SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Xantum 500/500 mg Powder for Solution for Infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 530.1 mg imipenem equivalent to 500 mg anhydrous imipenem and 530.7 mg cilastatin sodium equivalent to 500 mg cilastatin.

Each vial also contains 37.5 mg (1.63 mmol) of sodium.

When reconstituted (see section 6.6) the solution contains 5 mg/ml of imipenem and 5 mg/ml of cilastatin.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Powder for solution for infusion

White to pale yellow powder

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Imipenem/Cilastatin is indicated for the treatment of the following infections in adults and children 1 year of age and above (see sections 4.4 and 5.1):

•    complicated intra-abdominal infections

•    severe pneumonia including hospital and ventilator-associated pneumonia

•    intra- and post-partum infections

•    complicated urinary tract infections

•    complicated skin and soft-tissue infections

Xantum may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

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

4.2 Posology and method of administration

Posology

The dose recommendations for Xantum represent the quantity of imipenem/cilastatin to be administered.

The daily dose of Xantum should be based on the type and severity of infection, the pathogen(s) isolated, the patient's renal function and body weight (see also section 4.4 and

5.1).

Adults and adolescents

For patients with normal renal function (creatinine clearance of >70 ml/min/1.73 m²), the recommended dose regimens are:

500 mg/500 mg every 6 hours OR

1000 mg/1000 mg every 8 hours OR every 6 hours

It is recommended that infections suspected or proven to be due to less susceptible bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in neutropenic patients with a fever) should be treated with 1000 mg/1000 mg administered every 6 hours.

A reduction in dose is necessary when:

2

-    creatinine clearance is < 70 ml/min/l.73 m (see Table 1) or

-    body weight is < 70 kg. The proportionate dose for patients < 70 kg would be calculated using the following formula:

Actual body weight (kg) X standard dose 70 (kg)

The maximum total daily dose should not exceed 4000 mg/4000 mg per day.

Renal impairment

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

1.    The total daily dose (i.e. 2000/2000, 3000/3000 or 4000/4000 mg) that would usually be applicable to patients with normal renal function should be selected.

2.    From table 1 the appropriate reduced dose regimen is selected according to the patient's creatinine clearance. For infusion times see Method of administration.

*

Table 1: Reduced dose in adults with impaired renal function and body weight >70 kg

Total daily dose for patients	Creatinine clearance (ml/min/1.73 m2)
with normal renal function	41-70	21-40 6-20
(mg/day)	dose in mg (interval hrs)

2000/2000	500/500 (8)	250/250 (6)	250/250 (12)
3000/3000	500/500 (6)	500/500 (8)	500/500 (12) **
4000/4000 ^-1	750/750 (8)	500/500 (6)	500/500 (12) **

A further proportionate reduction in dose administered must be made for patients with a body weight <70 kg. The proportionate dose for patients <70 kg would be calculated by dividing the patient's actual body weight (in kg) by 70 kg multiplied by the respective dose recommended in Table 1.

**When the 500 mg/500 mg dose is used in patients with creatinine clearances of 6 to 20 ml/min/l.73 m², there may be an increased risk of seizures.

2

Patients with a creatinine clearance of <5 ml/min/1.73 m

These patients should not receive Xantum unless haemodialysis is instituted within 48 hours. Patients on haemodialysis

When treating patients with creatinine clearances of <5 ml/min/1.73 m² who are undergoing dialysis use the dose recommendation for patients with creatinine clearances of 6 to 20 ml/min/1.73 m² (see table 1).

Both imipenem and cilastatin are cleared from the circulation during haemodialysis. The patient should receive Xantum after haemodialysis and at 12 hour intervals timed from the end of that haemodialysis session. Dialysis patients, especially those with background central nervous system (CNS) disease, should be carefully monitored; for patients on haemodialysis, Xantum is recommended only when the benefit outweighs the potential risk of seizures (see section 4.4).

Currently there are inadequate data to recommend use of Xantum for patients on peritoneal dialysis.

Hepatic impairment

No dose adjustment is recommended in patients with impaired hepatic function (see section

5.2) .

Elderly

No dose adjustment is required for the elderly patients with normal renal function (see section

5.2) .

Paediatric population >1 year of age

For paediatric patients >1 year of age, the recommended dose is 15/15 or 25/25 mg/kg/dose administered every 6 hours.

