IMIPENEM AND CILASTATIN Powder for solution for injection Ref.[10466] Active ingredients: Imipenem and Cilastatin

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 Imipenem and Cilastatin for Injection (I.V.), careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams and other allergens. If an allergic reaction to Imipenem and Cilastatin for Injection (I.V.) occurs, discontinue the drug immediately. Serious anaphylactic reactions require immediate emergency treatment as clinically indicated.

5.2 Seizure Potential

Seizures and other CNS adverse experiences, such as confusional states and myoclonic activity, have been reported during treatment with Imipenem and Cilastatin for Injection (I.V.), especially when recommended dosages were exceeded [see Adverse Reactions (6.1, 6.2)]. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function [see Use in Specific Populations (8.6)]. However, there have been reports of CNS adverse experiences in patients who had no recognized or documented underlying CNS disorder or compromised renal function.

Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of Imipenem and Cilastatin for Injection (I.V.) re-examined to determine whether it should be decreased or the antibacterial drug discontinued.

5.3 Increased Seizure Potential Due to Interaction with Valproic Acid

Case reports in the literature have shown that co-administration of carbapenems, including Imipenem and Cilastatin for Injection (I.V.), to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of Imipenem and Cilastatin for Injection (I.V.) and valproic acid/divalproex sodium is generally not recommended.

Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of Imipenem and Cilastatin for Injection (I.V.) is necessary, supplemental anti-convulsant therapy should be considered [see Drug Interactions (7.3)]. Close adherence to the recommended dosage and dosage schedules is urged, especially in patients with known factors that predispose to convulsive activity.

5.4 Clostridium difficile-Associated Diarrhea (CDAD)

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Imipenem and Cilastatin for Injection (I.V.), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains 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.

5.5 Development of Drug-Resistant Bacteria

As with other antibacterial drugs, prolonged use of Imipenem and Cilastatin for Injection (I.V.) may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Prescribing Imipenem and Cilastatin for Injection (I.V.) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

The following serious adverse reactions are described in greater detail in the Warnings and Precautions section.

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Seizure Potential [see Warnings and Precautions (5.2)]
• Increased Seizure Potential Due to Interaction with Valproic Acid [see Warnings and Precautions (5.3)]
• Clostridium difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4)]
• Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.5)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Patients

During clinical investigations 1,723 patients were treated with Imipenem and Cilastatin for Injection (I.V.). Table 4 shows the incidence of adverse reactions reported during the clinical investigations of adult patients treated with Imipenem and Cilastatin for Injection (I.V.).

Table 4. Incidence (%)* of Adverse Reactions Reported During Clinical Investigations of Adult Patients Treated with Imipenem and Cilastatin for Injection (I.V.):

^* Adverse reactions with an incidence ≥0.2% of Imipenem and Cilastatin for Injection (I.V.) - treated adult patients.

Additional adverse reactions reported in less than 0.2% of the patients or reported since the drug was marketed are listed within each body system in order of decreasing severity [see Table 5].

Table 5. Additional Adverse Reactions Occurring in Less than 0.2% of Adult Patients Listed within Each Body System in Order of Decreasing Severity:

Adverse Laboratory Changes

The following adverse laboratory changes were reported during clinical trials:

Hepatic: Increased alanine aminotransferase (ALT or SGPT), aspartate aminotransferase (AST or SGOT), alkaline phosphatase, bilirubin, and lactate dehydrogenase (LDH)

Hemic: Increased eosinophils, positive Coombs test, increased WBC, increased platelets, decreased hemoglobin and hematocrit, increased monocytes, abnormal prothrombin time, increased lymphocytes, increased basophils

Electrolytes: Decreased serum sodium, increased potassium, increased chloride

Renal: Increased BUN, creatinine

Urinalysis: Presence of urine protein, urine red blood cells, urine white blood cells, urine casts, urine bilirubin, and urine urobilinogen.

Pediatric Patients

Table 6. Incidence (%)* of Adverse Reactions Reported During Clinical Investigations of Pediatric Patients Greater Than or Equal to 3 Months of Age Treated with Imipenem and Cilastatin for Injection (I.V.):

^* Adverse reactions that occurred in >1% of Imipenem and Cilastatin for Injection (I.V.)-treated pediatric patients (greater than or equal to 3 months of age)

Table 7. Incidence (%)* of Adverse Reactions Reported During Clinical Investigations of Pediatric Patients Neonates to 3 Months of Age Treated with Imipenem and Cilastatin for Injection (I.V.):

^* Adverse reactions that occurred in >1% of Imipenem and Cilastatin for Injection (I.V.)-treated pediatric patients (neonates to 3 months of age)

Adverse Laboratory Changes

The following adverse laboratory changes were reported in studies of 178 pediatric patients 3 months of age: increased AST (SGOT), decreased hemoglobin/hematocrit, increased platelets, increased eosinophils, increased ALT (SGPT), increased urine protein, decreased neutrophils.

The following adverse laboratory changes were reported in studies of 135 patients (neonates to 3 months of age): increased eosinophils, increased AST (SGPT), increased serum creatinine, increased/decreased platelet count, increased/decreased bilirubin, increased ALT (SGPT), increased alkaline phosphatase, increased/decreased hematocrit.

