Vancomycin 500 Mg Powder For Concentrate For Solution For Infusion
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Vancomycin 500 mg Powder for Concentrate for Solution for Infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 500 mg vancomycin (equivalent to 525,000 IU) (as vancomycin hydrochloride). When reconstituted with 10 ml of water for injections, the resulting concentrate for solution for infusion contains 50 mg/ml vancomycin.
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for Concentrate for Solution for Infusion. A white crystalline powder
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Intravenous vancomycin is indicated in the following severe infections caused by gram-positive bacteria susceptible to vancomycin which cannot be treated with or failed to respond or are resistant to other antibiotics such as penicillins and cephalosporins.
■ endocarditis
■ infections of the bones (osteitis, osteomyelitis)
■ pneumonia
■ soft-tissue infections
Endocarditis caused by enterococci, S. viridans or S. bovis should be treated with a combination of vancomycin and an aminoglycoside.
Vancomycin may be used for the perioperative prophylaxis against bacterial endocarditis, in patients at high risk of developing bacterial endocarditis when they undergo major surgical procedures (e.g., cardiac and vascular procedures, etc) and are unable to receive a suitable beta-lactam antibacterial agent.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
Vancomycin Powder for Concentrate for Solution for Infusion must be administered intravenously (by infusion).
Each intravenous dose should be administered at a rate not exceeding 10 mg/min and over a period of time of at least 60 minutes in concentrations not exceeding 5 mg/ml (500 mg diluted in at least 100 ml and 1 g1000 mg in at least 200 ml of appropriate diluent). In some patients in need of restricted fluid intake, solutions up to 10 mg/ml may be used (500mg/50 ml or 1000mg/100ml). However, the use of higher concentrations may increase the risk of infusion-related adverse events reactions (see section 4.8).
The dose should be individually adapted according to weight, age and renal function.
The following dosage regimens are recommended:
Intravenous administration
Patients with normal renal function
Adults, adolescents and children from the age of 12 years:
The recommended daily intravenous dose is of 2 g, divided into doses of 500 mg every 6 hours or 1 g every 12 hours.
For bacterial endocarditis, the generally accepted regimen is 1000 mg vancomycin intravenously every 12 hours for 4 weeks either alone or in combination with other antibiotics (gentamicin plus rifampin, gentamicin, streptomycin). Enterococcal endocarditis is treated for 6 weeks with vancomycin in combination with an aminoglycoside - according to national recommendations.
Peri-operative prophylaxis against bacterial endocarditis: Adults receive 1000 mg vancomycin intravenously prior to surgery (prior to induction of anaesthesia) and depending on time and type of surgery, the dose of 1000 mg of vancomycin i.v. 12 hours postoperatively can be given.
Children one month to 12 years of age:
The recommended intravenous dose is 10 mg/kg, every 6 hours.
Infants and newborns:
The recommended initial dose is 15 mg/kg, followed by 10 mg/kg every 12 hours during the first week of life and every 8 hours after that age and up to 1
month of age. Careful monitoring of serum concentration of vancomycin is recommended (see below).
Elderly patients:
Lower maintenance doses may be required due to the age-related reduction in renal function.
Obese patients:
Modification of the usual daily doses may be required.
Patients with impaired renal function
The dose must be adjusted in patients with impaired renal function and the following nomogram can serve as guidance. Careful monitoring of serum concentration of vancomycin is recommended (see below).
|
POSOLOGY FOR VANCOMYCIN IN PATIENTS WITH RENAL FAILURE | |
|
Creatinine clearance (ml/min) |
Dose of vancomycin (mg/24 hours) |
|
100 |
1,545 |
|
90 |
1,390 |
|
80 |
1,235 |
|
70 |
1,080 |
|
60 |
925 |
|
50 |
770 |
|
40 |
620 |
|
30 |
465 |
|
20 |
310 |
|
10 |
155 |
Creatinine clearance (ml/s)
0.50
1.00
1.50
1.545 1.390 1.235 1.080
925 770 620 465 310
Creatinine clearance (ml/min)
Dosing nomogram for adults with impaired renal function
In patients with mild or moderate renal failure, the starting dose must not be less than 15 mg/kg. In patients with severe renal failure, it is preferable to administer a maintenance dose between 250 mg and 1 g at a spacing of several days rather than administer lower daily doses.
