Data Sheet

PRIMAXIN^®

imipenem/cilastatin

500 mg /500 mg injection

Presentation

PRIMAXIN for intravenous use is supplied as a white sterile powder in 13 mL vials. Each vial contains 500 mg of imipenem equivalent and 500 mg cilastatin equivalent. The reconstituted solution is clear (however variations in colour from colourless to yellow do not affect the potency of the product).

Note: PRIMAXIN for intramuscular use is not available in New Zealand.

Therapeutic Class

Cilastatin is a competitive, reversible and specific inhibitor of dehydropeptidase-I enzyme.

Indications

The activity of PRIMAXIN against an unusually broad spectrum of pathogens makes it particularly useful in the treatment of polymicrobic mixed aerobic/anaerobic infections as well as initial therapy prior to the identification of the causative organisms. PRIMAXIN is indicated for the treatment of the following infections due to susceptible organisms:

• Intra-abdominal infections
• Lower respiratory tract infections
• Gynaecological infections
• Septicaemia
• Genitourinary tract infections
• Bone and joint infections
• Skin and soft tissue infections
• Endocarditis

PRIMAXIN 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 faecal 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 PRIMAXIN.

PRIMAXIN has demonstrated efficacy against many infections caused by aerobic and anaerobic gram-positive and gram-negative bacteria resistant to the cephalosporins, including cefazolin, cefoperazone, cephalothin, cefoxitin, cefotaxime, moxalactam, cefamandole, ceftazidime and ceftriaxone. Similarly, many infections caused by organisms resistant to aminoglycosides (gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin-G, ticarcillin, piperacillin, azlocillin, mezlocillin) responded to treatment with PRIMAXIN.

PRIMAXIN is not indicated for the treatment of meningitis.

Dosage and Administration

The dosage recommendations for PRIMAXIN (for intravenous use only) represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present.

The total daily dosage of PRIMAXIN 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 pathogens, renal function and body-weight.

Adult Dosage Schedule for Patients with Normal Renal Function

Doses cited in Table 1 are based on a patient with normal renal function (creatinine clearance of > 70 mL/min/1.73m²) and a body weight of > 70 kg. A reduction in dose must be made for a patient with a creatinine clearance < 70 mL/min/1.73m² (see Table 2) and/or a body weight < 70 kg. 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 1 g b.i.d. dosage regimen may also be used. In infections due to less susceptible organisms, the daily dosage of PRIMAXIN I.V. may be increased to a maximum of 4 g/day or 50 mg/kg/day, whichever is lower.

Each dose of < 500 mg of PRIMAXIN I.V. 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.

TABLE 1

I.V. DOSAGE SCHEDULE FOR ADULTS WITH NORMAL RENAL FUNCTION AND BODY WEIGHT ≥ 70 KG*

* A further proportionate reduction in dose administered must be made for patients with a body weight < 70 kg.

Due to high antimicrobial activity of PRIMAXIN, 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 PRIMAXIN at doses up to 90 mg/kg/day in divided doses not exceeding 4 g/day.

PRIMAXIN has been used successfully as monotherapy in immunocompromised cancer patients for confirmed or suspected infections such as sepsis.

Adult Dosage Schedule for Patients with Impaired Renal Function

To determine the reduced dose for adults with impaired renal function:

1. The total daily dose is chosen from Table 1 based on infection characteristics.
2. From Table 2 the appropriate reduced dosage regimen is selected based on the daily dose from Table 1 and the patient's creatinine clearance category. (For infusion times see Adult Dosage Schedule for Patients with Normal Renal Function).

TABLE 2

REDUCED DOSAGE OF PRIMAXIN I.V. IN ADULTS WITH IMPAIRED RENAL FUNCTION AND BODY WEIGHT ≥ 70 kg*

* A further proportionate reduction in dose administered must be made for patients with a body weight < 70 kg.

When the 500 mg dose is used in patients with creatinine clearances of 6 - 20 mL/min/1.73m² there may be an increased risk of seizures.

Patients with creatinine clearances of < 5 mL/min/1.73 m² should not receive PRIMAXIN I.V. unless haemodialysis is instituted within 48 hours.

Haemodialysis

When treating patients with creatinine clearances of < 5 mL/min/1.73 m² who are undergoing haemodialysis, use the dosage recommendations for patients with creatinine clearances of 6 - 20 mL/min/1.73 m² (see Adult Dosage Schedule for Patients with Impaired Renal Function).

