Imipenem/Cilastatin 500 mg/500 mg Powder for Solution for Infusion

Each vial contains 530 mg of Imipenem monohydrate and 530 mg of Cilastatin sodium corresponding to 500 mg of Imipenem and 500 mg of Cilastatin.

Content: 1.6 mmol (37.5 mg) of sodium/vial

For a full list of excipients, see section 6.1.

Powder for solution for infusion.

Off white to yellowish white hygroscopic powder.

Treatment of the following severe infections due to susceptible organisms (see section 4.4 and 5.1):

• Nosocomial pneumonia or complicated community acquired pneumonia requiring hospitalisation

• Complicated intra-abdominal infections

• Complicated genito-urinary infections

• Complicated skin and soft tissue infections

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

For intravenous administration only

The dosage of imipenem/cilastatin should be based on the type or severity of infection, consideration of degree of susceptibility of the pathogen(s), renal function and bodyweight. The total daily requirement should be given in equally divided doses.

For instructions on dilution of the medicinal product, see section 6.3 and section 6.6.

The dosage recommendations that follow specify the amounts of imipenem to be given. One vial of Imipenem/Cilastatin 500 mg/500 mg provides the equivalent of 500 mg imipenem and 500 mg cilastatin.

Adults

Doses cited are based on a bodyweight of 70 kg. The usual adult daily dosage is 1.5 – 2 g administered in 3 – 4 equally divided doses (see chart below). In infections due to less sensitive organisms, the daily dose may be increased to a maximum dose of 50 mg/kg/day (not exceeding 4 g daily).

Usual adult intravenous dosage

Each dose of 250 mg or 500 mg should be given by intravenous infusion over 20 – 30 minutes. Each dose of 1000 mg should be infused over 40 – 60 minutes. In patients who develop nausea during infusion, the infusion rate may be slowed.

IVadministration

* primarily some strains of P.aeruginosa

Use in elderly patients

Age does not usually affect the tolerability and efficacy of imipenem/cilastatin.

In patients with renal insufficiency

As in patients with normal renal function, dosing is based on the severity of the infection. The dosage for patients with various degrees of renal functional impairment is shown in the following table. Doses cited are based on a bodyweight of 70 kg. proportionate reduction in dose administered should be made for patients with lower bodyweight.

Maximum dosage in relation to renal function

* The higher dose should be reserved for infections caused by less susceptible organisms.

** Patients with creatinine clearance of 6-20 ml/min should be treated with 250 mg (or 3.5 mg/kg, whichever is lower) every 12 hours for most pathogens. When the 500 mg dose is used in these patients there may be an increased risk of convulsions.

Patients with a creatinine clearance of 5 ml/min should not receive imipenem/cilastatin unless haemodialysis is started within 48 hours. Imipenem/cilastatin is cleared by haemodialysis. The patient should receive imipenem/cilasatin immediately after haemodialysis and at 12-hourly intervals thereafter. Dialysis patients, especially those with background CNS disease, should be carefully monitored. Patients on haemodialysis should receive imipenem/cilastatin only when the benefit outweighs the potential risk of convulsions (see section 4.4).

There are currently inadequate data to recommend the use of imipenem/cilastatin for patients on peritoneal dialysis.

Paediatric dosage

The maximum daily dose should not exceed 2 g.

Children and adolescents over 40 kg bodyweight should be dosed as adults.

Clinical data are insufficient to recommend an optimal dose for children under 3 years of age or infants and children with impaired renal function (serum creatinine >177 µmol/l).

Imipenem/cilastatin is not recommended for treatment of meningitis. If meningitis is suspected an appropriate agent should be used.

Hypersensitivity to imipenem, cilastatin or any of the excipients.

Hypersensitivity to any other beta-lactam type antibiotic (e.g. penicillin, cephalosporin).

Imipenem/cilastatin should only be used in severe or complicated infections suspected or due to bacteria resistant to other beta-lactams and susceptible to imipenem/cilastatin.