The following adverse reactions have been identified during post-approval use of Imipenem and Cilastatin for Injection (I.V.). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Table 8. Adverse Reactions Identified During Post Approval Use of Imipenem and Cilastatin for Injection (I.V.):

Adverse Laboratory Changes

Adverse laboratory changes reported since the drug was marketed were:

Hematologic: agranulocytosis.

Examination of published literature and spontaneous adverse reactions reports suggested a similar spectrum of adverse reactions in adult and pediatric patients.

7.1 Ganciclovir

Generalized seizures have been reported in patients who received ganciclovir and Imipenem and Cilastatin for Injection (I.V.). These drugs should not be used concomitantly with Imipenem and Cilastatin for Injection (I.V.) unless the potential benefits outweigh the risks.

7.2 Probenecid

Concomitant administration of Imipenem and Cilastatin for Injection (I.V.) and probenecid results in increases in the plasma level and half-life of imipenem. Therefore, it is not recommended that probenecid be given concomitantly with Imipenem and Cilastatin for Injection (I.V.).

7.3 Valproic Acid

Case reports in the literature have shown that co-administration of carbapenems, including Imipenem and Cilastatin for Injection (I.V.), 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 [see Warnings and Precautions (5.3)]. The concomitant use of Imipenem and Cilastatin for Injection (I.V.) and valproic acid/divalproex sodium is generally not recommended. Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well-controlled on valproic acid or divalproex sodium.

Risk Summary

Available data from a small number of postmarketing cases with Imipenem and Cilastatin for Injection (I.V.) use in pregnancy are not sufficient to identify any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Developmental toxicity studies with imipenem and cilastatin sodium (alone or in combination) administered to mice, rats, rabbits, and monkeys at doses 0.4 to 2.9 times the recommended human dose (RHD), (based on body surface area), showed no drug-induced fetal malformations.

Embryofetal development studies with imipenem/cilastatin administered to cynomolgus monkeys at doses similar to the RHD (based on body surface area) showed an increase in embryonic loss (see Data).

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population.

Data

Animal Data

Reproductive toxicity studies with imipenem and cilastatin (alone or in combination) administered to mice, rats, and rabbits showed no evidence of effects on embryofetal (mice, rats and rabbits) or pre/postnatal (rats) development.

Imipenem was administered intravenously to rats (gestation days (GD) 7 to 17) and rabbits (GD 6 to 18) at doses up to 900 and 60 mg/kg/day, respectively, approximately 2.9 and 0.4 times the RHD (based on body surface area).

Cilastatin was administered subcutaneously to rats (GD 6 to 17) and intravenously to rabbits (GD 6 to 18) at doses up to 1000 and 300 mg/kg/day, respectively, approximately 3.2 and 1.9 times the RHD (based on body surface area).

Imipenem/cilastatin was administered intravenously to mice at doses up to 320 mg/kg/day (GD 6 to 15). In two separate studies, imipenem/cilastatin was administered to rats (GD 6 to 17 and GD 15 to day 21 postpartum) both intravenously at doses up to 80 mg/kg/day and subcutaneously at 320 mg/kg/day. The higher dose is approximately equal to the RHD (based on body surface area).

Imipenem/cilastatin administered intravenously to pregnant cynomolgus monkeys during organogenesis at 100 mg/kg/day, approximately 0.6 times the RHD (based on body surface area), at an infusion rate mimicking human clinical use, was not associated with fetal malformations, but there was an increase in embryonic loss relative to controls. Imipenem/cilastatin administered to pregnant cynomolgus monkeys during organogenesis at 40 mg/kg/day by bolus intravenous injection caused significant maternal toxicity including death and embryofetal loss.

Risk Summary

There are insufficient data on the presence of imipenem/cilastatin in human milk, and no data on the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Imipenem and Cilastatin for Injection (I.V.) and any potential adverse effects on the breastfed child from Imipenem and Cilastatin for Injection (I.V.) or from the underlying maternal condition.

Use of Imipenem and Cilastatin for Injection (I.V.) in pediatric patients is supported by evidence from adequate and well-controlled trials of Imipenem and Cilastatin for Injection (I.V.) in adults and clinical studies in pediatric patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Imipenem and Cilastatin for Injection (I.V.) is not recommended in pediatric patients with CNS infections because of the risk of seizures.

Imipenem and Cilastatin for Injection (I.V.) is not recommended in pediatric patients less than 30 kg with renal impairment, as no data are available.

Of the approximately 3,600 subjects ≥ 18 years of age in clinical studies of Imipenem and Cilastatin for Injection (I.V.), including postmarketing studies, approximately 2,800 received Imipenem and Cilastatin for Injection (I.V.). Of the subjects who received Imipenem and Cilastatin for Injection (I.V.), data are available on approximately 800 subjects who were 65 and over, including approximately 300 subjects who were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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.

No dosage adjustment is required based on age [see Clinical Pharmacology (12.3)]. Dosage adjustment in the case of renal impairment is necessary [see Dosage and Administration (2.3)].

Dosage adjustment is necessary in patients with renal impairment [see Dosage and Administration (2.3)]. Adult patients with creatinine clearances of less than or equal to 30 mL/min, whether or not undergoing hemodialysis, had a higher risk of seizure activity than those without impairment of renal function [see Warnings and Precautions (5.2)]. Therefore, close adherence to the dosing guidelines and regular monitoring of creatinine clearance for these patients is recommended.