Tienam

Tienam

imipenem + cilastatin

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Merck Sharp & Dohme
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Contents
Imipenem, cilastatin sodium.
Description
TIENAM (imipenem and cilastatin sodium, MSD) is a broad spectrum beta-lactam antibiotic supplied as a formulation for intravenous infusion only. TIENAM consists of two components: imipenem, the first of a new class of beta-lactam antibiotics, the thienamycins; and cilastatin sodium, a specific enzyme inhibitor that blocks the metabolism of imipenem in the kidney, and substantially increases the concentration of intact imipenem in the urinary tract. Imipenem and cilastatin sodium are present in TIENAM in a 1:1 ratio by weight.
The thienamycin class of antibiotics, to which imipenem belongs, is characterized by a broad spectrum of bactericidal activity.
TIENAM for intravenous infusion is supplied as a sterile powder in vials containing 500mg imipenem equivalent and 500mg cilastatin equivalent.
In addition, TIENAM contains Sterile Sodium Bicarbonate as inactive ingredient.
Action
Pharmacology: Animal Pharmacology: A variety of studies have been performed in experimental animal models, including pyelonephritis and peritonitis in the rat, Pseudomonas aeruginosa lung infection in the guinea pig, and meningitis and endocarditis in the rabbit. These studies have demonstrated the extremely broad spectrum of antibacterial activity of imipenem, confirmed the in vitro susceptibility data, and shown that imipenem penetrates into body tissues and cerebrospinal fluid.
In mice, imipenem showed protective efficacy against experimental infections, at dosages considerably less than those required by cephalosporins and extended spectrum penicillins. Imipenem was more effective than aminocyclitols, such as gentamicin and amikacin, for treatment of Pseudomonas infections.
During the laboratory evaluation of imipenem as a single entity, generally low urinary recovery of the antibiotic was found in a number of species, including the chimpanzee, and this was subsequently confirmed in man also. Metabolism was shown to occur primarily in the kidney, affecting the secreted and filtered fraction of the antibiotic after its clearance from the blood.
The major pathway of metabolism of imipenem in the kidney is by hydrolysis of the beta-lactam ring by a renal dipeptidase (EC.3.4.13.11). This enzyme is also known as dehydropeptidase-I (DHP-I) and is localized on the luminal (brush-border) surface of the proximal renal tubular epithelium. Thus, the enzyme has access to the antibiotic both in the glomerular filtrate and during the transcellular secretory process.
In man, urinary recovery ranged from 5 to 40% of the administered dose, while good systemic persistence and blood levels were unaffected by metabolism in the kidney.
Low urinary tract bioavailability of imipenem is avoided by co-administration of cilastatin, a potent inhibitor of DHP-I isolated from a number of animal species.
The inhibition is competitive and freely reversible. Cilastatin did not significantly inhibit the activity of four other zinc metalloenzyme peptidases, including angiotensin converting enzyme. Cilastatin is devoid of antimicrobial activity per se, and has no significant effect on the antimicrobial activity of imipenem.
Pharmacokinetics: IMIPENEM: In normal volunteers, intravenous infusion of TIENAM over 20 minutes resulted in peak plasma levels of imipenem ranging from 12 to 20 mcg/mL for the 250 mg dose, from 21 to 58 mcg/ml for the 500 mg dose, and from 41 to 83 mcg/mL for the 1000 mg dose. The mean peak plasma levels of imipenem following the 250, 500 and 1000 mg doses were 17, 39, and 66 mcg/mL, respectively. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 mcg/mL or less in 4 to 6 hours.
The plasma half-life of imipenem was one hour. Approximately 70% of the administered antibiotic was recovered intact in the urine within 10 hours, and no further urinary excretion of the drug was detectable. Urine concentrations of imipenem exceeded 10 mcg/mL for up to 8 hours after a 500 mg dose of TIENAM.
The remainder of the administered dose was recovered in the urine as antibacterially inactive metabolites, and fecal elimination of imipenem is essentially nil.
No accumulation of imipenem in plasma or urine has been observed with regimens of TIENAM, administered as frequently as every 6 hours, in patients with normal renal function. Concomitant administration of TIENAM and probenecid resulted in minimal increases in the plasma levels and plasma half-life of imipenem. The urinary recovery of active (non metabolized) imipenem decreased to approximately 60% of the dose when TIENAM was administered with probenecid.