Both imipenem and cilastatin are cleared from the circulation during haemodialysis. The patient should receive PRIMAXIN after haemodialysis and at 12 hour intervals timed from the end of that haemodialysis session. Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on haemodialysis, PRIMAXIN is recommended only when the benefit outweighs the potential risk of seizures (see Warnings and Precautions).

Currently there are inadequate data to recommend use of PRIMAXIN I.V. 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.

Paediatric Dosing Schedule (3 months or older)

For children and infants the following dosage schedule is recommended:

• CHILDREN >40 kg body weight should receive adult doses.
• CHILDREN AND INFANTS <40 kg body weight should receive 15 mg/kg at six-hour intervals. The total daily dose should not exceed 2 g.

Clinical data are insufficient to recommend dosing for children less than 3 months of age, or paediatric patients with impaired renal function (serum creatinine >2 mg/dL).

PRIMAXIN is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used.

PRIMAXIN may be used in children with sepsis as long as they are not suspected of having meningitis.

Reconstitution, Intravenous Solution

PRIMAXIN I.V. for intravenous infusion is supplied as a white sterile powder in vials containing 500 mg imipenem equivalent and 500 mg cilastatin equivalent.

PRIMAXIN I.V. 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.

PRIMAXIN I.V. 500 contains 37.5 mg of sodium (1.6 mEq).

Sterile powder PRIMAXIN I.V. should be reconstituted as shown in Table 3. It should be shaken until a clear solution is obtained. Variations of colour from colourless to yellow do not affect the potency of the product.

TABLE 3

RECONSTITUTION OF PRIMAXIN I.V.

A suggested procedure is to add approximately 10 mL from the appropriate infusion solution to the vial. Shake well and transfer the resulting suspension to the infusion solution container.

Stability, PRIMAXIN I.V.

Store the dry powder at room temperature (E.P. = 15-25°C).

Table 4 shows the stability period for PRIMAXIN I.V. when reconstituted with selected infusion solutions, and stored at room temperature or under refrigeration.

CAUTION:
PRIMAXIN I.V. is chemically incompatible with lactate and should not be reconstituted in diluents containing lactate.
PRIMAXIN I.V. can be administered, however, into an I.V. system through which a lactate solution is being infused.
PRIMAXIN I.V. should not be mixed with or physically added to other antibiotics.

TABLE 4

STABILITY OF RECONSTITUTED PRIMAXIN I.V.

Contraindications

Hypersensitivity to any component of this product.

Warnings and Precautions

General

There is some clinical and laboratory evidence of partial cross-allergenicity between PRIMAXIN and the other beta-lactam antibiotics, penicillins and cephalosporins. Severe reactions (including anaphylaxis) have been reported with most beta-lactam antibiotics. Before therapy with PRIMAXIN, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. If an allergic reaction to PRIMAXIN occurs, the medicine should be discontinued and appropriate measures undertaken.

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 diarrhoea 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.

Use in Pregnancy

There are no adequate and well controlled studies in pregnant women. PRIMAXIN should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Nursing Mothers

Imipenem has been detected in human milk. If the use of PRIMAXIN is deemed essential, the patient should stop nursing.

Paediatric Use

Clinical data are insufficient to recommend the use of PRIMAXIN for children under 3 months of age or paediatric patients with impaired renal function (serum creatinine >2 mg/dL). (See also Paediatric Dosage Schedule.)

Central Nervous System

As with other beta lactam antibiotics, CNS side effects such as myoclonic activity, confusional states, or seizures have been reported, especially when recommended dosages based on renal function and bodyweight 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 and Administration). Anticonvulsant therapy should be continued in patients with a known seizure disorder.

If focal tremors, myoclonus, or seizures occur, patients should be elevated neurologically and placed on anticonvulsant therapy if not already instituted. If CNS symptoms continue, the dosage of PRIMAXIN should be decreased or discontinued.

Patients with creatinine clearances of <5 mL/min/1.73 m² should not receive PRIMAXIN unless haemodialysis is instituted within 48 hours. For patients on haemodialysis, PRIMAXIN is recommended only when the benefit outweighs the potential risk of seizures.

