Zimilast

ZIMILAST

(Imipenem and Cilastain for Injection USP)

 

Each combipack contains:

Each vial Contains:

Imipenem USP (Sterile)	500 mg
Cilastatin Sodium USP (Sterile)
eq to Cilastatin	500 mg
(Buffered with sodium Bicarbonate)

Each Ampoule Contains

Sterile water for injection USP

10 ml

 

DESCRIPTION

ZIMILAST is a sterile formulation of imipenem (a thienamycin antibiotic) and cilastatin sodium (the inhibitor of the renal dipeptidase, dehydropeptidase I) with sodium bicarbonate added as buffer, for intravenous use.

ZIMILAST (imipenem-cilastatin) is a potent broad-spectrum antibacterial agent for intravenous administration only. Imipenem (N-formamidoylaminothienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Sterptomyces cattleya. It is chemically designed as (5R,6S)-3-[[2-(formamidoylam-inothienamycin) ethyl]thio]-6-[(R)-1-hydroxyethyl]-7-oxo-1azabicyclo3.2.0)hept- 2-ene-2carboxylic acid monohydrate. The empirical formula for imipenem is C12 H17N304S.H20, and its molecular weight is 317.36.

Cilastatin sodium is the sodium salt of a derivalized heptanoic acid. It is chemically designated as sodium (Z)-7-[[(R) -2-amino-2-carboxyethy|]thio]-2-[(S)-2,2-dimethylcyclopropanecarboxamido]-2-heptenoate. The empirical formula for cilastatin sodium is C16H25N2Na05S, and its molecular weight is 380.44. Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase I resulting in relatively low levels in urine. Cilastatin sodium, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem so that when imipenem and cilastatin sodium are given concomitantly, fully adequate antibacterial levels of imipenem are achieved in the urine.

 

PHARMACOLOGY

Mechanism of action

The bactericidal activity of imipenem results from the inhibition of cell wall synthesis. Its greatest affinity is for penicillin-binding proteins (PBPs) 1A, 1B, 2, 4, 5 and 6 of Escherichia coli, and 1A, 1B, 2, 4 and 5 Pseudomonas aeruginosa. The lethal effect is related to binding to PBP 2 and PBP 1 B. Imipenem has a high degree of stability in the presence of beta lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria. It is a potent inhibitor of beta-lactamases from certain gram negative bacteria which are inherently resistant to many beta-lactam antibiotics, e.g, Pseudomonas aeruginosa, Serratia spp. and Enterobacter spp.

Pharmacokinetics

Intravenous infusion of imipenem-cilastatin over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from 14 to 24 μg/ml for the 250 mg dose. from 21 to 58 μg/ml for the 500 mg dose, and from 41 to 83 μg/ml for the 1000 mg dose. At these doses plasma levels of imipenem antimicrobial activity decline to below 1 μg/ml or less in 4 to 6 hours. Peak plasma levels of cilastatin following a 20-minute intravenous infusion of imipenem-cilastatin, range from 15 to 25 μg/ml for the 250 mg dose, from 31 to 49 μg/ml for the 500 mg dose, and from 56 to 88 μg/ml for the 1000 mg dose.

The plasma half-life of each component is approximately 1 hour. The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%.

Approximately, 70% of the administered imipenem is recovered in the urine within 10 hours after which no further urinary excretion is detectable. Urine concentrations of imipenem is excess of 10μg/ml can be maintained for up to 8 hours with intravenous imipenem-cilastatin at 500 mg dose. Approximately, 70% of the cilastatin sodium dose is recovered in the urine within 10 hours of administration of imipenem-cilastatin IV.

No accumulation of imipenem-cilastatin in plasma or urine is observed with regimens administered as frequently as every 6 hours in patients with normal renal function. Imipenem-cilastatin sodium is haemo dialyzable. However usefulness of this procedure is the overdosage setting is questionable.