Warning

There is some clinical and laboratory evidence of partial cross-allergenicity between imipenem/cilastatin and the other beta-lactam antibiotics, penicillins and cephalosporins. Severe reactions (including anaphylaxis) have been reported with most beta-lactam antibiotics.

Before initiating therapy with imipenem/cilastatin, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. If an allergic reaction to imipenem/cilastatin occurs, the drug should be discontinued and appropriate measures undertaken.

Pseudomembranous colitis, reported with virtually all antibiotics, can range from mild to life-threatening in severity. Imipenem/cilastatin should be prescribed with caution in patients with a history of gastro-intestinal disease, particularly colitis. Treatment-related diarrhoea should always be considered as a pointer of diagnosis. While studies indicate that a toxin of Clostridium difficile is one of the primary causes of antibiotic-associated colitis, other causes should be considered.

In case of long-term-treatment liver and renal function as well as blood values should be controlled regularly.

Paediatric use

The clinical data demonstrating the efficacy and safety of imipenem/cilastatin in children is rather limited. Therefore, caution should be exercised when administering this drug to children 3 years and above. Efficacy and tolerability in children under 3 years of age have yet to be established; therefore, imipenem/cilastatin is not recommended for use below this age.

Efficacy and tolerability in children with renal impairment has not been yet established.

Central nervous system

Note: Imipenem/cilistatin is not indicated against central nervous system infections.

Patients with CNS disorders and/or compromised renal function (accumulation of imipenem/cilastatin may occur) have shown CNS side effects, especially when recommended dosages based on bodyweight and renal function were exceeded. Hence it is recommended that the dosage schedules of imipenem/cilastatin should be strictly adhered to, and established anticonvulsant therapy continued.

If focal tremors, myoclonus or convulsions occur, the patient should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If these symptoms continue, the dosage should be reduced, or imipenem/cilastatin withdrawn completely.

Under the treatment of imipenem/cilastatin asthenia and the aggravation of myasthenia gravis may occur. Therefore, in case of any symptom indicating an exacerbation of myasthenia gravis a physician must be consulted.

Use in patients with renal insufficiency

Patients with creatinine clearances of < 5 ml/min should not receive imipenem/cilastatin unless haemodialysis is instituted within 48 hours. For patients on haemodialysis, imipenem/cilastatin is recommended only when the benefit outweighs the potential risk of convulsions.

This product contains 1.6 mmol (37.5 mg) of sodium per 500 mg dose. To be taken into consideration by patients on a controlled sodium diet.

General seizures have been reported in patients who received ganciclovir and imipenem/cilastatin. These drugs should not be used concomitantly unless the potential benefit outweighs the risk. Also the prodrug valganciclovir can provoke seizures in combination with imipenem/cilastatin .

Concomitant probenecid has been shown to double the plasma level and half-life of cilastatin, but with no effect on its urinary recovery.

Concomitant probenecid showed only minimal increases in plasma level and half-life of imipenem, with urinary recovery of active imipenem decreased to approximately 60% of the administered dose.

After co-administration with carbapenem agents, decreased plasma concentrations of valproic acid have been observed. The lowered valproic acid concentration can lead to inadequate seizure control. Alternative antibacterial agents should be considered. If imipenem and valproic acid are concomitantly administered, serum valproic acid concentrations should be closely monitored.

Imipenem cilastatin may cause positive Coombs test results.

Pregnancy

There are no adequate data for the use of imipenem/cilastatin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore imipenem/cilastatin should not be given in pregnancy unless the anticipated benefit to the mother outweighs the possible risk to the foetus.

Lactation

Imipenem/cilastatin has been detected in human milk. If the use of imipenem/cilastatin is deemed essential, the mother should stop breast-feeding.

No studies on the effects on the ability to drive and use machines have been performed.

