SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Amikacin 10 mg/ml solution for infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution for infusion contains 10 mg of amikacin, as amikacin sulphate.

1 bottle of 100 ml contains 1,000 mg of amikacin (as amikacin sulphate). Excipient: Each 100 ml contains 15 mmol (354 mg) sodium.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for infusion A clear colourless aqueous solution

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of the following severe infections due to bacteria susceptible to amikacin (see section 5.1) when less toxic antimicrobial agents are not effective:

-    Nosocomial lower respiratory tract infections including severe pneumonia,

-    Intra-abdominal infections, including peritonitis,

-    Complicated and recurrent urinary tract infections,

-    Skin and soft tissue infections including burn-wound infections,

-    Bacterial endocarditis,

-    Post-operative intra-abdominal infections.

Amikacin 10 mg/ml solution for infusion can also be used in the treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Amikacin 10 mg/ml solution for infusion is commonly used in combination with other appropriate antibiotics to cover the bacterial spectrum encountered in the respective infection.

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

4.2 Posology and method of administration

Amikacin 10 mg/ml solutions for infusion should only be administered by intravenous infusion. The preferred time period is 30 minutes but may be up to 60 minutes.

Patients with normal renal function

Adults;- and adolescents over 12 years (over 33 kg body weight):

The recommended intravenous dosage for adults and adolescents with normal renal function (creatinine clearance >50 ml/min) is 15 mg/kg body weight per day which may be administered as a single daily dose-or divided into 2 equal doses i.e. 7.5 mg/kg body weight every 12 hours.

The total daily dose should not exceed 1.5 g. In endocarditis and in febrile neutropenic patients dosing should be twice daily, as there is not enough data to support once daily dosing.

Infants, toddlers and children:

The recommended intravenous (slow intravenous infusion) dose in children with normal renal function is 15-20 mg/kg/day which may be administered as 15-20 mg/kg, once a day; or as 7.5 mg/kg every 12 hours. In endocarditis and in febrile neutropenic patients dosing should be twice daily, as there is not enough data to support once daily dosing.

Neonates:

An initial loading dose of 10 mg/kg followed by 7.5 mg/kg every 12 h (see sections 4.4 and 5.2).

Premature infants:

The recommended dose in prematures is 7.5 mg/kg in every 12 hours (see sections 4.4 and 5.2).

Infusion volumes in patients with normal renal function:

Body weight

Amikacin 10 mg / ml (100 ml = 1000 mg)

	2.5 kg	5kg	10 kg	12.5 kg	20k g	30kg	40k g	50kg	60kg	70kg	80kg	90kg	100k g
Amika cin in mg
7.5	1.8 8	3.7 5	7.5 0	9.38	15. 00	22.5 0	30.0 0	37.50	45.00	52.50	60.00	67.50	75.00
15	3.7 5	7.5 0	15.0 0	18.7 5	30. 00	45.0 0	60.0 0	75.00	90.00	105.0 0	120.0 0	135.0 0	150.0 0
20	5.0 0	10.0 0	20.0 0	25.0 0	40. 00	60.0 0	80.0 0	100.0 0	120.0 0	140.0 0	160.0 0	180.0 0	200.0 0

Accuracy of dosing is improved if Amikacin 10 mg/ml solution for infusion is administered with an infusion pump.

This is a ready to use formulation which should not be diluted prior to administration and which is for single use only.

To avoid overdosing especially in children, the most appropriate available strength should be chosen.

Specific recommendation for intravenous administration In paediatric patients the amount of diluents used will depend on the amount of amikacin tolerated by the patient. The solution should normally be infused over a 30 to 60 minute period. Infants should receive a 1 to 2 hour infusion.

Maximum daily dose:

In life-threatening infections the dose may be increased to 1.5 g per day but should not be administered for a period longer than 10 days and only under constant monitoring. A maximum total adult dose of 15 g should not be exceeded; other aminoglycoside treatment given previously must be included in this calculation.

Due to the requirement for dose adjustments once daily dosing of amikacin is not recommended for patients with weakened immunity, renal failure, cystic fibrosis, ascites, patients with extensive burns (more than 20% of the skin), elderly patients, and in pregnancy.