Animal Toxicity

Animal studies showed that the toxicity produced by imipenem, as a single entity, was limited to the kidney. Nephrotoxicity (characterised by proximal tubular necrosis) was observed in rabbits and monkeys receiving high doses of imipenem. The rabbit is more sensitive to the nephrotoxic effect of imipenem than the monkey. No adverse effects were observed after six months of imipenem administration in rats, at dosage levels up to 180 mg/kg/day, or in monkeys given up to 120 mg/kg/day.

No adverse effects were noted after intravenous administration of cilastatin to rats and monkeys at dosages up to 500 mg/kg/day for 14 weeks and five weeks, respectively. Acute studies with cilastatin supported the conclusion that this medicine is relatively nontoxic. In rats given 1250 mg/kg/day subcutaneously, or larger doses, very slight to slight proximal renal tubular degeneration was observed. After 5 weeks on these doses, no tubular necrosis was found, and there were no changes in any other tissues. Renal function remained normal.

Coadministration of cilastatin with imipenem in a 1:1 ratio prevented the nephrotoxic effects of imipenem in rabbits and monkeys, even when the dose of imipenem was 360 mg/kg/day or 180 mg/kg/day, respectively (dosage levels which are nephrotoxic when administered without cilastatin). This protective effect was seen in the monkey throughout six months of coadministration.

Rabbits receiving 14C-imipenem, at a dose known to cause proximal tubular degeneration, showed accumulation in their renal cortex of two radiolabelled metabolites of imipenem, accounting for 8 percent of the administered doses. A majority of radioactivity was found as hydrolysed imipenem, the product of DHP-I mediated metabolism. A second metabolite accumulating in the kidney, but undetectable in either plasma or urine, has been identified as a cysteine-adduct of imipenem, generated by a pathway independent of DHP-I. Levels of free imipenem in the cortex were much lower than those of either of the two metabolites. Co-administration of a protective dose of cilastatin results in a major reduction in levels of accumulated hydrolysed imipenem but not of the cysteine-adduct. Neither of the two metabolites caused renal damage, when administered intravenously to the rabbit at high dose rates.

Available evidence suggests that cilastatin prevents the nephrotoxicity of imipenem in animals, by preventing entry of imipenem into the tubular cells.

The intravenous LD50 of imipenem is greater than 2000 mg/kg in the rat and approximately 1500 mg/kg in the mouse.

The intravenous LD50 of cilastatin sodium is approximately 5000 mg/kg in the rat and approximately 8700 mg/kg in the mouse.

The intravenous LD50 of PRIMAXIN is approximately 1000 mg/kg in the rat and approximately 1100 mg/kg in the mouse.

Genotoxicity studies were performed in a variety of bacterial and mammalian tests in vivo and in vitro. The tests were: V79 mammalian cell mutation assay (imipenem, PRIMAXIN), Ames test (cilastatin, imipenem), unscheduled DNA synthesis assay (PRIMAXIN) and in vivo mouse cytogenicity test (PRIMAXIN). None of these tests showed any evidence of genetic damage.

Reproduction tests in male and female rats were performed with PRIMAXIN in doses up to 320 mg/kg/day. Slight decreases in live foetal body-weight were observed at this high dosage level. No other adverse effects were observed in fertility, reproductive performance, foetal viability, growth or post-natal development of pups. Similarly, no adverse effects on the foetus or on lactation were observed when PRIMAXIN was administered to rats late in gestation.

Teratogenicity studies with cilastatin sodium in rabbits and rats at 10 and 33 times the usual human dose of PRIMAXIN I.V. (30 mg/kg/day) respectively, showed no evidence of adverse effect on the foetus. No evidence of teratogenicity or adverse effect on postnatal growth or behaviour was observed in rats given imipenem at dosage levels up to 30 times the usual human intravenous dose. Similarly, no evidence of adverse effect on the foetus was observed in teratology studies in rabbits with imipenem at 2 times the usual human intravenous dose.

Teratology studies with imipenem-cilastatin sodium at doses up to 11 times the usual human intravenous dose 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, diarrhoea, and maternal deaths. When comparable doses of imipenem-cilastatin sodium were given to non-pregnant rabbits, body weight loss, diarrhoea, 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, diarrhoea, 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 3 times the usual recommended daily human intravenous dose) 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.

Effects On Ability To Drive Or Operate Machinery

There are some adverse effects associated with this product that may affect some patients' ability to drive or operate machinery (see Adverse Effects).

Adverse Effects

PRIMAXIN is generally well tolerated. In controlled clinical studies, PRIMAXIN was found to be tolerated as well as cefazolin, cephalothin, and cefotaxime. Adverse effects rarely require cessation of therapy and are generally mild and transient; serious adverse effects are rare. The most common adverse reactions have been local reactions.