The evaluation of adverse reactions is based on the following definition of frequency:

Very common (1/10)

Common (1/100 to <1/10)

Uncommon (1/1,000 to <1/100)

Rare (1/10,000 to <1/1000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

The following reactions are rare, very rare, and/or their frequency cannot be estimated from the available data, but they may be serious:

- Anaphylactic reactions: angioedema, toxic epidermal necrolysis/Stevens-Johnson syndrome, exfoliative dermatitis, acute renal failure

- Pseudomembranous colitis

- Seizures or convulsions

Such patients should receive immediate medical attention.

Infections and infestations

Rare: superinfections with Candida or Stenotrophomonas maltophilia

Blood and lymphatic system disorders

Common: eosinophilia, thrombocytosis

Uncommon: leucopenia, decreased haemoglobin and prolonged prothrombin time. A positive direct Coombs test may develop

Rare: neutropenia including agranulocytosis, thrombocytopenia, haemolytic anaemia

Very rare: depression of the bone marrow

Immune system disorders

Rare: erythema multiforme, anaphylactic reactions, severe allergic reactions (immediately)

Nervous system disorders

Uncommon: myoclonic activity, somnolence, dizziness, vertigo, headache, psychic disturbances, including hallucinations, paraesthesia, confusional states or convulsions

Rare: encephalopathy

Ear and labyrinth disorders

Rare: hearing loss

Not known: tinnitus

Cardiac disorders

Rare: hypotension

Not known: tachycardia, palpitations

Respiratory, thoracic and mediastinal disorders

Very rare: hyperventilation, dyspnoea

Gastrointestinal disorders

Uncommon: nausea, vomiting, diarrhoea, staining of teeth and/or tongue

Rare: pseudomembranous colitis, taste perversion

Not known: haemorrhagic colitis, gastro-enteritis, abdominal pain, glossitis, tongue papillar hypertrophy, heartburn, pharyngeal pain, increased salivation

Drug-related nausea and/or vomiting appear to occur more frequently in granulocytopenic patients than in non-granulocytopenic patients treated with inipenem/cilastatin.

Hepato-biliary disorders

Common: mild increases in serum transaminases, bilirubin and/or serum alkaline phosphatase

Rare: hepatitis with liver failure

Very rare: fulminant hepatitis

Skin and subcutaneous tissue disorders

Common: rash, pruritus, urticaria

Rare: erythema multiforme, Stevens-Johnson syndrome, angioedema, toxic epidermal necrolysis, exfoliative dermatitis

Not known: flushing, cyanosis, hyperhidrosis, skin texture changes, pruritus vulvae

Musculoskeletal and connective tissue disorders

Very rare: asthenia and aggravation of myasthenia gravis

Not known: polyarthralgia and chest discomfort/pain

Renal and urinary disorders

Rare: oliguria/anuria and polyuria

Very rare: acute renal failure, elevated serum creatinine and blood urea, a harmless urine discoloration, not to be confused with haematuria, has been seen in children

General disorders and administration site conditions

Common: erythema, local pain and induration, thrombophlebitis

Rare: asthenia/weakness

Unknown: fever including drug fever

No specific information is available on the treatment of overdose with the product. Imipenem and cilastatin are haemodialysable. However, the usefulness of this procedure in the event of overdose is unknown.

General properties

ATC classification:

Pharmacotherapeutic group: Antibacterial agents for systemic use, carbapenems

ATC Code: J01D H51

Mode of action

Imipenem is a potent inhibitor of bacterial cell wall synthesis and is highly reactive towards penicillin-binding protein. Imipenem is more potent in its bactericidal effect than other antibiotics studied.

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

PK/PD relationship

Imipenem exhibits primarily time-dependent killing. In common with other beta-lactams, the main PK/PD parameter that correlates with therapeutic efficacy is the time that concentrations in serum and tissue are above the MIC for the pathogens (t>MIC).