Duration of treatment

The total duration of therapy should be limited to 7 to 10 days, depending on severity of infection. In severe and complicated infections, where treatment with amikacin exceeds 10 days, the suitability of treatment with amikacin should be re-evaluated, as eventual treatment continuation requires the monitoring of serum amikacin levels and of renal, auditory and vestibular functions.

Patients with infections caused by susceptible germs should respond to therapy within 24 to 48 hours with the recommended dosage regime. When no clinical

response is seen within three to five days an alternate therapy should be considered.

Monitoring of drug concentration

Blood samples are taken at the end of a dosage interval (trough level) and immediately after the end of the infusion (peak level). The amikacin serum concentrations should be monitored on the second or third day after initiation of treatment and then twice weekly (see section 4.4). The level should not exceed 30 - 35 micrograms/ml at 30 minutes and 90 minutes after the infusion. The trough level should be less than 10 micrograms/ml. Monitoring of plasma concentrations is strongly recommended in patients with renal impairment.

Dosage in patients with impaired renal function

Note: Once daily administration of amikacin is not recommended in patients with renal function disorders (creatinine clearance <50 ml/min).

In renal impairment with a glomerular filtration rate of less than 70 ml/minute, dose reduction or longer dose intervals are advised, because an accumulation of amikacin can be expected. For patients with renal impairment, the loading dose is amikacin 7.5 mg/kg body weight. The dose interval for individual patients is calculated as 9 times the serum creatinine level. If for example the creatinine concentration is 2 mg/100 ml, then the recommended individual dose (7.5 mg/kg body weight) must be administered every 2 x 9 = 18 hours.

For patients with chronic renal failure and known creatinine clearance, the maintenance dose given at intervals of 12 hours is calculated with the formula: (patient creatinine clearance in ml/minute ^ normal creatinine clearance in ml/minute) x amikacin 7.5 mg/kg body weight.

The values presented in the following table may be taken as guidance

Creatinin clearance			Daily dose of amikacin			Dose of amikacin per 12 hours for a patient of 70 kg body weight
[ml/min]			[mg/kg body weight per day]			[mg]
70	-	80	7.6	-	8	266	-	280
60	-	69	6.4	-	7.6	224	-	266
50	-	59	5.4	-	6.4	186	-	224
40	-	49	4.2	-	5.4	147	-	186
30	-	39	3.2	-	4.2	112	-	147
20	-	29	2.1	-	3.1	77	-	112
15	-	19	1.6	-	2.0	56	-	77

Patients undergoing haemodialysis or peritoneal dialysis receive one dose at half the normal strength at the end of the dialysis procedure.

Elderly patients may require lower maintenance doses than younger adults in order to obtain therapeutic concentrations in plasma.

Amikacin is excreted by the renal route. Renal function should be assessed whenever possible and dosage adjusted where appropriate.

Obese patients

Amikacin diffuses poorly into fatty tissue.-The appropriate dose may be calculated using the patient's estimated ideal body weight, plus 40% of the excess, as the weight on which to determine mg/kg. Dose adjustment should be made depending on plasma monitoring. The maximum dose of 1.5 g per day must not be exceeded. The duration of treatment should be limited to 7 to 10 days.

Patients with ascites

Higher doses must be administered in order to obtain adequate serum concentrations in view of the relatively greater distribution in the extracellular fluid compartment.

4.3 Contraindications

-    Hypersensitivity to amikacin or other aminoglycosides or to any of the excipients.

-    Myasthenia gravis.

4.4 Special warnings and precautions for use

Caution is necessary on administration to patients with renal impairment, to patients with auditory or vestibular damage, to patients with neuromuscular disorders, and if patients were treated with another aminoglycoside drug immediately prior to amikacin.

The toxic effects of aminoglycosides, including amikacin, are more frequent in patients with renal impairment, if doses in excess of those recommended are administered, and if the recommended duration of treatment is exceeded. The safety of treatment over periods longer than 14 days has not been established. Other factors that increase the risk of aminoglycoside toxicity include advanced age and dehydration. Daily doses should be reduced and/or the interval between doses extended in the case of signs of renal dysfunction such as: cylindruria, the presence of leukocytes or red blood cells, albuminuria, reduction in creatinine clearance, hypodensity, hyperazotaemia, elevation of serum creatinine and oliguria. Treatment must be discontinued if azotaemia increases or if urine volume decreases gradually. Amikacin therapy should be stopped if tinnitus or subjective hearing loss develops or if follow-up audiograms show significant loss of high-frequency response.