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, diarrhoea, staining of teeth and/or tongue. In common with virtually all other broad spectrum antibiotics, pseudomembranous colitis has been reported.

Blood: Eosinophilia, leukopaenia, neutropenia, including agranulocytosis, thrombocytopenia, thrombocytosis and decreased haemoglobin, 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 PRIMAXIN 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 discolouration. This is harmless and should not be confused with haematuria.

Nervous System/Psychiatric: As with other beta-lactam antibiotics, CNS adverse experiences such as myoclonic activity, psychic disturbances, including hallucinations, confusional states, or seizures have been reported. Paresthesia, encephalopathy.

Special Senses: Hearing loss, taste perversion.

Granulocytopaenic Patients: Medicine-related nausea and/or vomiting appear to occur more frequently in granulocytopaenic patients than in non-granulocytopaenic patients treated with PRIMAXIN I.V.

Other: Bacterial or fungal superinfections.

Additional Adverse Effect

For the following adverse effects, a causal relationship has not been established.

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

Central Nervous System: Dizziness, somnolence, encephalopathy, vertigo, headache.

Special Senses: Tinnitus.

Respiratory: Chest discomfort, dyspnoea, hyperventilation, thoracic 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.

Interactions

Generalised seizures have been reported in patients who received ganciclovir and PRIMAXIN I.V. These medicines should not be used concomitantly unless the potential benefits outweigh the risks.

Also see Stability Section.

Decreased serum levels of valproic acid with co-administration of carbapenem antibiotics have been reported during post-marketing and in some cases breakthrough seizures have occurred. Careful monitoring of serum levels of valproic acid should be considered if imipenem is to be co-administered with valproic acid.

Overdosage

No specific information is available on the treatment of overdosage with PRIMAXIN. Imipenem-cilastatin sodium is haemodialysable. However, usefulness of this procedure in the overdosage setting is unknown.

Actions

Cilastatin is a competitive, reversible and specific inhibitor of dehydropeptidase-I enzyme, the renal enzyme which metabolises and inactivates imipenem. It is devoid of intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.

Imipenem is a beta-lactam antibiotic belonging to the thienamycin group. It 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.

PRIMAXIN shares with the new 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 PRIMAXIN includes Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis and Bacteroides fragilis, a diverse group of problem pathogens commonly resistant to other antibiotics.

PRIMAXIN 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 PRIMAXIN is broader than that of any other antibiotic studied, and includes virtually all clinically significant pathogens. Organisms against which PRIMAXIN is usually active in vitro include:

Gram-Negative Aerobes

Achromobacter spp.
Acinetobacter spp. (formerly Mima-Herellea)
Aeromonas hydrophilia
Alcaligenes spp.
Bordetella bronchicanis
Bordetella bronchiseptica
Bordetella pertussis
Brucella melitensis
Burkholderia pseudomallei (formerly Pseudomanas pseudomallei)
Burkholderia stutzeri (formerly Pseudomanas 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 multocida
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 PRIMAXIN.

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 haemolytic strains)

Enterococcus faecium and methicillin-resistant staphylococci are not susceptible to PRIMAXIN.

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 Bactoeroides 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 amino- glycoside antibiotics against some isolates of Pseudomonas aeruginosa.

Imipenem is not active against mycoplasma or chlamydia.

Susceptibility Testing

Based on blood levels of imipenem achieved in humans, breakpoint criteria have been adopted for imipenem.

* Kirby-Bauer procedure as modified by the National Committee for Clinical Laboratory Standards (NCCLS). Zone diameters are based on results obtained using a 10 mcg imipenem disc.

The standardised quality control procedure requires use of control organisms. The 10 mcg imipenem disc should give the zone diameters listed below for the quality control strains.

Dilution susceptibility tests should give MICs between the ranges listed below for the quality control strains.

For anaerobic bacteria the MIC of imipenem can be determined by agar or broth dilution (including microdilution) techniques.

Pharmacokinetics

Imipenem IV

In normal volunteers, intravenous infusion of PRIMAXIN over 20 minutes resulted in peak plasma levels of imipenem ranging from 21 - 58 mcg/mL for the 500 mg dose, and from 41 - 83 mcg/mL for the 1000 mg dose. The mean peak plasma levels of imipenem following the 500 and 1000 mg doses were 39 and 66 mcg/mL, respectively. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 mcg/mL in 4 - 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 medicine was detectable. Urine concentrations of imipenem exceeded 10 mcg/mL for up to 8 hours after a 500 mg dose of PRIMAXIN.