When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Individual urinary recoveries ranged from 5 to 40%, with an average recovery of 15-20% in several studies.
The binding of imipenem to human serum proteins is approximately 20%. (See Table 1.)


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CILASTATIN: Cilastatin is a specific inhibitor of dehydropeptidase-I enzyme, and effectively inhibits metabolism of imipenem, so that concomitant administration of imipenem and cilastatin allows therapeutic antibacterial levels of imipenem to be attained in both urine and plasma.
Peak plasma levels of cilastatin, following a 20-minute intravenous infusion of TIENAM, ranged from 21 to 26 mcg/mL for the 250 mg dose, from 21 to 55 mcg/mL for the 500 mg dose and from 56 to 88 mcg/mL for the 1000 mg dose. The mean peak plasma levels of cilastatin following the 250, 500, and 1000 mg doses were 22, 42, and 72 mcg/mL, respectively. The plasma half-life of cilastatin is approximately 1 hour. Approximately 70-80% of the dose of cilastatin was recovered unchanged in the urine as the parent drug within 10 hours of administration of TIENAM. No further cilastatin appeared in the urine thereafter. Approximately 10% was found as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of the parent drug. Activity of dehydropeptidase-I in the kidney returns to normal levels shortly after the elimination of cilastatin from the bloodstream.
Concomitant administration of TIENAM and probenecid doubled the plasma level and half-life of cilastatin, but had no effect on urinary recovery of cilastatin.
The binding of cilastatin to human serum proteins is approximately 40%. (See Table 2.)


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Microbiology: TIENAM is a potent inhibitor of bacterial cell wall synthesis and is bactericidal against a broad spectrum of pathogens - gram-positive and gram-negative, aerobic and anaerobic.
TIENAM shares with the newer cephalosporins and penicillins a broad spectrum of activity against gram-negative species, but is unique in retaining the high potency against gram-positive species, previously associated only with earlier narrow-spectrum beta-lactam antibiotics. The spectrum of activity of TIENAM includes Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis and Bacteroides fragilis, a diverse group of problem pathogens commonly resistant to other antibiotics.
TIENAM is resistant to degradation by bacterial beta-lactamases, which makes it active against a high percentage of organisms such as Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp. which are inherently resistant to most beta-lactam antibiotics.
The antibacterial spectrum of TIENAM is broader than that of any other antibiotic studied, and includes virtually all clinically significant pathogens. Organisms against which TIENAM is usually active in vitro include: Gram-Negative Aerobes: Achromobacter spp., Acinetobacter spp. (formerly Mima-Herellea), Aeromonas hydrophila, Alcaligenes spp., Bordetella bronchicanis, Bordetella bronchiseptica, Bordetella pertussis, Brucella melitensis, Burkholderia pseudomallei (formerly Pseudomonas pseudomallei), Burkholderia stutzeri (formerly Pseudomonas stutzeri), Campylobacter spp., Capnocytophaga spp., Citrobacter spp., Citrobacter freundii, Citrobacter koseri (formerly Citrobacter diversus), Eikenella corrodens, Enterobacter spp., Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (including beta-lactamase-producing strains), Haemophilus parainfluenzae, Hafnia alvei, Klebsiella spp., Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae, Moraxella spp., Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis, Pasteurella spp., Pasteurella multoacida, Plesiomonas shigelloides, Proteus spp., Proteus mirabilis, Proteus vulgaris, Providencia spp., Providencia alcalifaciens, Providencia rettgeri (formerly Proteus rettgeri), Providencia stuartii, Pseudomonas spp.**, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas putida, Salmonella spp., Salmonella typhi, Serratia spp., Serratia proteamaculans (formerly Serratia liquefaciens), Serratia marcescens, Shigella spp., Yersinia spp. (formerly Pasteurella), Yersinia enterocolitica, Yersinia pseudotuberculosis.
**Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia, formerly Pseudomonas maltophilia) and some strains of Burkholderia cepacia (formerly Pseudomonas cepacia) are generally not susceptible to TIENAM.