In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age). The pharmacokinetics of a single dose of imipenem 500 mg and cilastatin 500 mg administered intravenously over 20 minutes are consistent with those expected in subject with slight renal impairment for which no dosage alteration is considered necessary. The mean plasma half-lives of imipenem and cilastatin are 91±7.0 minutes and 69±15 minutes, respectively. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin and no accumulation of imipenem-cilastatin is observed.

After a 1 gram dose of imipenem-cilastatin administered intravenously measurable levels of imipenem were found in various tissues and fluids including vitreous humor, aqueous humor, lung tissues, sputum, pleural fluid, peritoneal fluid, bile, CFS (uninflamed), CFS (inflamed), fallopian tubes, endometrium, myometrium, bone, interstitial fluid, skin and fascia.

Antimicrobial spectrum

Imipenem has in vitro activity against a wide range of gram-positive and gram- negative organisms. Imipenem has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections treated with imipenem-cilastatin sodium intravenous formulation.

Gram-negative aerobes:

Acinetobactor spp., Citrobacter spp., Enterobacter spp, Escherichia coli, Gardnereilla vaginalis, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella spp. Morganella morganil Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa (Imipenem is inactive in vitro against Xanthomonas (Pseudomonas) maltophilia and some strains of P. cepacia.), Serratia spp. Aeromonas hydrophila, Alcaligenes spp., Capnocytophaga spp., Haemophilus ducreyi, Nessena gonorrhoeae including penicillinase-producing strains, Pasteurella spp., Providenicia stuartii including S. marcescens.

Gram-positive anaerobes:

Bifidobacterium spp., Clostridium spp., E-bacterium spp., Peptococcus spp., Peptostreptococcus spp., Propiombactenum spp.

Gram-negative anaerobes:

Bacteroides spp. including B. fragilis, Fusobacterium spp. Prevotella bivia, Prevotella disiens, Prevotella melaninogenica, Veillonella spp.

In vitro tests show imipenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.

The following in vitro data are available but their clinical significance is unknown, Imipenem exhibits in vitro minimum inhibitory concentrations (MICS) of 4 μg/ml or less against most (>90%) strains of the following microorganisms, however, the safety and effectiveness of imipenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive aerobes:

Bacillus spp., Listeria monocytogenes, Nocardia spp. Staphylococcs saprophyticus, Group C steptococci, Group G streptococci, Viridans group streptococci.

 

INDICATIONS

ZIMILAST (imipenem-cilastatin for intravenous injection) is indicated for the treatment of serious respiratory, genitourinary, intra-abdominal, bone and joint and dermatological infections and endocarditis and bacterial septicemia.

 

Dosage and administration;

Adults:

The dosage recommendations for intravenous ZIMILAST (imipenem-cilastatin) represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution. Each 125mg, 250mg, or 500mg dose should be given by intravenous administration over 20 to 30 minutes. Each 750 mg or 1000 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

The total daily dosage for intravenous imipenem-cilastatin 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. Adult patients with impaired renal function, as judged by creatinine clearance ≥ 70 ml/min/1.73m2, require adjustment of dosage as described below.

Intravenous Dosage Schedule for adults with normal renal function (creatinine clearance of ≥ 71 mL/min/1.73 m²) and body weight ≥ 70 kg

Dosage regimens in column A of Table I are recommended for infections caused by fully susceptible organisms which represent the majority of pathogenic species. Dosage regimens in column B of Table I are recommended for infections caused by organisms with moderate susceptibility to imipenem primarily some strains of P. aeruginosa.