Mechanism(s) of resistance

Imipenem is effectively stable to hydrolysis by most classes of beta-lactamases, including penicillinases, cephalosporinases and extended spectrum beta-lactamases, but not metallo-beta-lactamases. Resistance is generally due to a combination of decreased permeability and low-level beta-lactamase hydrolysis.

The mechanism of action of imipenem differs from that of other classes of antibiotics, such as quinolones, aminoglycosides, macrolides and tetracyclines. There is no target-based cross-resistance between imipenem and these substances. However, micro-organisms may exhibit resistance to more than one class of antibacterial agents when the mechanism is, or includes, impermeability to some compounds.

Breakpoints

EUCAST Breakpoints

Organism	Sensitive	Resistant
Enterobacteriaceae	2 mg/L	>8 mg/L
Pseudomonas	4 mg/L	>8 mg/L
Acinetobacter spp.	2 mg/L	>8 mg/L
Enterococcus spp.	4 mg/L	>8 mg/L
Streptococcus spp. (Groups A, B, C, G)	2 mg/L	>2 mg/L
Streptococcus pneumoniae	2 mg/L	>2 mg/L
Haemophilus .influenzae	2 mg/L	>2 mg/L
Moraxella catarrhalis	2 mg/L	>2 mg/L
Gram-negative anaerobes	2mg/L	>8 mg/L
Gram positive anaerobes	2mg/L	>8 mg/L
Non-species related breakpoints	2 mg/L	>8 mg/L

Susceptibility of staphylococci to carbapenems is inferred from the methicillin susceptibility.

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species

Aerobic Gram-positive

Enterococcus faecalis

Staphylococcus aureus (Methicillin-susceptible)

Staphylococcus coagulase negative (Methicillin-susceptible)

Streptococcus agalactiae

Streptococcus pneumoniae

Streoticiccus pyogenes

“Viridans group” streptococci

Aerobic Gram-negative

Acinetobacter baumannii

Citrobacter freundii

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Klebsiella exytoca

Klebsiella pneumoniae

Moraxella catarrhalis

Serratia marcescens

Anaerobic

Bacteroides fragilis

Fusobacterium spp.

Peptococcus spp.

Peptostreptococcus spp.

Prevotella spp.

Veillonella spp.

Clostridium spp. (except Clostridium difficile)

Species for which acquired resistance may be a problem

Aerobic Gram-positive

Enterococcus faecium+

Aerobic Gram-negative

Pseudomonas aeruginosa

Inherently resistant organisms

Aerobic Gram-positive

Staphylococcus (Methicillin-resistant)

Aerobic Gram-negative

Stenotrophomonas maltophilia

Anaerobic Gram-positive

Clostridium difficile

Others

Chlamydia spp.

Chlamydophila spp.

Mycoplasma spp.

Legionella pneumophila

Ureaplasma urealyticum

+ Species for which high rates of resistance (> 50%) have been observed in some European countries.

After oral administration, imipenem is not significantly absorbed. After i.v. administration of 500 mg, maximale plasma levels of about 36 µg/ml are observed. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem/cilastatin is observed.

Distribution:

Imipenem is bound to plasma proteins for about 20% and cilastatin for about 40%. The volume of distribution is approximately 10 l for both drugs.

Metabolism:

Imipenem is mainly metabolised in the proximal renal tubuli by dehydropeptidase I into the inactive open ring metabolite, resulting in relative low urinary imipenem concentrations. Imipenem systemic metabolism accounts for about 30%. Cilastatin, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem, resulting in higher imipenem urinary concentrations.

Cilastatin is partly metabolised to N-acetyl-cilastatin in the kidneys.

Elimination:

The plasma clearance of imipenem is 225 ml/min and that of cilastatin about 200 ml/min. Concomitant administration results in a decrease of the imipenem plasma clearance to about 195 ml/min, and an increase in renal clearance, urinary recovery and urinary concentrations. The plasma clearance of cilastatin is not affected. The elimation half-life is about 1 h for imipenem as well as for cilastatin. Approximately 70% of the administered imipenem dose is excreted intact in urine, and approximately 70-80% of the cilastatin dose.

