INTERACTIONS Hormonal Contraceptives: Effectiveness may be reduced; use an effective alternative non-hormonal form of contraception or additional contraceptive method. ( 7.4 , 12.3 )
7.1 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 VABOMERE is necessary, then supplemental anti-convulsant therapy should be considered <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> .
7.2 Probenecid Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Co-administration of probenecid with VABOMERE is not recommended <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.
7.3 Potential for VABOMERE to Affect Other Drugs When administering VABOMERE concomitantly with medicinal products that are predominantly metabolized by CYP1A2, CYP3A4, CYP2C, and/or are substrates of P-gp transporters, there is a potential risk of interaction which may result in decreased plasma concentrations and activity of the co-administered drug(s) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. When VABOMERE is concomitantly administered with the substrates of CYP1A2, CYP3A4, CYP2C, and/or P-gp, refer to the prescribing information for these concomitant medications for guidance on need for dosage adjustments and/or need for frequent drug level monitoring when administered with a weak CYP inducer(s). When administering VABOMERE concomitantly with medicinal products that are substrate of OAT3 transporters, there is a potential risk of interaction which may result in increased plasma concentrations and activity of the co-administered drug(s) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. When VABOMERE is concomitantly administered with OAT3 substrate(s), refer to the prescribing information for these concomitant medication(s) for guidance on need for dosage adjustments and/or need for frequent drug level monitoring when administered with an OAT3 inhibitor(s).
7.4 Hormonal Contraceptives Hormonal contraceptives (e.g., combined oral contraceptives containing a progestin and an estrogen) are metabolized by CYP3A and other pregnane X receptor (PXR)-regulated enzymes. Therefore, the blood concentration and the effectiveness of hormonal contraceptives may be reduced when used with VABOMERE <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Effective alternative non-hormonal forms of contraception or additional contraceptive methods are recommended for patients taking hormonal contraceptives when treated concomitantly with VABOMERE <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) and Clinical Pharmacology (12.3) ]</span>.
Meropenem for Injection and Sodium Chloride 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-lactams. Known hypersensitivity to product components or anaphylactic reactions to beta-lactams. ( 4 ) Contraindicated where the administration of sodium or chloride could be clinically detrimental. ( 4 )
AND PRECAUTIONS Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactams. ( 5.1 ) Severe cutaneous adverse reactions have been reported in patients receiving meropenem intravenous. Discontinue meropenem immediately if patients experience these signs and symptoms and consider alternative treatment. ( 5.2 ) Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue Meropenem for Injection and Sodium Chloride 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 ) Solutions containing sodium ions should be used with great care, if at all, in patients where the administration of sodium could be detrimental. ( 5.11 )
5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-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 beta-lactam. Before initiating therapy with Meropenem for Injection and Sodium Chloride Injection, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens. If an allergic reaction to Meropenem for Injection and Sodium Chloride 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . If signs and symptoms suggestive of these reactions appear, Meropenem for Injection and Sodium Chloride Injection 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 Sodium Chloride 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 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span>. Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Anti-convulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, place on anti-convulsant therapy if not already instituted, and re-examine the dosage of Meropenem for Injection and Sodium Chloride 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 and Sodium Chloride 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 and Sodium Chloride 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) , Use In Specific Populations (8.5) and (8.6) , 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>.
5.11 High Sodium Load Each 500 mg of Meropenem for Injection and Sodium Chloride Injection delivers 245.1 mg (10.7 mEq) of sodium and each 1 gram of Meropenem for Injection and Sodium Chloride Injection delivers 290.2 mg (12.6 mEq) of sodium. Avoid use of Meropenem for Injection and Sodium Chloride Injection in patients with congestive heart failure, elderly patients and patients requiring restricted sodium intake.