It is recommended that infections suspected or proven to be due to less susceptible bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in neutropenic patients with a fever) should be treated with 25/25 mg/kg administered every 6 hours.

Paediatric population <1 year of age

Clinical data are insufficient to recommend dosing for children less than 1 year of age. Paediatric population with renal impairment

Clinical data are insufficient to recommend dosing for paediatric patients with renal impairment (serum creatinine > 2 mg/dl). See section 4.4.

Method of administration

Xantum is to be reconstituted and further diluted (see section 6.2, 6.3 and 6.6) prior to administration. Each dose of <500 mg/500 mg should be given by intravenous infusion over 20 to 30 minutes. Each dose >500 mg/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.

4.3    Contraindications

•    Hypersensitivity to the active substances or to any of the excipients listed in section 6.1

•    Hypersensitivity to any other carbapenem antibacterial agent

•    Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins or cephalosporins).

4.4    Special warnings and precautions for use

General

The selection of imipenem/cilastatin to treat an individual patient should take into account the appropriateness of using a carbapenem antibacterial agent based on factors such as severity of the infection, the prevalence of resistance to other suitable antibacterial agents and the risk of selecting for carbapenem-resistant bacteria.

Hypersensitivity

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. Before initiating therapy with Xantum, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams and other allergens (see section

4.3). If an allergic reaction to Xantum occurs, discontinue the therapy immediately. Serious anaphylactic reactions require immediate emergency treatment.

Hepatic

Hepatic function should be closely monitored during treatment with imipenem/cilastatin due to the risk of hepatic toxicity (such as increase in transaminases, hepatic failure and fulminant hepatitis).

Use in patients with liver disease: patients with pre-existing liver disorders should have liver function monitored during treatment with imipenem/cilastatin. There is no dose adjustment necessary (see section 4.2).

Haematology

A positive direct or indirect Coombs test may develop during treatment with imipenem/cilastatin.

Antibacterial spectrum

The antibacterial spectrum of imipenem/cilastatin should be taken into account especially in life-threatening conditions before embarking on any empiric treatment. Furthermore, due to the limited susceptibility of specific pathogens associated with e.g. bacterial skin and soft-tissue infections, to imipenem/cilastatin, caution should be exercised. The use of imipenem/cilastatin is not suitable for treatment of these types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment. Concomitant use of an appropriate anti-MRSA agent may be indicated when MRSA infections are suspected or proven to be involved in the approved indications. Concomitant use of an aminoglycoside may be indicated when Pseudomonas aeruginosa infections are suspected or proven to be involved in the approved indications (see section 4.1).

Interaction with valproic acid

The concomitant use of imipenem/cilastatin and valproic acid/sodium valproate is not recommended (see section 4.5).

Clostridium difficile

Antibiotic-associated colitis and pseudomembranous colitis have been reported with imipenem/cilastatin and with nearly all other anti-bacterial agents and may range from mild to life-threatening in severity. It is important to consider this diagnosis in patients who develop diarrhoea during or after the use of imipenem/cilastatin (see section 4.8). Discontinuation of therapy with imipenem/cilastatin and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Meningitis

Xantum is not recommended for the therapy of meningitis.

Renal impairment

Imipenem-cilastatin accumulates in patients with reduced kidney function. CNS adverse reactions may occur if the dose is not adjusted to the renal function, see section 4.2 and 4.4 “Central nervous system” in this section.

Central nervous system

CNS adverse reactions such as myoclonic activity, confusional states, or seizures have been reported, especially when recommended doses 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 dose schedules is urged especially in these patients (see section 4.2). Anticonvulsant therapy should be continued in patients with a known seizure disorder.

Special awareness should be made to neurological symptoms or convulsions in children with known risk factors for seizures, or on concomitant treatment with medicinal products lowering the seizures threshold.

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 dose of Xantum should be decreased or discontinued.

2

Patients with creatinine clearances of <5 ml/min/1.73 m should not receive Xantum unless haemodialysis is instituted within 48 hours. For patients on haemodialysis, Xantum is recommended only when the benefit outweighs the potential risk of seizures (see section 4.2)

Paediatric population

Clinical data are insufficient to recommend the use of Xantum in children under 1 year of age or paediatric patients with impaired renal function (serum creatinine >2 mg/dl). See also above under Central nervous system.