Table 1: Intravenous dosage schedule for adults with normal renal function (creatinine clearance of 271 mL/min/1.73 m²) and body weight ≥ 70 kg

Type or Severity of Infection	A Fully susceptibleOrganisms includingGram positive and Gram negative aerobes and anaerobes	B Moderately susceptible organisms, primarily some strains of P.Aeruginosa
Mild	250 mg q6h (Total Daily Dose = 1.0g)	500 mg q6h (Total Daily Dose = 2.0g)
Moderate	500 mg q8h (Total Daily Dose=1.5g) Or 500 mg q6h (Total Daily Dose=2.0g)	500 mg q6h (Total Daily Dose = 2.0g) Or 1 g q8h (Total Daily Dose=3.0g)
Severe Life threatening Only	500 mg q6h (Total Daily Dose=2.0g)	1 g q8 h (Total Daily Dose=3.0g) Or 1 g q6 h (Total Daily Dose=4.0g)
Uncomplicated urinary tract Infection	250 mg q6h (Total Daily Dose=1.0g)	250 mg q6h (Total Daily Dose=1.0g)
Complicated urinary tract Infection	500 mg q6h (Total Daily Dose=2.0g)	500 mg q6h (Total Daily Dose=2.0g)

Due to the high antimicrobial activity of ZIMILASTI.V., it is recommended that the maximum total daily dosage not exceed 50 mg/kg/day or 4.0 g/day, whichever is lower.

However, patients over twelve years of age with cystic fibrosis and normal renal function have been treated with intravenous imipenem-cilastatin at doses up to 90 mg/kg/day in divided doses, not exceeding 4.0 g/day.

Reduced intravenous Schedule for Adults with Impaired Renal Function (creatinine clearance of 70 mL/min/1.73 m²) and body weight < 70 kg

Creatinine clearance may be calculated from serum creatinine concentration by the following equation:

Clcr (Males) =  (wt. in kg)(140-age) / (72)(creatinine in mg/dL)

Clcr (Females) = 0.85 x above value

To determine the dose for adults with impaired renal function and/or reduced body weight.

1.Choose a total daily dose from Table I based on infection characteristics:

2.a) If the total daily doses is 1.0g, 1.5 g, or 2.0 g, use the appropriate subsection of the table II and continue with step 3.

   b) If the total daily dose is 3.0g or 4.0g use the appropriate subsection of Table III and continue with step 3.

3.From Table II or III.

a)Select the body weight on the far left which is closed to the patient’s body weight(kg).

b) Select the patient’s creatinine clearance category.

c) When the row and column intersect is the reduced dosage regimen.

 

Table II: Reduced intravenous dosage of intravenous imipenem-cilastatin in adult patients with impaired renal function (creatinine clearance ≤ 70 ml min/1.73 m²) and/or body weight < 70 kg

 

If Total Daily Dose from Table I is:

1.0 g/day

1.5 g/day

2g/day

And body weight (kg) is:

and creatinine clearance (ml/min/1.73 m2) is:

and creatinine clearance (ml/min/1.73 m2) is:

and creatinine clearance (ml/min/1.73 m2) is:

≤ 71

41-70

21-40

6-20

≤ 71

41-70

21-40

6-20

≤ 71

41-70

21-40

6-20

Reduced Dosage

Reduced Dosage

Reduced Dosage

≤ 71

250 q6h

250 q8h

250 q12h

250 q12h

500 q8h

250 q6h

250 q8h

250 q12h

500 q6h

500 q8h

250 q6h

250 q12h

60

250 q8h

125 q6h

250 q12h

125 q12h

250 q6h

250 q8h

250 q8h

250 q12h

500 q8h

250 q6h

250 q8h

250 q12h

50

125 q6h

125 q6h

125 q8h

125 q12h

250 q6h

250 q8h

250 q12h

250 q12h

250 q6h

250 q6h

250 q8h

250 q12h

40

125 q6h

125 q8h

125 q12h

125 q12h

250 q8h

125 q6h

125 q8h

125 q12h

250 q6h

250 q8h

250 q12h

250 q12h

30

125 q8h

125 q8h

125 q12h

125 q12h

125 q6h

125 q8h

125 q8h

125 q12h

125 q8h

125 q6h

125 q8h

125 q12h

 