During treatment the patient must be well-hydrated and renal functions should be determined at the onset of treatment, particularly in patients with renal impairment. Renal functions should also be monitored closely during treatment, which is especially important in elderly patients. It is recommended to perform repeat audiometric examinations, especially in the case of patients at high risk. Whenever possible it is recommended to monitor amikacin serum concentrations twice weekly in order to avoid high concentrations that are potentially toxic (see section 4.2).

Administration of aminoglycosides to patients with neuromuscular disease such as for example parkinsonism requires extreme caution, as aminoglycosides act on the neuro-muscular junction similarly to curare and they may thus worsen muscle weakness.

Aminoglycosides applied locally as part of a surgical procedure are quickly and nearly completely absorbed (with the exception of the urinary bladder). In association with irrigation of the surgical field using aminoglycoside preparations (regardless of the extent) development of irreversible deafness, renal failure and death due to neuromuscular blockade have been reported.

Paediatric use

Aminoglycosides should be used with caution in premature and neonatal infants because of the renal immaturity of these patients and the resulting prolongation of serum half-life of these drugs.

The medicinal products contain 15 mmol (or 354 mg) sodium per 100 ml. This is to be taken into consideration for patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

A synergistic antibacterial effect results from the combination with beta-lactam antibiotic drugs.

Concomitant or subsequent administration and systemic or topical administration of other ototoxic or nephrotoxic substances should be avoided in view of the possibility of additive effects. Amikacin toxicity may be increased by the following oto- and/or nephrotoxic substances:

-    Other aminoglycosides

-    Other anti-infective chemotherapeutics e.g.    bacitracin, amphotericin B,

cephalosporins, vancomycin, kanamycin, paromomycin, polymyxin B, colistin

-    Cytostatics: carboplatin (at high doses), cisplatin, oxaliplatin (particularly in cases of pre-existing renal insufficiency)

-    Immunosuppressants: cyclosporine, tacrolismus

-    Rapid acting diuretics e.g. furosemide or ethacrynic acid (functional renal insufficiency due to dehydration, potential ototoxic action by themselves). Irreversible deafness may result.

When amikacin is combined with a potentially nephro- or ototoxic agent, hearing capacity and renal function must be monitored very closely. In the case of concurrent use with a rapid acting diuretic the patient’s hydration status should be monitored.

Amikacin/methoxyflurane anaesthesia

Aminoglycosides may increase the kidney damaging effect of methoxyflurane. When used concurrently, extremely severe neuropathies are possible.

Amikacin/muscle relaxants and other substances

On concurrent treatment with amikacin and a muscle-relaxant drug (e.g. d-tubocurarin), curarising agents, botulinum toxin, polymyxin antibiotics, procainamide, large quantities of citrated blood or inhalation anaesthesia (e.g. halothane) it must be expected that the neuromuscular blockade exerted by those drugs will be increased. In the event of surgery the anaesthetist should be informed that this medicinal product is being administered. Injection of calcium salts may reverse the neuromuscular blockade due to aminoglycosides (see section 4.9).

Indomethacin may increase the plasma concentration of amikacin in neonates.

4.6 Pregnancy and lactation

Pregnancy

There are limited amount of data from the use of aminoglycosides in pregnant women. Aminoglycosides can cause foetal harm. Aminoglycosides cross the placenta and there have been reports of total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although adverse effects on the foetus or newborns have not been reported in pregnant women treated with other aminoglycosides, the potential for harm exists. If amikacin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.

Amikacin 10 mg/ml solution for infusion should not be used during pregnancy unless the clinical condition of the woman requires treatment with amikacin. If treatment is deemed necessary this should only happen under medical supervision (see section 4.4).

Lactation

It is unknown whether amikacin/metabolites are excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Amikacin 10 mg/ml solution for infusion therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Amikacin should be administered to pregnant women and neonatal infants only when clearly needed and under medical supervision (see section 4.4).