Xantum 500 mg/500 mg contains 37.5 mg (1.63 mmol) which should be taken into consideration by patients on a controlled sodium diet.

Interaction with other medicinal products and other forms of interaction

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

Decreases in valproic acid levels that may fall below the therapeutic range have been reported when valproic acid was co-administered with carbapenem agents. The lowered valproic acid levels can lead to inadequate seizure control; therefore, concomitant use of imipenem and valproic acid/sodium valproate is not recommended and alternative antibacterial or anticonvulsant therapies should be considered (see section 4.4).

Oral anti-coagulants

Simultaneous administration of antibiotics with warfarin may augment its anti-coagulant effects. There have been many reports of increases in the anti-coagulant effects of orally administered anti-coagulant agents, including warfarin in patients who are concomitantly receiving antibacterial agents. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the antibiotic to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of antibiotics with an oral anti-coagulant agent.

Concomitant administration of Xantum 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 Xantum was administered with probenecid. Concomitant administration of Xantum and probenecid doubled the plasma level and half-life of cilastatin, but had no effect on urine recovery of cilastatin.

4.6 Fertility, Pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies for the use of Xantum in pregnant women.

Studies in pregnant monkeys have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Xantum should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

Imipenem and cilastatin are excreted into the mother’s milk in small quantities. Little absorption of either compound occurs following oral administration. Therefore it is unlikely that the suckling infant will be exposed to significant quantities. If the use of Xantum is deemed necessary, the benefit of breast feeding for the child should be weighed against the possible risk for the child.

Fertility

There are no data available regarding potential effects of imipenem/cilastatin treatment on male or female fertility.

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, there are some side effects (such as hallucination, dizziness, somnolence, and vertigo) associated with this product that may affect some patients’ ability to drive or operate machinery (see section 4.8).

4.8    Undesirable effects

Summary of the safety profile

In clinical trials including 1,723 patients treated with imipenem/cilastatin intravenous the most frequently reported systemic adverse reactions that were reported at least possibly related to therapy were nausea (2.0%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%) (see section 4.4), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%). Similarly, the most frequently reported local adverse reactions were phlebitis/thrombophlebitis (3.1%), pain at the injection site (0.7%), erythema at the injection site (0.4%) and vein induration (0.2%). Increases in serum transaminases and in alkaline phosphatase are also commonly reported.

The following adverse reactions have been reported in clinical studies or during postmarketing experience.

Tabulated list of adverse reactions

All adverse reactions are listed under system organ class and frequency: Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <1/1,000), Very rare (<1/10,000) and not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class	Frequency	Event
Infections and infestations	Rare	pseudomembranous colitis, candidiasis
	Very rare	gastro-enteritis
Blood and lymphatic system disorders	Common	eosinophilia
	Uncommon	pancytopenia, neutropenia, leucopenia, thrombocytopenia, thrombocytosis
	Rare	agranulocytosis
	Very rare	haemolytic anaemia, bone marrow depression
Immune system disorders	Rare	anaphylactic reactions
Psychiatric disorders	Uncommon	psychic disturbances including hallucinations and confusional

Nervous system disorders

Ear and labyrinth disorders

Cardiac disorders Vascular disorders

Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders

Hepatobiliary disorders

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders Renal and urinary disorders

Reproductive system and breast disorders	Very rare	pruritus vulvae
General disorders and	Uncommon	fever, local pain and induration at
administration site conditions		the injection site, erythema at the injection site
	Very rare	chest discomfort, asthenia/weakness
Investigations	Common	increases in serum transaminases, increases in serum alkaline phosphatase
	Uncommon	A positive direct Coombs' test, prolonged prothrombin time, decreased haemoglobin, increases in serum bilirubin, elevations in serum creatinine, elevations in blood urea nitrogen

Paediatric population (3 months of age)

In studies of 178 paediatric patients >3 months of age, the reported adverse reactions were consistent with those reported for adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9    Overdose

Symptoms of overdose that can occur are consistent with the adverse reaction profile; these may include seizures, confusion, tremors, nausea, vomiting, hypotension, bradycardia. No specific information is available on treatment of overdose with Xantum. Imipenem-cilastatin sodium is haemodialyzable. However, usefulness of this procedure in the overdose setting is unknown.

