Imipenem and Cilastatin Injection

Imipenem and Cilastatin for Injection (I.V.) is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

(1) Lower respiratory tract infections. Staphylococcus aureus (penicillinase-producing strains), Acinetobacter species, Enterobacter species, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae*, Klebsiella species, Serratia marcescens

(2) Urinary tract infections (complicated and uncomplicated). Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii*, Proteus vulgaris*, Providencia rettgeri*, Pseudomonas aeruginosa

(3) Intra-abdominal infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Staphylococcus epidermidis, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii*, Proteus species, Pseudomonas aeruginosa, Bifidobacterium species, Clostridium species, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species*, Bacteroides species including B. fragilis, Fusobacterium species

(4) Gynecologic infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Staphylococcus epidermidis, Streptococcus agalactiae (Group B streptococci), Enterobacter species*, Escherichia coli, Gardnerella vaginalis, Klebsiella species*, Proteus species, Bifidobacterium species*, Peptococcus species*, Peptostreptococcus species, Propionibacterium species*, Bacteroides species including B. fragilis*

(5) Bacterial septicemia. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia species*, Bacteroides species including B. fragilis*

(6) Bone and joint infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter species, Pseudomonas aeruginosa

(7) Skin and skin structure infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii, Proteus vulgaris, Providencia rettgeri*, Pseudomonas aeruginosa, Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis, Fusobacterium species*

(8) Endocarditis. Staphylococcus aureus (penicillinase-producing strains)

(9) Polymicrobic infections. Imipenem and Cilastatin for Injection (I.V.) is indicated for polymicrobic infections including those in which S. pneumoniae (pneumonia, septicemia), S. pyogenes (skin and skin structure), or nonpenicillinase-producing S. aureus is one of the causative organisms. However, monobacterial infections due to these organisms are usually treated with narrower spectrum antibiotics, such as penicillin G.

Imipenem and Cilastatin for Injection (I.V.) is not indicated in patients with meningitis because safety and efficacy have not been established.

For Pediatric Use information, see PRECAUTIONS, Pediatric Use, and DOSAGE AND ADMINISTRATION sections.

Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria, Imipenem and Cilastatin for Injection (I.V.) is useful for the treatment of mixed infections and as presumptive therapy prior to the identification of the causative organisms.
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* Efficacy for this organism in this organ system was studied in fewer than 10 infections.

Although clinical improvement has been observed in patients with cystic fibrosis, chronic pulmonary disease, and lower respiratory tract infections caused by Pseudomonas aeruginosa, bacterial eradication may not necessarily be achieved.

As with other beta-lactam antibiotics, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with Imipenem and Cilastatin for Injection (I.V.) During therapy of Pseudomonas aeruginosa infections, periodic susceptibility testing should be done when clinically appropriate.

Infections resistant to other antibiotics, for example, cephalosporins, penicillin, and aminoglycosides, have been shown to respond to treatment with Imipenem and Cilastatin for Injection (I.V.).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Imipenem and Cilastatin for Injection (I.V.) and other antibacterial drugs, Imipenem and Cilastatin for Injection (I.V.) should be used only 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. 

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

When recommended doses were exceeded, adult patients with creatinine clearances of ≤20 mL/min/1.73 m2, whether or not undergoing hemodialysis, had a higher risk of seizure activity than those without impairment of renal function. Therefore, close adherence to the dosing guidelines for these patients is recommended. (See DOSAGE AND ADMINISTRATION.)

Patients with creatinine clearances of ≤5 mL/min/1.73 m2 should not receive Imipenem and Cilastatin for Injection (I.V.) unless hemodialysis is instituted within 48 hours.

For patients on hemodialysis, Imipenem and Cilastatin for Injection (I.V.) is recommended only when the benefit outweighs the potential risk of seizures.

Close adherence to the recommended dosage and dosage schedules is urged, especially in patients with known factors that predispose to convulsive activity. 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 antibiotic discontinued.

As with other antibiotics, 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.

Information for Patients
Patients should be counseled 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 Imipenem and Cilastatin for Injection (I.V.). If treatment with Imipenem and Cilastatin for Injection (I.V.) is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed.