Gram-Positive Aerobes: Bacillus spp., Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Nocardia spp., Pediococcus spp., Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis (including penicillinase-producing strains), Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus Group C, Streptococcus Group G, Streptococcus pneumoniae, Streptococcus pyogenes, Viridans group streptococci (including alpha and gamma hemolytic strains), Enterococcus faecium and methicillin-resistant staphylococci are not susceptible to TIENAM.
Gram-Negative Anaerobes: Bacteroides spp., Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Bilophila wadsworthia, Fusobacterium spp., Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica (formerly Bacteroides asaccharolyticus), Prevotella bivia (formerly Bacteroides bivius), Prevotella disiens (formerly Bacteroides disiens), Prevotella intermedia (formerly Bacteroides intermedius), Prevotella melaninogenica (formerly Bacteroides melaninogenicus), Veillonella spp.
Gram-Positive Anaerobes: Actinomyces spp., Bifidobacterium spp., Clostridium spp., Clostridium perfringens, Eubacterium spp., Lactobacillus spp., Mobiluncus spp., Microaerophilic streptococcus, Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp. (including P. acnes).
Other: Mycobacterium fortuitum, Mycobacterium smegmatis.
In vitro tests show imipenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.
Indications/Uses
TREATMENT: TIENAM is indicated for the treatment of the following infections including polymicrobic and mixed aerobic/anaerobic infections caused by susceptible organisms: Intra-abdominal infections, Lower respiratory tract infections, Gynecological infections, Septicemia, Genitourinary tract infections, Bone and joint infections, Skin and soft tissue infections, Endocarditis.
TIENAM is indicated for the treatment of mixed infections caused by susceptible strains of aerobic and anaerobic bacteria. The majority of these mixed infections are associated with contamination by fecal flora or flora originating from the vagina, skin and mouth. In these mixed infections, Bacteroides fragilis is the most commonly encountered anaerobic pathogen and is usually resistant to aminoglycosides, cephalosporins and penicillins. However, Bacteroides fragilis is usually susceptible to TIENAM.
TIENAM is not indicated for the treatment of meningitis.
PROPHYLAXIS: TIENAM is also indicated for the prevention of certain post-operative infections in patients undergoing contaminated or potentially contaminated surgical procedures or where the occurrence of post-operative infection could be especially serious.
Dosage/Direction for Use
The dosage recommendations for TIENAM represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present.
The total daily dosage and route of administration of TIENAM should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s), renal function and body weight.
INTRAVENOUS INFUSION: TREATMENT: ADULT DOSAGE SCHEDULE FOR PATIENTS WITH NORMAL RENAL FUNCTION: Doses cited in Table 3 are based on a patient with normal renal function (creatinine clearance of >70 mL/min/1.73 m2) and a body weight of ≥ 70 kg. A reduction in dose must be made for a patient with a creatinine clearance ≤ 70 mL/min/1.73 m2 and/or a body weight < 70 kg (see Table 4 and Table 5). The reduction for body weight is especially important for patients with much lower body weights and/or moderate/severe renal insufficiency.
Most infections respond to a daily dose of 1-2 g administered in 3-4 divided doses. For the treatment of moderate infection, a 1g b.i.d. dosage regimen may also be used. In infections due to less susceptible organisms, the daily dosage of TIENAM may be increased to a maximum of 4 g/day or 50 mg/kg/day, whichever is lower.
Each dose of ≤ 500 mg of TIENAM should be given by intravenous infusion over 20 to 30 minutes. Each dose > 500 mg should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed. (See Table 3.)


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Due to high antimicrobial activity of TIENAM, it is recommended that the maximum total daily dosage not exceed 50 mg/kg/day or 4 g/day, whichever is lower. However, cystic fibrosis patients with normal renal function have been treated with TIENAM at doses up to 90 mg/kg/day in divided doses, not exceeding 4 g/day.
TIENAM has been used successfully as monotherapy in immunocompromised cancer patients for confirmed or suspected infections such as sepsis.
TREATMENT: ADULT DOSAGE SCHEDULE FOR PATIENTS WITH IMPAIRED RENAL FUNCTION AND/ OR BODY WEIGHT <70 KG: Patients with creatinine clearance of ≤70 mL/min/1.73 m2 and/or body weight less than 70 kg require dosage reduction of TIENAM as indicated in the tables as follows. Creatinine clearance may be calculated from serum creatinine concentration by the following equation: See equation.