5.    PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems, ATC code:

J01D H51

Mechanism of action

Xantum consists of two components: imipenem and cilastatin sodium in a 1:1 ratio by weight.

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

Imipenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Grampositive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).

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

Pharmacokinetic/Pharmacodynamic (PK/PD) relationship

Similar to other beta-lactam antibacterial agents, the time that imipenem concentrations exceed the MIC (T>MIC) has been shown to best correlate with efficacy.

Mechanism of resistance

Resistance to imipenem may be due to the following:

•    Decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins)

•    Imipenem may be actively removed from the cell with an efflux pump

•    Reduced affinity of PBPs to imipenem

•    Imipenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of relatively rare carbapenem hydrolysing beta-lactamases. Species resistant to other carbapenems do generally express co-resistance to imipenem. There is no target-based cross-resistance between imipenem and agents of the quinolone, aminoglycoside, macrolide and tetracycline classes.

Breakpoints

EUCAST MIC breakpoints for imipenem to separate susceptible (S) pathogens from resistant (R) pathogens are as follows (v 1,1 2010-04-27):

1

•    Enterobacteriaceae : S <2 mg/l, R >8 mg/l

2

•    Pseudomonas spp. : S <4 mg/l, R >8 mg/l

•    Acinetobacter spp.: S <2 mg/l, R >8 mg/l

3

•    Staphylococcus spp. : Inferred from cefoxitin susceptibility

•    Enterococcus spp.: S <4 mg/l, R >8 mg/l

•    Streptococcus A, B, C, G: The beta-lactam susceptibility of beta-haemolytic streptococcus groups A, B, C and G is inferred from the penicillin susceptibility.

4

•    Streptococcus pneumoniae : S <2 mg/l, R >2 mg/l

4

•    Other streptococci : S <2 mg/l, R >2 mg/l

4

•    Haemophilus influenzae : S <2 mg/l, R >2 mg/l

4

•    Moraxalla catarrhalis : S <2 mg/l, R >2 mg/l

•    Neisseria gonorrhoeae: There is insufficient evidence that Neisseria gonorrhoeae is a good target for therapy with imipenem.

•    Gram-positive anaerobes: S <2 mg/l, R >8 mg/l

•    Gram-negative anaerobes: S <2 mg/l, R >8 mg/l

5

•    Non-species related breakpoints : S <2 mg/l, R >8 mg/l 1

Proteus and Morganella species are considered poor targets for imipenem.

2

The breakpoints for Pseudomonas relate to high dose frequent therapy (1g every 6 hours).

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

4

Strains with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate must be sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant.

5

Non-species related breakpoint have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the overview of species-related breakpoints or footnotes.

Susceptibility

The prevalence of acquired 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.

Gram negative aerobes:

Some strains of Burkholderia cepacia (formerly Pseudomonas cepacia) Legionella spp.

Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia, formerly

_Pseudomonas maltophilia)_

Others:_

Chlamydia spp.

Chlamydophila spp.

Mycoplasma spp.

Ureoplasma urealyticum

■*-

All methicillin-resistant staphylococci are resistant to imipenem/cilastatin.

**

EUCAST non-species related breakpoint is used.

5.2 Pharmacokinetic properties

Imipenem

Absorption

In normal volunteers, intravenous infusion of Xantum over 20 minutes resulted in peak plasma levels of imipenem ranging from 12 to 20 pg/ml for the 250 mg/250 mg dose, from 21 to 58 pg/ml for the 500 mg/500 mg dose, and from 41 to 83 pg/ml for the 1000 mg/1000 mg dose. The mean peak plasma levels of imipenem following the 250 mg/250 mg, 500 mg/500 mg, and 1000 mg /1000 mg doses were 17, 39, and 66 pg/ml, respectively. At these doses, plasma levels of imipenem decline to below 1 pg/ml or less in four to six hours.

Distribution

The binding of imipenem to human serum proteins is approximately 20%.

Biotransformation

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.

Elimination

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.

The plasma half-life of imipenem was one hour. Approximately 70% of the administered antibiotic was recovered intact in the urine within ten hours, and no further urinary excretion of imipenem was detectable. Urine concentrations of imipenem exceeded 10 pg/ml for up to eight hours after a 500 mg/500 mg dose of Xantum. The remainder of the administered dose was recovered in the urine as antibacterially inactive metabolites, and faecal elimination of imipenem was essentially nil.