Fertility

In reproduction toxicity studies in mice and rats no effects on fertility were reported.

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.

In the case of administration to outpatients, caution is advised when driving and using machines in view of the possible undesired effects such as balance disturbances.

4.8 Undesirable effects

Under certain conditions amikacin shows ototoxic and/or nephrotoxic effects. Renal impairment is uncommonly observed in patients treated with amikacin and is usually reversible upon withdrawal of the drug.

Important note on therapy:

Renal impairment and hearing impairment due to neurological effects can be for the most part avoided with the observance of precautionary measures. Control renal status as well as the senses of hearing and equilibrium before, during and after therapy. Maintain adequate hydration and urine production. Monitor the drug concentration in serum for patients at particular risk and adjust dosage accordingly (see section 4.2).

The adverse reactions considered at least possibly related to treatment are listed below by body system organ class and absolute frequency. The following terminologies have been used in order to classify the occurrence of undesirable effects:

-    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)

-    Not known (cannot be estimated from the available data)

Infections and infestations:
Rare:	Supra-infection or colonisation (with resistant microbes or yeast-like fungi)
Blood and lymphatic system disorders:
Rare:	anaemia, leukopaenia, granulocytopenia, thrombocytopenia, eosinophilia
Immune system disorders:
Rare:	Hypersensitivity reactions3
Very rare:	Anaphylactic shock (isolated cases)
Not known	Cross-allergy between aminoglycosides
Metabolism and nutrition disorders:
Rare:	Hypomagnesaemia
Nervous system disorders:
Uncommon:	Dizziness1, vertigo1
Rare:	Headache, migraine, paraesthesia, tremor
Eye disorders:
Uncommon:	Nystagmus1
Ear and labyrinth disorders:
Uncommon:	Tinnitus1, pressure in the ears1, hearing impairment1
Very rare:	Deafness1 (isolated cases)
Vascular disorders:
Rare:	Hypotension
Respiratory, thoracic and mediastinal disorders:
Rare:	Respiratory function depression4
Very rare:	Respiratory paralysis4 (isolated cases)
Gastrointestinal disorders:
Uncommon:	Nausea1
Rare:	Vomiting
Skin and subcutaneous tissue disorders:
Rare:	Skin rash, exanthema, pruritus, urticaria (hypersensitivity reactions)3
Musculoskeletal and connective tissue disorders:
Rare:	Arthralgia
Very rare:	Neuromuscular blockage
Renal or urinary disorders:
Uncommon:	Damage to renal tubuli2, renal impairment2
Very rare:	Toxic nephropathy, acute renal failure
General disorders and administration site conditions:
Rare:	Drug-related fever3
Investigations:
Rare:	Aspartate aminotransferase increased, Alanine aminotransferase increased, alkaline phosphatase increased (slight and transient)

Further information on particular undesirable effects

(1) These effects were seen in particular when the recommended dosage level was exceeded, in treatment lasting longer than 10 days, or when the dose was not adequately reduced for patients with renal dysfunction. Initial symptoms of vestibular disturbances are dizziness, nausea and vomiting. The clinical examination often reveals a nystagmus. Vestibular disturbances are reversible in almost any case. The first symptoms of

cochlear dysfunction often include a loss of high-tone perception (>4,000 Hertz) that precedes hearing loss and is detected only by audiometry.

(2) Another uncommon adverse effect is damage to the renal tubules with renal impairment. The mechanism of renal damage involves accumulation in the lysosomes, phospholipase inhibition and necrosis of tubular cells after repeated administration of amikacin. Once daily dosing may reduce the risk of nephrotoxicity. Renal damage is reversible to varying degrees but exacerbates the risk of a cumulation process which may cause or intensify ototoxic effects. An increase in the serum creatinine concentration, the presence of albumin, red and white blood cells or cylinders in urine, uraemia and oliguria are possible.

(3) Rare adverse effects are hypersensitivity reactions such as exanthema, itching, hives, and drug fever.

(4) In rare cases, if intravenous infusion of the drug is too fast, respiratory functions may be seriously depressed. In isolated cases this can lead to respiratory paralysis; the risk also exists when amikacin is administered in combination with anaesthesia and muscle relaxants (see section 4.5).