Table II: Reduced intravenous dosage of intravenous imipenem-cilastatin in adult patients with impaired renal function (creatinine clearance ≤ 70 ml min/1.73 m²) and/or body weight < 70 kg

 

If Total Daily Dose from Table I is:
	3.0 g/day				4.0 g/day
And body weight (kg) is:	and creatinine clearance (ml/min/1.73 m2) is:				and creatinine clearance (ml/min/1.73 m2) is:
	≤ 71	41-70	21-40	20-Jun	≤ 71	41-70	21-40	20-Jun
	Reduced Dosage				Reduced Dosage
≤ 71	1000 q8h	500 q6h	500 q8h	500 q12h	1000 q6h	750 q8h	500 q6h	500 q12h
60	750 q8h	500 q8h	500 q8h	500 q12h	1000 q8h	750 q8h	500 q8h	500 q12h
50	500 q6h	500 q8h	250 q6h	250 q12h	750 q8h	500 q6h	500 q8h	500 q12h
40	500 q8h	250 q6h	250 q8h	250 q12h	500 q6h	500 q8h	250 q6h	250 q12h
30	250 q6h	250 q8h	250 q8h	250 q12h	500 q8h	250 q6h	250 q8h	250 q12h

Patient with creatinine clearance of 6 to 20 mL/min/1.73 m² should be treated with intravenous imipenem-cilastatin 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 clearance of <5 mL/min/1.73 m² should not receive intravenous imipenem-cilastatin unless hemodialysis instituted within 48 hours. There ia inadequate information to recommend usage of intravenous imipenem-cilastatin for patient undergoing peritoneal dialysis.

Hemodialysis

When treating patient with creatinine clearance of <5 mL/min/1.73 m² who are undergoing hemodialysis, use the dosage recommendations

 

STABILITY AND COMPATIBILITY

Before reconstitution the dry powder should be stored at a temperature below 25°C (77° F).

Solutions of ZIMILAST range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

ZIMILAST reconstituted with the following diluents (See DIRECTIONS FOR USE), maintains satisfactory potency for 4 hours at room temperature (25°C) or for 24 hours under refrigeration (5°C).

Solutions of ZIMILAST should not be frozen.

0.9% Sodium Chloride Injection

5% or 10% Dextrose Injection

5% Dextrose and 0.9% Sodium Chloride Injection

5% Dextrose Injection with 0.225% or 0.45% saline solution

5% Dextrose Injection with 0.15% potassium chloride solution

Mannitol 5% and 10%

ZIMILAST should not be mixed with or physically added to other antibiotics.

However, ZIMILAST may be administered concomitantly with other antibiotics, such as aminoglycosides.

 

PRECAUTIONS

General

Intravenous imipenem-cilastatin is not indicated in patients with meningitis because safety and efficacy have not been established.

Intravenous imipenem-cilastatin is indicated for polymicrobial infections including those in which S.pneumoniae (pneumonia, septicemia), S.pyogenes (skin and skin structure), or non-penicillinase producing S. aureus is one of the causative organisms. However, mono bacterial infections due to these organism are usually treated with narrower spectrum antibiotics, such as penicillin G. Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria, intravenous imipenem- cilastatin is useful for the treatment of mixed infections and as presumptive therapy pior to the identification of the causative organisms. 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, bacterial eradication may develop resistance fairly during treatment with intravenous imipenem-cilastatin. 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 intravenous imipenem- cilastatin CNS adverse experience such as myoclonic activity, confusional states and seizures have been reported with intravenous imipenem-cilastatin, especially when the recommended dose exceeded.

These experience have occurred most commonly in patients with CNS disorders (e.g. brain lesions or history of seizures) and compromised renal function. However, there were reports in which there was no recognized or documented underlying CNS discover or compromised renal functions.

When recommended dose of intravenous imipenem-cilastatin were exceeded in adult. patients with creatinine clearance 20ml/min/1.73m, 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.