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To determine the dose for adults with impaired renal function and/or reduced body weight: 1. The total daily dose is chosen from Table 3 based on infection characteristics.
2. a) If the total daily dose is 1.0 g, 1.5 g, or 2.0 g, use the appropriate subsection of Table 4 and continue with step 3.
b) If the total daily dose is 3.0 g or 4.0 g, use the appropriate subsection of Table 5 and continue with step 3.
3. From Table 4 or 5: a) Select the body weight on the far left which is closest to the patient's body weight (kg).
b) Select the patient's creatinine clearance category.
c) Where the row and column intersect is the reduced dosage regimen. (See Tables 4 and 5.)


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Patients with creatinine clearances of 6 to 20 mL/min/1.73 m2 should be treated with TIENAM 125 mg or 250 mg every 12 hours for most pathogens. There may be an increased risk of seizures when doses of 500 mg every 12 hours are administered to these patients.
Patients with creatinine clearances of ≤ 5 mL/min/1.73 m2 should not receive TIENAM unless hemodialysis is instituted within 48 hours.
Hemodialysis: When treating patients with creatinine clearances of ≤ 5 mL/min/1.73 m2 who are undergoing hemodialysis, use the dosage recommendations for patients with creatinine clearances of 6 - 20 mL/min/1.73 m2 (see TREATMENT: ADULT DOSAGE SCHEDULE FOR PATIENTS WITH IMPAIRED RENAL FUNCTION AND/ OR BODY WEIGHT <70 KG).
Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive TIENAM after hemodialysis and at 12 hour intervals timed from the end of that hemodialysis session. Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on hemodialysis, TIENAM is recommended only when the benefit outweighs the potential risk of seizures (see PRECAUTIONS).
Currently there are inadequate data to recommend use of TIENAM for patients on peritoneal dialysis.
Renal status of elderly patients may not be accurately portrayed by measurement of BUN or creatinine alone. Determination of creatinine clearance is suggested to provide guidance for dosing in such patients.
PROPHYLAXIS: ADULT DOSAGE SCHEDULE: For prophylaxis against post-surgical infections in adults, 1000 mg TIENAM should be given intravenously on induction of anesthesia and 1000 mg three hours later. For high-risk (e.g. colorectal) surgery, two additional 500 mg doses can be given at eight and sixteen hours after induction.
There are insufficient data on which to base a dosage recommendation for prophylaxis in patients with a creatinine clearance of ≤ 70 mL/min/1.73m2.
TREATMENT: PEDIATRIC DOSAGE SCHEDULE: For children and infants the following dosage schedule is recommended: (a) CHILDREN ≥ 40 kg body weight should receive adult doses.
(b) CHILDREN AND INFANTS < 40 kg body weight: For pediatric patients ≥3 months of age, the recommended dose for non-CNS infections is 15-25 mg/kg/dose administered every six hours. Based on studies in adults, the maximum daily dose for treatment of infections with fully susceptible organisms is 2.0 g per day, and of infections with moderately susceptible organisms (primarily some strains of P. aeruginosa) is 4.0 g/day. Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis.
For pediatric patients ≤3 months of age (weighing ≥1,500 gms), the following dosage schedule is recommended for non-CNS infections: <1 week of age: 25 mg/kg every 12 hours; 1-4 weeks of age: 25 mg/kg every 8 hours; 4 weeks-3 months of age: 25 mg/kg every 6 hours.
Doses less than or equal to 500 mg should be given by intravenous infusion over 15 to 30 minutes. Doses greater than 500 mg should be given by intravenous infusion over 40 to 60 minutes.
TIENAM is not recommended in pediatric patients <30 kg with impaired renal function, as no data are available.
TIENAM is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used.
TIENAM may be used in children with sepsis as long as they are not suspected of having meningitis.
RECONSTITUTION, INTRAVENOUS SOLUTION: TIENAM for intravenous infusion is supplied as a sterile powder in vials containing 500mg imipenem equivalent and 500mg cilastatin equivalent.
TIENAM is buffered with sodium bicarbonate to provide solutions in the pH range of 6.5 to 8.5. There is no significant change in pH when solutions are prepared and used as directed. TIENAM contains 37.5 mg of sodium (1.6 mEq).