Patients should be counseled that antibacterial drugs including Imipenem and Cilastatin for Injection (I.V.) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Imipenem and Cilastatin for Injection (I.V.) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken 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 Imipenem and Cilastatin for Injection (I.V.) or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, 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 antibiotic. If this occurs, patients should contact their physician as soon as possible.

Laboratory Tests
While Imipenem and Cilastatin for Injection (I.V.) possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Drug Interactions
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 unless the potential benefits outweigh the risks. 

Since concomitant administration of Imipenem and Cilastatin for Injection (I.V.) and probenecid results in only minimal increases in plasma levels of imipenem and plasma half-life, it is not recommended that probenecid be given with Imipenem and Cilastatin for Injection (I.V.).

Imipenem and Cilastatin for Injection (I.V.) should not be mixed with or physically added to other antibiotics. However, Imipenem and Cilastatin for Injection (I.V.) may be administered concomitantly with other antibiotics, such as aminoglycosides.

Case reports in the literature have shown that co-administration of carbapenems, including imipenem, 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, Seizure Potential).

Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term studies in animals have not been performed to evaluate carcinogenic potential of imipenem-cilastatin. Genetic toxicity studies were performed in a variety of bacterial and mammalian tests in vivo and in vitro. The tests used were: V79 mammalian cell mutagenesis assay (imipenem-cilastatin sodium alone and imipenem alone), Ames test (cilastatin sodium alone and imipenem alone), unscheduled DNA synthesis assay (imipenem-cilastatin sodium) and in vivo mouse cytogenetics test (imipenem-cilastatin sodium). None of these tests showed any evidence of genetic alterations. 

Reproductive tests in male and female rats were performed with imipenem-cilastatin sodium at intravenous doses up to 80 mg/kg/day and at a subcutaneous dose of 320 mg/kg/day, approximately equal to the highest recommended human dose of the intravenous formulation (on a mg/m2 body surface area basis). Slight decreases in live fetal body weight were restricted to the highest dosage level. No other adverse effects were observed on fertility, reproductive performance, fetal viability, growth or postnatal development of pups.

Pregnancy: Teratogenic Effects
Pregnancy Category C: Teratology studies with cilastatin sodium at doses of 30, 100, and 300 mg/kg/day administered intravenously to rabbits and 40, 200, and 1000 mg/kg/day administered subcutaneously to rats, up to approximately 1.9 and 3.2 times†† the maximum recommended daily human dose (on a mg/m2 body surface area basis) of the intravenous formulation of imipenem-cilastatin sodium (50 mg/kg/day) in the two species, respectively, showed no evidence of adverse effect on the fetus. No evidence of teratogenicity was observed in rabbits given imipenem at intravenous doses of 15, 30 or 60 mg/kg/day and rats given imipenem at intravenous doses of 225, 450, or 900 mg/kg/day, up to approximately 0.4 and 2.9 times†† the maximum recommended daily human dose (on a mg/m2 body surface area basis) in the two species, respectively. 

Teratology studies with imipenem-cilastatin sodium at intravenous doses of 20 and 80, and a subcutaneous dose of 320 mg/kg/day, up to 0.5 times†† (mice) to approximately equal to (rats) the highest recommended daily intravenous human dose (on a mg/m2 body surface area basis) in pregnant rodents during the period of major organogenesis, revealed no evidence of teratogenicity.

Imipenem-cilastatin sodium, when administered subcutaneously to pregnant rabbits at dosages equivalent to the usual human dose of the intravenous formulation and higher (1000 to 4000 mg/day), caused body weight loss, diarrhea, and maternal deaths. When comparable doses of imipenem-cilastatin sodium were given to non-pregnant rabbits, body weight loss, diarrhea, and deaths were also observed. This intolerance is not unlike that seen with other beta-lactam antibiotics in this species and is probably due to alteration of gut flora.