The remainder of the administered dose was recovered in the urine as anti-bacterially inactive metabolites, and faecal elimination of imipenem is essentially nil.

No accumulation of imipenem in plasma or urine has been observed with regimens of PRIMAXIN administered as frequently as every 6 hours in patients with normal renal function. Concomitant administration of PRIMAXIN and probenecid resulted in minimal increases in the plasma levels and plasma half-life of imipenem. The urinary recovery of active (non metabolised) imipenem decreased to approximately 60% of the dose when PRIMAXIN was administered with probenecid.

When administered alone, imipenem is metabolised in the kidneys by dehydropeptidase-I. Individual urinary recoveries of metabolites 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%.

TISSUE & BODY FLUID LEVELS OF IMIPENEM
AFTER A 1 GRAM DOSE OF PRIMAXIN I.V.

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 humans 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 localised 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 of metabolites ranged from 5 to 40% of the administered dose, while good systemic persistence and blood levels were unaffected by metabolism in the kidney.

Cilastatin I.V.

Peak plasma levels of cilastatin, following a 20-minute intravenous infusion of PRIMAXIN, ranged 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 500 and 1000 mg doses were 42 and 72 mcg/mL respectively. The plasma half-life of cilastatin is approximately one hour. Approximately 70-80% of the dose of cilastatin was recovered unchanged in the urine as the parent medicine within 10 hours of administration of PRIMAXIN. 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 medicine. Activity of dehydropeptidase-I in the kidney returns to normal levels shortly after the elimination of cilastatin from the bloodstream.

Concomitant administration of PRIMAXIN 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%.

Low urinary tract bioavailability of imipenem is avoided by coadministration 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.

Pharmaceutical Precautions

Store at room temperature (EP = 15-25°C). (See also Dosage and Administration section.)

Medicine Classifications

Prescription medicine.

Package Quantities

PRIMAXIN intravenous 1 vial (13 mL) contains 500 mg imipenem and 500 mg cilastatin.

PRIMAXIN intramuscular is not commercially available in New Zealand.

Further Information

Imipenem

The thienamycins are distinguished by novel structural features, the most important of which is the substitution of a methylene (-CH2-) group for the sulphur atom contained in the ring systems of most beta-lactam antibiotics. This substitution makes imipenem more reactive toward proteins in the bacterial cell wall and, therefore, more potent in its bactericidal effect. In further contrast to the penicillins and cephalosporins, the hydroxyethyl side chain of imipenem is attached to the beta-lactam ring in a trans orientation, and this unusual configuration endows imipenem with an unusually high stability to bacterial beta-lactamases.

The chemical name of imipenem is [5R-[5α,6α(R*)]]-6-(1-hydroxyethyl)-3-[[2-[(iminomethyl) amino]ethyl] thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate. The empirical formula of imipenem is C12H17N3O4S.H2O and the molecular weight is 317.37. It is a light tan to white, nonhygroscopic, ultraviolet light-sensitive, crystalline compound which is sparingly soluble in water, and slightly soluble in methanol.

Imipenem, also referred to as N-formimidoyl thienamycin monohydrate, is a semi-synthetic derivative of thienamycin, the parent compound produced by the filamentous bacterium Streptomyces cattleya. The structural formula of imipenem is:

Cilastatin sodium

Cilastatin sodium is a competitive, reversible and specific inhibitor of dehydropeptidase-I, the renal enzyme which metabolises and inactivates imipenem. It is devoid of intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.

The chemical name of the sodium salt of cilastatin is [R-[R*,S*-(Z)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl] amino]-2-heptenoic acid, monosodium salt. The empirical formula of cilastatin sodium is C₁₆H₂₅N₂NaO₅S and the molecular weight is 380.44. It is an off-white to yellowish-white, hygroscopic, amorphous compound which is very soluble in water or methanol. The structural formula of cilastatin sodium is:

Name and Address

Merck Sharp & Dohme (New Zealand) Limited
P O Box 99 851
Newmarket
Auckland
NEW ZEALAND
Tel: 0800 500 673

Date of Preparation

2 November 2007

DP-TEN-1007(021107)

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