No accumulation of imipenem in plasma or urine has been observed with regimens of Xantum, administered as frequently as every six hours, in patients with normal renal function.

Cilastatin

Absorption

Peak plasma levels of cilastatin, following a 20 minute intravenous infusion of Xantum, ranged from 21 to 26 pg/ml for the 250 mg/250 mg dose, from 21 to 55 pg/ml for the 500 mg/500 mg dose and from 56 to 88 pg/ml for the 1000 mg/1000 mg dose. The mean peak plasma levels of cilastatin following the 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg doses were 22, 42, and 72 pg/ml respectively.

Distribution

The binding of cilastatin to human serum proteins is approximately 40%.

Biotransformation and elimination

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 cilastatin within 10 hours of administration of Xantum. 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 cilastatin. Activity of dehydropeptidase-I in the kidney returned to normal levels shortly after the elimination of cilastatin from the blood stream.

Renal impairment

Following a single 250 mg/250 mg intravenous dose of Xantum, the area under the curve

(AUCs) for imipenem increased 1.1-fold, 1.9-fold, and 2.7-fold in subjects with mild

2

(Creatinine Clearance (CrCL) 50-80 ml/min/1.73 m ), moderate (CrCL 30-<50 ml/min/1.73

2 2

m ), and severe (CrCL <30 ml/min/1.73 m ) renal impairment, respectively, compared to

2

subjects with normal renal function (CrCL >80 ml/min/1.73 m ), and AUCs for cilastatin increased 1.6-fold, 2.0-fold, and 6.2-fold in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. Following a single 250 mg/250 mg intravenous dose of Xantum given 24 hours after haemodialysis, AUCs for imipenem and cilastatin were 3.7-fold and 16.4-fold higher, respectively, as compared to subjects with normal renal function. Urinary recovery, renal clearance and plasma clearance of imipenem and cilastatin decrease with decreasing renal function following intravenous administration of Xantum. Dose adjustment is necessary for patients with impaired renal function (see section 4.2).

Hepatic impairment

The pharmacokinetics of imipenem in patients with hepatic insufficiency have not been established. Due to the limited extent of hepatic metabolism of imipenem, its pharmacokinetics are not expected to be affected by hepatic impairment. Therefore, no dose adjustment is recommended in patients with hepatic impairment (see section 4.2).

Paediatric population

The average clearance (CL) and volume of distribution (Vdss) for imipenem were approximately 45% higher in paediatric patients (3 months to 14 years) as compared to adults. The AUC for imipenem following administration of 15/15 mg/kg per body weight of imipenem/cilastatin to paediatric patients was approximately 30% higher than the exposure in adults receiving a 500 mg/500 mg dose. At the higher dose, the exposure following administration of 25/25 mg/kg imipenem/cilastatin to children was 9% higher as compared to the exposure in adults receiving a 1000 mg/1000 mg dose.

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 Xantum 500 mg/500 mg administered intravenously over 20 minutes were consistent with those expected in subjects with slight renal impairment for which no dose alteration is considered necessary. The mean plasma half-lives of imipenem

and cilastatin were 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 was observed (see section 4.2).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on repeated dose toxicity and genotoxicity studies.

Animal studies showed that the toxicity produced by imipenem, as a single entity, was limited to the kidney. Co-administration of cilastatin with imipenem in a 1:1 ratio prevented the nephrotoxic effects of imipenem in rabbits and monkeys. Available evidence suggests that cilastatin prevents the nephrotoxicity by preventing entry of imipenem into the tubular cells.

A teratology study in pregnant cynomolgus monkeys given imipenem-cilastatin sodium at doses of 40/40 mg/kg/day (bolus intravenous injection) resulted in maternal toxicity including emesis, inappetence, body weight loss, diarrhoea, abortion, and death in some cases. When doses of imipenem-cilastatin sodium (approximately 100/100 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 (see section 4.6).

Long term studies in animals have not been performed to evaluate carcinogenic potential of imipenem-cilastatin.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydrogen carbonate

6.2 Incompatibilities

Imipenem/Cilastatin is chemically incompatible with lactate and should not be reconstituted with solvent containing lactate. Imipenem/Cilastatin can, however, be administered into an IV tubing through which a lactate solution is being infused. Imipenem/Cilastatin should not be mixed or physically added to other antibiotics.