Patients with creatinine clearances of <5ml/min/1.73m’ should not receive intravenous imipenem-cilastatin unless hemodialysis is instituted within 48 hours.

Warnings

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-cilastatin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta- lactam, and other allergens.

If an allergic reaction occurs, imipenem-cilastatin should be discontinued. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen intravenous steroids, and airway management, including intubation, may also be administered as indicated.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including imipenem-cilastatin, and may range in severity from mild to life-threating. Therefore it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile as one primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against difficile colitis.

 

Contraindications

ZIMILAST (imipenem-cilastatin) is contraindicated in patients who have shown hypersensitivity to any component of this product.

Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women.

Imipenem-Cilastatin should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Teratology studies with cilastatin sodium in rabbits and rats at 6 to 20 times” the maximum recommended human dose of the intravenous formulation of imipenem-cilastatin sodium (50 mg /kg/ day”), respectively, showed no evidence of adverse effect on the fetus.

No evidence of teratogenicity was observed in rabbits and rats given imipenem at dose up to 1 and 18 times” the maximum recommended daily human dose of the intravenous formulation of imipenem-cilastatin sodium, respectively.

Teratology studies with imipenem-cilastatin sodium at dose up to 11 times” the usual recommended human dose of the intravenous formulation (30 mg/kg/day) in pregnant mice and rats during the period of major organogenesis revealed no evidence of teratogenicity.

Imipenem-cilastatin sodium, when administered to pregnant rabbits at dosages equivalent to the usual human dose of the . Intravenous formulation and higher, caused body weight loss, diarrhea, and maternal deaths. When comparable dose of imipenem-cilastatin sodium were given to non-pregnant rabbits, body weight loss, diarrhea, and deaths were also observed. This intolerance is not I 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 40mg/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 (approximately 100 mg/kg/day or approximately 2 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 material deaths, no evidence of teratogenicity, but an increase in embryonic loss relative to control groups. (” Bases on patient weight of 70 kg.)

Paediatrics

Use of intravenous imipenem-cilastatin in paediatric patients, neonates to 16 years of age, is supported by evidence from adequate and well-controlled studies of intravenous imipenem-cilastatin in adults and by the clinical studies and published literature on paediatric patients.

In paediatric patients > 3 months of age (with non CNS infections), the recommended dose of intravenous imipenem-cilastatin is 15-25 mg/kg/dose administered every six hours. Doses of 25 mg/hg/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 concentration of imipenem of 1.1±4 mcg/ml and 0.6 ± 0.2 mcg/ml following multiple 60-minute infusions, respectively; trough urinary concentration of imipenem were in excess of 10 mcg/ml for both doses. These doses have provided adequate plasma and urine concentration for the treatment of non-CNS infections. Based on studies in adults, the maximum daily dose for treatment of infection with fully susceptible organisms is 2.0 g per day, and of infections with moderately susceptible organism (primarily some strains of P.aeruginosa) ia 4.0 g/day. Higher doses (up to 90 mg/kg/day in order children) have been used in patients with cystic fibrosis. Based on studies of paediatric 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 hrs

1 – 4 weeks of age: 25 mg/kg every 8 hrs

4 weeks – 3 months of age: 25 mg kg every 6 hrs

Geriatrics

No overall differences in safety or effectiveness between elderly subjects ( ≥ 65 years) and younger subjects have been reported. However, a 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. Dosage adjustment in the case of renal impairment is necessary (see DOSAGE AND ADMINISTRATION).

 

Carcinogenicity/Mutagenicity/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 bacteria and mammalian test in vivo and in vitro. The tests used were: V79 mammalian cell mutagenesis assay (imipenem- cilastatin sodium and imipenem alone), Ames test (cilastatin sodium alone 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 dosage levels up to 11 times the maximum daily recommended human dose of the Intramuscular formulations (on a mg/kg 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. similarly no adverse effect on the fetus or on lactation were observed when imipenem-, cilastatin sodium was administered to rats late in gestation.