4.9 Overdose

Overdosing may cause nephrotoxicity, ototoxicity or a curarising effect (neuromuscular blockage).

Treatment

In the case of overdose or toxic reactions infusion of amikacin has to be stopped and forced diuresis may be applied to accelerate the removal of amikacin from blood if necessary. Peritoneal dialysis or haemodialysis may help to eliminate amikacin, which accumulates in the blood. Haemodialysis is more effective than peritoneal dialysis in removing amikacin from blood.

An exchange transfusion may be considered in neonates, however, expert advice must be sought before such a measure is implemented.

Calcium salts are indicated to neutralise the curarising effect. Mechanical ventilation may be necessary in respiratory paralysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other aminoglycosides, ATC code: J01GB06

Amikacin is a semisynthetic aminoglycoside antibiotic derived from kanamycin. It was obtained by acylation with an amino-hydroxybutyric acid at the C-1 aminogroup of the 2-deoxystreptamine moiety.

Mode of action

Amikacin acts via the inhibition of protein synthesis at the bacterial ribosome through interaction with the ribosomal RNA and subsequent inhibition of the translation in susceptible microbes. This results in a bactericidal action.

PK/PD relationship

The most important PK/PD parameters to predict the bactericidal effect of amikacin is the ratio of the maximum concentration in serum (Cmax) and the minimal inhibitory concentration (MIC) of the respective pathogen. A C_max/MIC ratio of 8:1 or 10:1 is considered to result in efficient bacterial killing and prevention of bacterial re-growth.

Amikacin shows a post-antibiotic effect in vitro and in vivo. The postantibiotic effect permits the dosage interval to be extended without loss of efficacy against most Gram-negative bacilli.

Mechanism(s) of resistance

Resistance to amikacin may emerge from the following mechanisms:

-    Enzymatic inactivation: An enzymatic modification of the aminoglycoside molecules is the most prevalent resistance mechanism. This is mediated by acetyltransferases, phosphotransferases, or nucleotidyltransferases, which are mainly encoded by plasmids. Amikacin has been shown to be effective against many aminoglycoside-resistant strains due to its ability to resist to degradation by aminoglycoside-inactivating enzymes.

-    Reduced penetration and active efflux: These resistance mechanisms are observed in Pseudomonas aeruginosa. Recent data indicate the emergence of similar resistance mechanisms in Acinetobacter spp.

-    Alteration of the target structure: Modifications within the ribosomes are only occasionally observed as the cause of resistance.

The emergence of resistance during therapy is unusual. A partial crossresistance between amikacin and other aminoglycoside antibiotics exists. Breakpoints

According to EUCAST, the following limit values apply for amikacin:

_Enterococci_

_Streptococci_

_- Group A pyogenes_

_- Group B,C,G_

_- S. pneumoniae_

Aerobic Gram-negative micro-organisms

_Burkholderia cepacia_

_Stenotrophomonas maltophila_

Anaerobes_

Bacteroides spp.

In the elderly with a mean creatinine clearance of 64 ml/min, administration of a dose of 15 mg/kg by a 30 minute i.v. infusion results in a serum concentration of 55 pg/ml at the end of the infusion and 5.4 pg/ml and 1.3 pg/ml, 12 and 24 hours after the end of the infusion, respectively.

In multiple dose studies, no accumulation effects have been shown in people with normal renal function, who have received single daily doses of 15 to 20 mg/kg.

Distribution:

The apparent distribution volume of amikacin is approximately 24 l (28% of body weight). The plasma protein binding rate has been determined at 4% -10%.

After administration of the recommended dose, therapeutic levels of amikacin are found in bone, the heart, the gallbladder, lung tissue, urine, bile, bronchial secretions, sputum, interstitial fluid, pleural fluid and synovial fluid.

It diffuses sufficiently into the liquor of inflamed meninges. Approximately 10% to 20% of the serum concentration passes through healthy meninges, which may rise to 50% when the meninges are inflamed.

The substance accumulates in the renal cortex and inner ear fluid, and it is only slowly eliminated from these deep compartments.

Amikacin passes the placental barrier and is excreted in human milk. Concentrations reaching 20% of those in the mother have been found in foetal blood and in amniotic fluid.