Sterile powder TIENAM should be reconstituted as shown in Table 6. It should be shaken until a clear solution is obtained. Variations of color, from colorless to yellow, do not affect the potency of the product. (See Table 6.)


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STABILITY OF RECONSTITUTED OF TIENAM: Table 7 shows the stability period for TIENAM when reconstituted with selected infusion solutions, and stored at room temperature or under refrigeration. TIENAM as supplied in single use vials and reconstituted with the following diluents maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (2°C-8°C).
CAUTION: TIENAM is chemically incompatible with lactate and should not be reconstituted in diluents containing lactate. TIENAM can be administered, however, into an I.V. system through which a lactate solution is being infused.
TIENAM should not be mixed with or physically added to other antibiotics. (See Table 7.)


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Overdosage
No specific information is available on the treatment of overdosage with TIENAM. Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is unknown.
Contraindications
Hypersensitivity to any component of this product.
Special Precautions
GENERAL: There is some clinical and laboratory evidence of partial cross-allergenicity between TIENAM and the other beta-lactam antibiotics, penicillins and cephalosporins. Severe reactions (including anaphylaxis) have been reported with most beta-lactam antibiotics. Before therapy with TIENAM, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. If an allergic reaction to TIENAM occurs, the drug should be discontinued and appropriate measures undertaken.
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. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of imipenem and valproic acid/divalproex sodium is generally not recommended. Anti-bacterials 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 TIENAM is necessary, supplemental anti-convulsant therapy should be considered (See INTERACTIONS.)
Pseudomembranous colitis has been reported with virtually all antibiotics and can range from mild to life- threatening in severity. Antibiotics should, therefore, be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. It is important to consider a diagnosis of pseudomembranous colitis in patients who develop diarrhea in association with antibiotic use. While studies indicate that a toxin produced by Clostridium difficile is a primary cause of antibiotic-associated colitis, other causes should also be considered.
CENTRAL NERVOUS SYSTEM: As with other beta-lactam antibiotics, CNS side effects such as myoclonic activity, confusional states, or seizures have been reported with the I.V. formulation, especially when recommended dosages based on renal function and body weight were exceeded. These experiences have been reported most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function in whom accumulation of the administered entities could occur. Hence, close adherence to recommended dosage schedules is urged, especially in these patients (see DOSAGE & ADMINISTRATION). Anticonvulsant therapy should be continued in patients with a known seizure disorder.
If focal tremors, myoclonus or seizures occur, patients should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If CNS symptoms continue, the dosage of TIENAM should be decreased or discontinued.
Patients with creatinine clearances of ≤ 5 mL/min/1.73m2 should not receive TIENAM unless hemodialysis is instituted within 48 hours. For patients on hemodialysis, TIENAM is recommended only when the benefit outweighs the potential risk of seizures.
EFFECTS ON ABILITY TO DRIVE OR OPERATE MACHINERY: There are some side effects associated with this product that may affect some patients' ability to drive or operate machinery (see SIDE EFFECTS).
USE IN PREGNANCY: There are no adequate and well-controlled studies in pregnant women. TIENAM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
USE IN LACTATION: Imipenem has been detected in human milk. If the use of TIENAM is deemed essential, the patient should stop nursing.
USE IN CHILDREN: Use of TIENAM in pediatric patients, neonates to 16 years of age, is supported by evidence from adequate and well-controlled studies of TIENAM 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 TIENAM is 15-25 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 3-12 years of age were associated with mean trough plasma concentrations of imipenem of 1.1±0.4 µg/mL and 0.6±0.2 µg/mL following multiple 60-minute infusions, respectively; trough urinary concentrations of imipenem were in excess of 10 µg/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 2.0 g per day, and of infections with moderately susceptible organisms (primarily some strains of P. aeruginosa) is 4.0 g/day. (See Table 3, DOSAGE & ADMINISTRATION.) Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis. (See DOSAGE & ADMINISTRATION.)
* Two patients were less than 3 months of age.
Based on studies of 135** pediatric patients ≤3 months of age (weighing ≥1,500 gms), the following dosage schedule is recommended for non-CNS infections: <1 wk of age: 25 mg/kg every 12 hrs.
1-4 wks of age: 25 mg/kg every 8 hrs.