A teratology study in pregnant cynomolgus monkeys given imipenem-cilastatin sodium at doses of 40 mg/kg/day (bolus intravenous injection) or 160 mg/kg/day (subcutaneous injection) resulted in maternal toxicity including emesis, inappetence, body weight loss, diarrhea, abortion, and death in some cases. In contrast, no significant toxicity was observed when non-pregnant cynomolgus monkeys were given doses of imipenem-cilastatin sodium up to 180 mg/kg/day (subcutaneous injection). When doses of imipenem-cilastatin sodium (approximately 100 mg/kg/day or approximately 0.6 times†† the maximum recommended daily human dose of the intravenous formulation) were administered to pregnant cynomolgus monkeys at an intravenous infusion rate which mimics human clinical use, there was minimal maternal intolerance (occasional emesis), no maternal deaths, no evidence of teratogenicity, but an increase in embryonic loss relative to control groups.

No adverse effects on the fetus or on lactation were observed when imipenem-cilastatin sodium was administered subcutaneously to rats late in gestation at dosages up to 320 mg/kg/day, approximately equal to the highest recommended human dose (on a mg/m2 body surface area basis).

There are, however, no adequate and well-controlled studies in pregnant women. Imipenem and Cilastatin for Injection (I.V.) should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Mothers
It is not known whether imipenem-cilastatin sodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Imipenem and Cilastatin for Injection (I.V.) is administered to a nursing woman.

Pediatric Use
Use of Imipenem and Cilastatin for Injection (I.V.) in pediatric patients, neonates to 16 years of age, is supported by evidence from adequate and well-controlled studies of Imipenem and Cilastatin for Injection (I.V.) in adults and by the following clinical studies and published literature in pediatric patients: Based on published studies of 178** pediatric patients ≥3 months of age (with non-CNS infections), the recommended dose of Imipenem and Cilastatin for Injection (I.V.) is 15 to 25 mg/kg/dose administered every six hours. Doses of 25 mg/kg/dose in patients 3 months to <3 years of age, and 15 mg/kg/dose in patients 3 to 12 years of age were associated with mean trough plasma concentrations of imipenem of 1.1±0.4 mcg/mL and 0.6±0.2 mcg/mL following multiple 60-minute infusions, respectively; trough urinary concentrations of imipenem were in excess of 10 mcg/mL for both doses. These doses have provided adequate plasma and urine concentrations for the treatment of non-CNS infections. Based on studies in adults, the maximum daily dose for treatment of infections with fully susceptible organisms is 2 g per day, and of infections with moderately susceptible organisms (primarily some strains of P. aeruginosa) is 4 g/day. (See DOSAGE AND ADMINISTRATION, Table 3.) Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis. (See DOSAGE AND ADMINISTRATION.)

Based on studies of 135*** pediatric patients ≤3 months of age (weighing ≥1,500 g), the following dosage schedule is recommended for non-CNS infections:

    <1 wk of age: 25 mg/kg every 12 hrs
    1 to 4 wks of age: 25 mg/kg every 8 hrs
    4 wks to 3 mos. of age: 25 mg/kg every 6 hrs.

In a published dose-ranging study of smaller premature infants (670 to 1,890 g) in the first week of life, a dose of 20 mg/kg q12h by 15 to 30 minutes infusion was associated with mean peak and trough plasma imipenem concentrations of 43 mcg/mL and 1.7 mcg/mL after multiple doses, respectively. However, moderate accumulation of cilastatin in neonates may occur following multiple doses of Imipenem and Cilastatin for Injection (I.V.) The safety of this accumulation is unknown.

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 <30 kg with impaired renal function, as no data are available.

Geriatric Use
Of the approximately 3600 subjects ≥18 years of age in clinical studies of Imipenem and Cilastatin for Injection (I.V.), including postmarketing studies, approximately 2800 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, Adults). Dosage adjustment in the case of renal impairment is necessary (see DOSAGE AND ADMINISTRATION, Reduced Intravenous Schedule for Adults with Impaired Renal Function and/or Body Weight < 70 kg).
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†† Based on patient body surface area of 1.6 m2 (weight of 60 kg).
** Two patients were less than 3 months of age.
*** One patient was greater than 3 months of age.

Adults
Imipenem and Cilastatin for Injection (I.V.) is generally well tolerated. Many of the 1,723 patients treated in clinical trials were severely ill and had multiple background diseases and physiological impairments, making it difficult to determine causal relationship of adverse experiences to therapy with Imipenem and Cilastatin for Injection (I.V.).