Biotransformation:

Amikacin is not metabolised in the human body.

Elimination:

In patients with normal renal function mean amikacin serum clearance is 100 ml/min and renal clearance is 94 ml/min. Amikacin is eliminated by glomerular filtration as the predominant elimination pathway. Most of the volume (60% - 82%) is excreted unchanged in the urine within the first 6 hours. Only very small amounts are excreted in bile. In patients with normal renal function 91% and 95% of the dose of amikacin (i.m.) are excreted unchanged in urine within 8 and 24 hours, respectively.

Amikacin can be eliminated via haemodialysis and at a lower rate by peritoneal dialysis. Depending on the dialysis method 50% (range 29% - 81%) or 40% - 80% of the administered dose are removed within four or 8 hours, respectively.

Paediatric patients:

Data from multiple daily dose trials show that spinal fluid levels in normal infants are approximately 10 to 20% of the serum concentrations and may reach 50% in meningitis.

Intravenous administration

In neonates and particularly in premature babies, the renal elimination of amikacin is reduced.

In a single study in newborns (1-6 days of post natal age) grouped according to birthweights (<2000, 2000-3000 and >3000g). Amikacin was administered . intramuscularly and/or intravenously at a dose of 7.5 mg/kg. Clearance in neonates >3000 g was 0.84 ml/min/kg and terminal half-life was about 7 hours. In this group, the initial volume of distribution and volume of distribution at steady state was 0.3 ml/kg and 0.5 mg/kg, respectively. In the groups with lower birth weight clearance/kg was lower and half-life longer. Repeated dosing every 12 hours in all the above groups did not demonstrate accumulation after 5 days.

5.3 Preclinical safety data

In repeat-dose toxicity studies, the main effects were nephrotoxicity and ototoxicity.

No studies of the mutagenic or carcinogenic potential of amikacin have been conducted.

In studies on reproduction toxicity, amikacin caused dose-related nephrotoxicity in pregnant rats and their foetuses, and reproductive toxicity studies in offspring of mice, rats and rabbits revealed increased foetal death rates. There is a potential risk of inner ear and renal damage to the foetus as was observed for the class of aminoglycoside antibiotics.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

Amikacin 10 mg/ml are ready-to-use formulations and must not be mixed with any other medicinal products but must be administered separately, in accordance with the recommended dose and method for administration.

On no account may aminoglycosides be mixed in an infusion solution with beta-lactam antibiotics (e.g. penicillins, cephalosporins), as this may cause chemical-physical inactivation of the combination partner.

Chemical incompatibilities are known for amphotericin, chlorothiazides, erythromycin, heparin, nitrofurantoin, novobiocin, phenytoin, sulfadiazine, thiopentone, chlortetracycline, vitamin B, and vitamin C. Amikacin must not be pre-mixed with these medicinal products.

Inactivation when aminoglycosides and beta-lactam antibiotics are mixed may also persist when samples are taken to measure the serum levels of antibiotics and may result in considerable underestimation with dosage errors and risks of toxicity as a consequence. Samples must be handled rapidly and placed in ice or beta-lactamase should be added.

6.3 Shelf life

Unopened: 3 years.

In-use shelf-life (after opening):

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8° C.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions of the opened medicinal product, see section 6.3.

6.5 Nature and contents of container

Bottles of low-density polyethylene, containing 100 ml, available in pack sizes of

10 x 100 ml 20 x 100 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements, immediately after use.

For intravenous use only.

Single use only.

Unused solution should be discarded.

The solution is to be inspected visually for particulate matter and discoloration prior to administration.

Only clear solutions free from particles should be used.

The solution should be administered with sterile equipment using an aseptic technique. The equipment should be primed with the solution in order to prevent air entering the system.

For further information please refer to section 4.2.

7 MARKETING AUTHORISATION HOLDER

B. Braun Melsungen AG Carl-Braun-Strasse 1 34212 Melsungen Germany

Phone: +49/5661/71-0 Fax: +49/5661/71-4567

Postal address:

34209 Melsungen Germany

MARKETING AUTHORISATION NUMBER(S)

PL 03551/0132

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/12/2010

DATE OF REVISION OF THE TEXT

03/06/2011

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