4 wks-3 mos. of age: 25 mg/kg every 6 hrs.
** One patient was greater than 3 months of age.
In a published dose-ranging study of smaller premature infants (670-1,890 gms) in the first week of life, a dose of 20 mg/kg q12h by 15-30 minutes infusion was associated with mean peak and trough plasma imipenem concentrations of 43 µg/mL and 1.7 µg/mL after multiple doses, respectively. However, moderate accumulation of cilastatin in neonates may occur following multiple doses of TIENAM The safety of this accumulation is unknown.
TIENAM is not recommended in pediatric patients with CNS infections because of the risk of seizures. TIENAM is not recommended in pediatric patients <30 kg with impaired renal function (serum creatinine >2 mg/dL), as no data are available. (See also Intravenous Infusion: Treatment: Pediatric Dosage Schedule under Dosage & Administration.)
Use In Pregnancy & Lactation
USE IN PREGNANCY: There are no adequate and well-controlled studies in pregnant women. TIENAM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NURSING MOTHERS: Imipenem has been detected in human milk. If the use of TIENAM is deemed essential, the patient should stop nursing.
Side Effects
TIENAM is generally well tolerated. In controlled clinical studies, TIENAM was found to be tolerated as well as cefazolin, cephalothin, and cefotaxime. Side effects rarely require cessation of therapy and are generally mild and transient; serious side effects are rare. The most common adverse reactions have been local reactions.
The following side effects have been reported during clinical studies and in post-marketing experience.
LOCAL REACTIONS: Erythema, local pain and induration, thrombophlebitis.
ALLERGIC REACTIONS/SKIN: Rash, pruritus, urticaria, erythema multiforme, Stevens-Johnson syndrome, angioedema, toxic epidermal necrolysis (rarely), exfoliative dermatitis (rarely), candidiasis, fever including drug fever, anaphylactic reactions.
GASTROINTESTINAL REACTIONS: Nausea, vomiting, diarrhea, staining of teeth and/or tongue. In common with virtually all other broad spectrum antibiotics, pseudomembranous colitis has been reported.
BLOOD: Eosinophilia, leukopenia, neutropenia, including agranulocytosis, thrombocytopenia, thrombocytosis, and decreased hemoglobin, pancytopenia and prolonged prothrombin time have been reported. A positive direct Coombs' test may develop in some individuals.
LIVER FUNCTION: Increases in serum transaminases, bilirubin and/or serum alkaline phosphatase; hepatic failure (rarely), hepatitis (rarely) and fulminant hepatitis (very rarely).
RENAL FUNCTION: Oliguria/anuria, polyuria, acute renal failure (rarely). The role of TIENAM 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.
Elevations in serum creatinine and blood urea nitrogen have been observed. Urine discoloration. This is harmless and should not be confused with hematuria.
NERVOUS SYSTEM /PSYCHIATRIC: Paresthesia, encephalopathy, agitation, and dyskinesia. As with other beta-lactam antibiotics, CNS side effects such as myoclonic activity, psychic disturbances, including hallucinations, confusional states, or seizures have been reported with the I.V. formulation.
SPECIAL SENSES: Hearing loss, taste perversion.
GRANULOCYTOPENIC PATIENTS: Drug-related nausea and/or vomiting appear to occur more frequently in granulocytopenic patients than in non-granulocytopenic patients treated with TIENAM.
Tell the doctor or pharmacist promptly about any of these or any other unusual symptoms.
Drug Interactions
Generalized seizures have been reported in patients who received ganciclovir and TIENAM. These drugs should not be used concomitantly unless the potential benefits outweigh the risks.
Also see STABILITY OF RECONSTITUTED OF TIENAM under Dosage & Administration.
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 of 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 PRECAUTIONS.)
Caution For Usage
CAUTION: TIENAM is chemically incompatible with lactate and should not be reconstituted in diluents containing lactate. TIENAM can be administered, however, into an I.V. system through which a lactate solution is being infused.
TIENAM should not be mixed with or physically added to other antibiotics.
Storage
Store the dry powder below 30°C.
SHELF LIFE: 24 months from manufacturing date.
MIMS Class
ATC Classification
J01DH51 - imipenem and cilastatin ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.
Presentation/Packing
Infusion (vial) 1's.
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