 

Drug Interactions

Generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin. These drugs should not be used concomitantly unless the potential benefits outweighs the risks.

Concomitant administration of imipenem-cilastain and probenecid results in only minimal increases in plasma levels and half-life of imipenem, with urinary recovery of active imipenem reduced to approximately 60% of administered dose. However, the plasma levels and half-life of cilastatin are almost doubled. Concomitant administration probenecid with imipenem-cilastatin is not recommended. Imipenem-cilastatin should not be mixed with or physically added to other antibiotics. However, imipenem-cilastatin may be administered concomitantly with other antibiotics, such as aminoglycosides.

 

Adverse reactions is generally well tolerated. Side effect rarely require cessation of therapy and are generally mild and transient, serious side effects are rare.

Local reactions: erythema, local pain and induration, thrombophlebitis.

Allergic: rash pruritus, urticaria, erythema, multiforme, Stevens-Johnson syndrome, angioedema, toxic epidermal necrolysis (rarely), exfoliative dermatitis, (rarely), candidiasis, fever including drug fever, anaphylactic reactions.

Gastrointestinal: nausea, vomiting, diarrhea, staining of teeth and/or tongue. Pseudomembranous colitis has been reported.

Blood: eosinophilia, leucopenia, neutropenia including agranulocytosis, thrombocytopenia, thrombocytosis, decreased haemoglobin and prolonged prothrombin time. A positive direct Coombs test may develop.

Liver function: mild increases in serum transaminases, bilirubin and/or serum alkaline phosphatase hepatitis rarely have been reported.

Renal function: oliguria/anuria, polyuria, acute rental failure (rarely). The role of imipenem- cilastatin in changes in renal function is difficult to assess, since factors predisposing to pre- rental uraemia or to impaired renal function usually have been present. Elevated serum creatinine and blood urea have been seen. A harmless urine discoloration, not to be confused with hematuria, has been seen in children.

Central nervous system: myoclonic activity, physical disturbances including hallucinations. paraesthesia, confusional states or convulsions have been reported. Dizziness, somnolence, encephalopathy, vertigo, headache.

Special senses: hearing loss, taste preversion, tinnitus.

Other reported reactions with an unknown casual relationship

Gastrointestinal: haemorrhagic colitis, gastroenteritis, abdominal pain, glossitis, tongue papillar hypertrophy, heartburn, pharyngeal pain, increased salivation.

Respiratory chest discomfort, dyspnea, hyperventilation, thorasic spine pain.

Cardiovascular: hypotension, palpitations, tachycardia.

Skin: flushing, cyanosis, hyperhidrosis, skin texture changes, pruritus vulvae.

Body as a whole: polyarthralgia, asthenia/weakness.

Blood: haemolytic anaemia. pancytopenia, bone marrow depression.

The spectum of adverse events in pediatric patients has been reported to be similar to that in adults.

 

OVERDOSAGE

In the case of overdosage, discontinue intravenous imipenem-cilastatin, treat symptomatically, and institute supportive measures as required. Imipenem-cilastatin sodium is hemo dialyzable. However usefulness of this procedure in the overdosage setting is questionable.

The acute intravenous toxicity of imipenem-cilastatin sodium in a ratio of 1:1 was studied in mice at dose of 75 to 1359 mg/kg. Following drug administration, ataxia was rapidly produced and clonic convulsions were noted in about 45 minutes. Deaths, occurred within 4- 56 minutes at all doses. The acute intravenous toxicity of imipenem-cilastatin sodium was produced within 5-10 minutes in rats at doses of 771 to 1583 mg/kg. In another rat study female rats shows ataxia, bradypnea, and decreased activity in all but the lowest dose (550mg/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.

 

STORAGE

Store below 30°C, protected from light and moisture. Keep out of reach of children.

 

PRESENTATION

One vial in a carton with leaflet.

 

Updated on February 9, 2024.