Injection Vial (NDC 72572-416-01) and packaged in cartons of 10 vials (NDC 72572-416-10).

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.

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 meropenem 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.

• Cockcroft DW, MH Gault, 1976, Prediction of creatinine clearance from serum creatinine, Nephron, 16:31-41.
• Kawamura S, AW Russell, SJ Freeman, and RA Siddall, 1992, Reproductive and Developmental Toxicity of Meropenem in Rats, Chemotherapy, 40:S238-250.

Risk Summary

Meropenem has been reported to be excreted in human milk. No information is available on the effects of meropenem on the breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for meropenem and any potential adverse effects on the breast-fed child from meropenem or from the underlying maternal conditions.

Meropenem for injection is a sterile, pyrogen-free, synthetic, carbapenem antibacterial for intravenous administration. It 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]hept-2-ene-2-carboxilic acid trihydrate. Its empirical formula is C ₁₇H ₂₅N ₃O ₅S∙3H ₂O with a molecular weight of 437.52. Its structural formula is:

Meropenem for injection is a white to pale yellow crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3.

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.

When re-constituted as instructed, each 1 gram meropenem for injection vial will deliver 1 gram of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). Each 500 mg meropenem for injection vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq) [ see Dosage and Administration (2.4) ].

Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem.  Co-administration of probenecid with meropenem is not recommended.

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.

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 vitroand 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 is necessary, then supplemental anti-convulsant therapy should be considered [ see Warnings and Precautions (5.4) ].

The safety and effectiveness of meropenem 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.

Of the total number of subjects in clinical studies of meropenem, 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 meropenem in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [ see Clinical Pharmacology (12.3) ].

The recommended dose of meropenem for injection 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.

Meropenem for injection 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.

Meropenem 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:

• 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) ]

• Co-administration of meropenem with probenecid inhibits renal excretion of meropenem and is therefore not recommended. ( 7.1)
• The concomitant use of meropenem 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)

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), (8.6) , Clinical Pharmacology (12.3) ].

The percentage of time of a dosing interval that unbound plasma concentration of meropenem exceeds the meropenem minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection.

Seizures and other adverse CNS experiences have been reported during treatment with meropenem. 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),  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 to determine whether it should be decreased or discontinued.

Meropenem for injection is a penem antibacterial indicated for the treatment of:

• Complicated skin and skin structure infections (adult patients and pediatric patients 3 months of age and older only).
  
  ( 1.1)
• Complicated intra-abdominal infections (adult and pediatric patients). ( 1.2)
• Bacterial meningitis (pediatric patients 3 months of age and older only). ( 1.3)

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.

Meropenem is an antibacterial drug [ see Microbiology (12.4) ].

Four hundred forty-six patients (397 pediatric patients 3 months to less than 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n=225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n=187) or ceftriaxone (n=34), at the approved dosing regimens. A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture.

Patients were defined as clinically not cured if any one of the following three criteria were met:

• At the 5 to 7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of greater than 60 decibels in one or both ears, or blindness.
• During therapy the patient's clinical status necessitated the addition of other antibacterial drugs.
• Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse.

Using the definition, the following efficacy rates were obtained, per organism (noted in Table 10). The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses.

Table 10: Efficacy rates by Pathogen in the Clinically Evaluable Population with Bacterial Meningitis

Sequelae were the most common reason patients were assessed as clinically not cured.

Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa).

With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy. The following Table 11shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients.

Table 11: Hearing Loss at Post-Therapy in the Evaluable Population Treated with Meropenem

Freshly prepared solutions of meropenem for injection should be used. However, re-constituted solutions of meropenem for injection maintain satisfactory potency under the conditions described below. Solutions of intravenous meropenem for injection should not be frozen.

• 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. ( 5.2)
• Seizures and other adverse CNS experiences have been reported during treatment. ( 5.3)
• Co-administration of meropenem 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)

• 500 mg every 8 hours by intravenous infusion over 15 to 30 minutes for complicated skin and skin structure infections (cSSSI) for adult patients. When treating infections caused by Pseudomonas aeruginosa, a dose of 1 gram every 8 hours is recommended. ( 2.1)
• 1 gram every 8 hours by intravenous infusion over 15 minutes to 30 minutes for intra-abdominal infections for adult patients. ( 2.1)
• 1 gram every 8 hours by intravenous bolus injection (5 mL to 20 mL) over 3 minutes to 5 minutes for adult patients.
  
  ( 2.1)
• Dosage should be reduced in adult patients with renal impairment. ( 2.2)

Pediatric patients 3 months of age and older

Pediatric patients less than 3 months of age

Single dose clear glass vials of meropenem for injection containing 500 mg or 1 gram (as the trihydrate blended with anhydrous sodium carbonate for re-constitution) of sterile meropenem powder.

The following adverse reactions have been identified during post-approval use of meropenem. 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.

• Renal Impairment: Dose adjustment is necessary, if creatinine clearance is 50 mL/min or less. ( 2.2, 8.6)

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, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to meropenem occurs, discontinue the drug immediately.

For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported with meropenem, 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),  (8.6),  Clinical Pharmacology (12.3) ].

• Counsel patients that antibacterial drugs including meropenem for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When meropenem for injection is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, take the medication exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by meropenem for injection or other antibacterial drugs in the future.
• Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible [ see Warnings and Precautions (5.5) ].
• Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with meropenem for injection. If treatment with meropenem for injection is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed [ see Warnings and Precautions (5.4) ].
• Patients receiving meropenem for injection on an outpatient basis must be alerted of 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, patients should not operate machinery or motorized vehicles [ see Warnings and Precautions (5.9) ].

Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less [ see Dosage and Administration (2.2) , Warnings and Precautions (5.8) , Clinical Pharmacology (12.3) ].

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 [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.

Alert patients receiving meropenem 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 is well tolerated, advise patients not to operate machinery or motorized vehicles [ see Adverse Reactions (6.1) ].

Prescribing meropenem 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.

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.

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.

One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial).

Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the presumptive microbiologic eradication/clinical cure rates and statistical findings are provided in Table 9:

Table 9: Presumptive Microbiologic Eradication and Clinical Cure Rates at Test-of-Cure Visit in the Evaluable Population with Complicated Intra-Abdominal Infection

The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm. Currently there is no additional information available to further interpret this observation.

NDC 72572-416-01

Meropenem for Injection, USP

1 g per vial

Meropenem Equivalent

For Intravenous Use Only

Rx only

Contents are Sterile

Each vial contains meropenem equivalent to 1 g of meropenem activity.

Sodium content is 90.2 mg (3.92 mEq).

Usual Dosage: See package insert.

For IV Preparation: Dilute with approved diluent and prepare as specified in the package insert.

Prior to Constitution: Store at 20 ^oC to 25 ^oC (68 ^oto 77 ^oF) [see USP Controlled Room Temperature]

After Constitution: See package insert.

Distr by Civica, Inc., Lehi, Utah 84043

Mfd by Savior Lifetec Corp., Taiwan, R.O.C

Rev: 07/2020

976143

NDC 72572-415-01

Meropenem for Injection, USP

500 mg per vial

Meropenem Equivalent

For Intravenous Use Only

Rx only

Contents are Sterile

Each vial contains meropenem equivalent to 500 mg of meropenem activity. Sodium content is 45.1 mg (1.96 mEq).

Usual Dosage: See package insert.

For IV Preparation: Dilute with approved diluent and prepare as specified in the package insert.

Prior to Constitution: Store at 20 ^oC to 25 ^oC (68 ^oto 77 ^oF) [see USP Controlled Room Temperature]

After Constitution: See package insert.

Distr by Civica, Inc., Lehi, Utah 84043

Mfd by Savior Lifetec Corp., Taiwan, R.O.C.

Rev: 07/2020

976142

NDC 72572-416-10

Rx only

Meropenem for Injection, USP

1 g per vial

Meropenem Equivalent

For Intravenous Use Only

Discard unused portion

10 x 1 g Single Dose Vials

CIVICA

Each vial contains meropenem equivalent to 1 g of meropenem activity.

Sodium content is 90.2 mg (3.92 mEq).

Usual Dosage: See package insert.

For IV Preparation: Dilute with approved diluent and prepare as specified in the package insert.

Prior to Constitution: Store at 20 ^oC to 25 ^oC (68 ^oto 77 ^oF) [see USP Controlled Room Temperature]

After Constitution: See package insert.

Distributed by Civica, Inc., Lehi, Utah 84043

Manufactured by Savior Lifetec Corporation

4F, No. 12 & 16 Chuangye Rd., Tainan City 74144, Taiwan, R.O.C.

Product of Taiwan

Rev: 07/2020

977134

NDC72572-415-10

Rx only

Meropenem for Injection, USP

500 mg per vial



Meropenem Equivalent

For Intravenous Use Only

Discard unused portion

10 x 500 mg Single Dose Vials

CIVICA

Each vial contains meropenem equivalent to 500 mg of meropenem activity.

Sodium content is 45.1 mg (1.96 mEq).

Usual Dosage: See package insert.

For IV Preparation: Dilute with approved diluent and prepare as specified in the package insert.

Prior to Constitution: Store at 20 ^oC to 25 ^oC (68 ^oto 77 ^oF) [see USP Controlled Room Temperature]

After Constitution: See package insert.

Distributed by Civica, Inc., Lehi, Utah 84043

Manufactured by Savior Lifetec Corporation

4F, No. 12 & 16 Chuangye Rd., Tainan City 74144, Taiwan, R.O.C.

Product of Taiwan

Rev: 07/2020

977134

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem, 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. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficilecause 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. difficilemay 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.

Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. (See dosing Tablebelow.)

When only serum creatinine is available, the following formula (Cockcroft and Gault equation) ¹may be used to estimate creatinine clearance.

Males: Creatinine Clearance (mL/min) =

Females: 0.85 × above value

Table 1: Recommended Meropenem for Injection Dosage Schedule for Adult Patients with Renal Impairment

There is inadequate information regarding the use of meropenem for injection in patients on hemodialysis or peritoneal dialysis.

Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial. The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours. The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure). The trial was conducted in the United States, South Africa, Canada, and Brazil. At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention. The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin. Two hundred and sixty one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable. The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm.

The success rates for the clinically evaluable population are provided in Table 7.

Table 7: Success Rates at Test-of-Cure Visit for Clinically Evaluable Population with Complicated Skin and Skin Structure Infections

The clinical efficacy rates by pathogen are provided in Table 8. The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set).

Table 8: Clinical Efficacy Rates by Pathogen for Clinically Evaluable Population

The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (meropenem, 2.5% and imipenem-cilastatin, 2.7%).

Meropenem for injection 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 Peptostreptococcusspecies .

Meropenem for injection is indicated for the treatment of bacterial meningitis caused by  Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae.

Meropenem for injection has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.

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 is necessary, consider supplemental anti-convulsant therapy [ see Drug Interactions (7.2) ].

Meropenem for injection 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 Peptostreptococcusspecies .