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

6.3 Shelf life

Unopened:

2 years

Reconstituted solution:

This product should be used immediately after reconstitution.

Compatibility and stability

In keeping with good clinical and pharmaceutical practice, Imipenem/Cilastatin should be administered as a freshly prepared solution 0.9 % Sodium Chloride is used as solvent.

For the precaution for handling please refer section 6.6

6.4 Special precautions for storage

Store below 25°C. Keep the vial/infusion bottle in the outer carton.

6.5 Nature and contents of container

Xantum 500 mg/500 mg Powder for Solution for Infusion is available in a Type I clear glass infusion bottle with a bromobutyl rubber plug and polypropylene flip-off seal.

The bottle size is 100 ml.

Pack size:    1 infusion bottle

10 infusion bottles (5x2)

Xantum 500 mg/500 mg Powder for Solution for Infusion is available in a 22 ml ‘monovial’, which consists of a Type 1 clear glass vial with chlorobutyl rubber plug and transfer set consisting of capsule needle guard, overcap and “O” sealing ring.

Pack size:    1 vial

Xantum 500 mg/500 mg Powder for Solution for Infusion is also available in a 30 ml clear glass Type 1 vial with grey bromobutyl rubber plug and polypropylene flip off seal.

6.6 Special precautions for disposal

Preparation of intravenous solution

The following table is provided for convenience in reconstituting Imipenem/Cilastatin for intravenous infusion. 0.9 % sodium chloride intravenous infusion is the recommended solvent

Strength	Volume of solvent (0.9% Sodium Chloride) added (ml)	Approximate concentration of imipenem (mg/ml)
Imipenem/Cilastatin 500mg/500mg	100	5

Addition of Imipenem/Cilastatin in a Monovial to an infusion solution

1.    Check before use that there is no foreign material in the powder and that the seal between the cap and the vial is intact.

2.    Remove the cap by twisting and pulling until the seal breaks.

3.    The cannula is inserted into the addition port of the infusion bag. Push the cannula protector against the vial until you hear a click.

4.    Hold the vial upright and squeeze the infusion bag a few times so that 2/3 of the vial is filled with the solvent (0.9 % Sodium Chloride). Shake the vial until the powder is completely dissolved.

5.    Invert the vial and transfer the content of the vial back into the infusion bag by squeezing the infusion bag.

Repeat steps 4 and 5 until the vial is completely empty.

6.    A part of the label of the vial may be detached and affixed to the infusion bag.

The bottle can be removed or can remain on the infusion bag.

Preparation of intravenous solution (30ml vial)

The following table is provided for convenience in reconstituting

Imipenem/Cilastatin for intravenous infusion. Strength	Volume of solvent (0.9% Sodium Chloride) added (ml)	Approximate concentration of imipenem (mg/ml)
Imipenem/Cilastatin 500mg/500mg	100	5

The preparation of the intravenous solution must be performed in appropriate conditions and environment.

Contents of the vials must be suspended and transferred to 100 ml of an appropriate infusion solution (see section Compatibility and stability). A suggested procedure is:

1.    Check before use that there is no foreign material in the powder and that the seal between the cap and the vial is intact.

2.    Remove the cap by twisting and pulling until the seal breaks.

3.    Add approximately 10 ml from the appropriate infusion solution to the vial. Shake well

4.    Transfer the resulting suspension to the infusion solution container

5.    Repeat the step 3 and 4.

CAUTION: THE SUSPENSION IS NOT FOR DIRECT INFUSION.

6.    The resulting mixture should be agitated until clear.

The reconstituted solution should be inspected visually for particulate matter and discoloration prior to administration. Variations of colour, from colourless to yellow, do not affect the potency of the product.

Any unused solution and the vial should be adequately disposed of, in accordance with local requirements.

After reconsitution: The product should be used immediately.

7. MARKETING AUTHORISATION HOLDER

Ranbaxy (UK) Limited 5 th floor, Hyde Park, Hayes 3 11 Millington Road Hayes, UB3 4AZ United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 14894/0666

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 02 Septmeber 2009 Date of latest renewal: 28 July 2012

10 DATE OF REVISION OF THE TEXT

10/08/2016