Special patient groups:

Elderly:

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 subjects with slight renal impairment for which no dosage alteration is considered necessary.

Patients with renal impairment:

Imipenem plasma clearance is decreased approximately 40% in subjects with moderate renal impairment to 70% in patients with severe renal impairment. In addition the elimination half-life is increased to approximately 2.5 hours. Haemodialysis patients have an elimination half-life of about 3.4 hours. Cilastatin clearance is decreased approximately 50% in subjects with moderate renal impairment to 80% in patients with severe renal impairment. In addition the elimination half-life is increased to approximately 4 hours. Haemodialysis patients have an elimination half-life of about 12 hours. During haemodialysis a higher clearance is observed for imipenem and cilastatin.

Children:

The volume of distribution of imipenem and cilastatin in children is slightly higher than in adults. The elimination half-life for imipenem is about 1 h, and that for cilastatin about 40 min. 50-70% of the administered imipenem/cilastatin dose is excreted in urine.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and mutagenicity. No long-term carcinogenicity studies of imipenem and cilastatin sodium have been performed. In studies on reproductive toxicity, no effects of imipenem/cilastatin but weight losses of foetuses in the fertility study were observed in rats. No teratogenicity was observed in mice. Pregnant monkeys showed evidence of maternal and foetal toxicity with bolus injections of imipenem/cilastatin at doses equivalent to twice the human dose.

Sodium hydrogen carbonate

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

The product is chemically incompatible with lactate and must not be reconstituted in solutions that contain it. However, it can be administered into an IV tubing, through which a lactate solution is to be infused.

The product must not be mixed or physically added to other antibiotics.

Unopened:

2 years

After reconstitution and dilution:

Reconstituted and diluted solution should be used immediately.

This medicinal product does not require any special storage conditions.

After first opening/dilution (In use):

Do not freeze.

For storage conditions of the reconstituted/diluted product see section 6.3.

• 20 ml Type I glass vials with a bromo butyl rubber stopper and red flip off seal.

Pack size: 5 vials per carton

• 100 ml Type I glass vials with a bromo butyl rubber stopper and royal blue flip off seal.

Pack size: 1 vial per carton

Not all pack sizes may be marketed.

Reconstitution of the intravenous solution

The product is supplied as dry sterile powder in vials containing the equivalent of 500 mg of imipenem and 500 mg of cilastatin.

The product is buffered with sodium hydrogen carbonate, in order to obtain pH solutions between 6.5 and 8.5. There is no significant modification of the pH when the solutions are prepared and used as indicated. The product contains 37.5 mg of sodium (1.6 mmol).

For single use only. Discard any unused solution.

The reconstitution of powder is to be made under aseptic conditions using the diluents mentioned below. The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if it is clear and free from particles.

Reconstituted solution stability has been established for 0.9% sodium chloride injection and sterile Water for Injections.

Reconstitution of the 100 ml vial

The sterile powder must be reconstituted as directed below. It must be shaken until a clear solution is obtained allowing 3-4 minutes to reconstitute the powder. The variations in colour, from colourless to yellow, do not affect the potency of the product.

Reconstitution of the 20 ml vial

The contents of the vial must be suspended and transferred to 100 ml of an appropriate solution for infusion. A suggested procedure is to add approximately 10 ml of appropriate infusion solution to the vial. Shake well and transfer the resulting suspension to the infusion solution container

Caution: The suspension is not for direct infusion.

Repeat with an additional 10 ml of infusion solution to ensure complete transfer of the vial contents to the infusion solution. The resulting mixture must be shaken until clear.

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire CV31 3RW

UK

PL 04515/0237

29/07/2010

29/07.2010