Local Adverse Reactions
Adverse local clinical reactions that were reported as possibly, probably, or definitely related to therapy with Imipenem and Cilastatin for Injection (I.V.) were:
       Phlebitis/thrombophlebitis 3.1%
       Pain at the injection site 0.7%
       Erythema at the injection site 0.4%
       Vein induration 0.2%
       Infused vein infection 0.1%

Systemic Adverse Reactions
The most frequently reported systemic adverse clinical reactions that were reported as possibly, probably, or definitely related to Imipenem and Cilastatin for Injection (I.V.) were nausea (2%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%) (see PRECAUTIONS), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%).

Additional adverse systemic clinical reactions reported as possibly, probably, or definitely drug related occurring 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: Gastrointestinal pseudomembranous colitis (the onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment, see WARNINGS), hemorrhagic colitis, hepatitis (including fulminant hepatitis), hepatic failure, jaundice, gastroenteritis, abdominal pain, glossitis, tongue papillar hypertrophy, staining of the teeth and/or tongue, heartburn, pharyngeal pain, increased salivation; Hematologic pancytopenia, bone marrow depression, thrombocytopenia, neutropenia, leukopenia, hemolytic anemia; CNS encephalopathy, tremor, confusion, myoclonus, paresthesia, vertigo, headache, psychic disturbances including hallucinations, dyskinesia, agitation; Special Senses hearing loss, tinnitus, taste perversion; Respiratory chest discomfort, dyspnea, hyperventilation, thoracic spine pain; Cardiovascular palpitations, tachycardia; Skin Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, angioneurotic edema, flushing, cyanosis, hyperhidrosis, skin texture changes, candidiasis, pruritus vulvae; Body as a whole polyarthralgia, asthenia/weakness, drug fever; Renal acute renal failure, oliguria/anuria, polyuria, urine discoloration. The role of Imipenem and Cilastatin for Injection (I.V.) in changes in renal function is difficult to assess, since factors predisposing to pre-renal azotemia or to impaired renal function usually have been present.

Adverse Laboratory Changes
Adverse laboratory changes without regard to drug relationship that were reported during clinical trials or reported since the drug was marketed were:
Hepatic: Increased ALT (SGPT), AST (SGOT), alkaline phosphatase, bilirubin, and LDH
Hemic: Increased eosinophils, positive Coombs test, increased WBC, increased platelets, 
             decreased hemoglobin and hematocrit, agranulocytosis, 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
In studies of 178 pediatric patients ≥3 months of age, the following adverse events were noted:

In studies of 135 patients (newborn to 3 months of age), the following adverse events were noted:

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

To report SUSPECTED ADVERSE EVENTS, contact FDA at 1-800-FDA-1088 or www.fda.gov.

The acute intravenous toxicity of imipenem-cilastatin sodium in a ratio of 1:1 was studied in mice at doses of 751 to 1359 mg/kg. Following drug administration, ataxia was rapidly produced and clonic convulsions were noted in about 45 minutes. Deaths occurred within 4 to 56 minutes at all doses.

The acute intravenous toxicity of imipenem-cilastatin sodium was produced within 5 to 10 minutes in rats at doses of 771 to 1583 mg/kg. In all dosage groups, females had decreased activity, bradypnea, and ptosis with clonic convulsions preceding death; in males, ptosis was seen at all dose levels while tremors and clonic convulsions were seen at all but the lowest dose (771 mg/kg). In another rat study, female rats showed ataxia, bradypnea, and decreased activity in all but the lowest dose (550 mg/kg); deaths were preceded by clonic convulsions. Male rats showed tremors at all doses and clonic convulsions and ptosis were seen at the two highest doses (1130 and 1734 mg/kg). Deaths occurred between 6 and 88 minutes with doses of 771 to 1734 mg/kg.

In the case of overdosage, discontinue Imipenem and Cilastatin for Injection (I.V.), treat symptomatically, and institute supportive measures as required. Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable.

NDC 0409-3508-01

25 x 250 mg/250 mg SINGLE DOSE VIALS

Imipenem and Cilastatin
for Injection, USP (I.V.)

250 mg/250 mg per vial

CAUTION: SINGLE DOSE VIAL
FOR I.V. USE ONLY
NOT FOR DIRECT INFUSION

Rx Only

Hospira