Patients with anuria (with practically no renal function) should receive a dose of 15 mg/kg body weight until the therapeutic serum concentration is reached. The maintenance doses are 1.9 mg/kg body weight per 24 hours. In order to facilitate the procedure, adult patients with strongly impaired renal function may obtain a maintenance dose of 250 - 1000 mg at intervals of several days instead of a daily dose.
Dosage in case of hemodialysis
For patients without any renal function, even under regular hemodialysis, the following dosage is also possible:
Saturating dose 1000 mg, maintenance dose 1000 mg every 7 - 10 days.
If polysulfone membranes are used for hemodialysis („high flux dialysis“), the half time of vancomycin is shortened. For patients with regular hemodialysis an additional maintenance dose may be necessary.
Patients with hepatic insufficiency
There is no evidence that the dose has to be reduced in patients with hepatic insufficiency.
Monitoring of vancomycin serum concentrations
The serum concentration of vancomycin should be monitored at the second day of treatment immediately prior to the next dose, and one hour post infusion. Therapeutic vancomycin blood levels should be between 30 and 40 mg/l (maximum 50 mg/l) one hour after the end of the infusion, the minimum level (short prior to the next administration) between 5 and 10 mg/l.
The concentrations should normally be monitored twice or three times per week.
Method of administration
Parenterally vancomycin shall only be administered intravenously by slow infusion (not more than 10 mg/min - over at least 60 min) which is sufficiently diluted (at least 100 ml per 500 mg or at least 200 ml per 1 g). Patients requiring fluid restriction can receive a solution of 500 mg / 50 ml or 1 g / 100 ml. With these higher concentrations the risk for infusion related adverse reactions can be increased.
For information about the preparation of the solution, please refer to section 6.6.
Duration of treatment
The duration of the treatment depends on the severity of the infection as well as on the clinical and bacteriological progress.
4.3 Contraindications
Hypersensitivity to vancomycin.
4.4 Special warnings and precautions for use
Warnings:
In the presence of acute anuria or cochlear damage, vancomycin must be used only on vital indications.
In case of severe acute hypersensitivity reactions (e.g. anaphylaxis), the treatment with vancomycin has to be discontinued immediately and the usual appropriate emergency measures have to be started (e.g. antihistaminics, corticosteroides, and - if necessary - artificial respiration).
Rapid bolus administration is associated with hypotension, shock and, rarely, cardiac arrest (see section 4.8) and it must therefore be administered diluted, over a period of not less than 60 minutes at rate not greater than 10 mg/min. These reactions cease after interruption of the infusion.
Nephrotoxicity: vancomycin must be used with caution in patients with renal failure as the possibility of developing toxic effects is much higher in the presence of prolonged high blood concentrations. In the treatment of these patients and in those who are receiving concomitant treatment with other nephrotoxic medicinal products (i.e. aminoglycosides), serial tests of renal function must be performed and the appropriate dose regimens adhered to in order to reduce the risk of nephrotoxicity to a minimum (see section 4.2).
Ototoxicity: Ototoxicity, which may be transitory or permanent (see section 4.8) has been reported in patients with prior deafness, who have received excessive intravenous doses, or who receive concomitant treatment with another ototoxic medicinal product such as an aminoglycoside. The onset of deafness may be preceded by tinnitus. The risk of auditory damage is greater in the elderly. To reduce the risk of ototoxicity, blood levels should be determined periodically and periodic testing of auditory function is recommended. Deafness may be progressive despite cessation of treatment.
Vancomycin must be administered only intravenously (by infusion), owing to the risk of necrosis. The risk of venous irritation is minimized by giving vancomycin in the form of a dilute infusion (2.5 to 5 g/l) and by changing the injection site.
The administration of vancomycin by intraperitoneal injection during continuous ambulatory peritoneal dialysis has been associated with a syndrome of chemical peritonitis.
Precautions:
Thrombophlebitis may develop, the frequency and severity of which may be minimised by administering the medicinal product slowly and in diluted form (2.5 to 5 g/l), and if the sites of injection are changed regularly.
The frequency of infusion-related reactions (hypotension, flushing, erythema, urticaria and pruritus) increases with the concomitant administration of anaesthetic agents. This may be reduced by administering the vancomycin by infusion over 60 minutes, before anaesthetic induction.
Vancomycin must be administered with caution in patients allergic to teicoplanin as allergic cross-reactions have been detected between vancomycin and teicoplanin.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including vancomycin, and may range in the severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of vancomycin. Antiperistaltics are contraindicated.
As with other antibiotics, the prolonged use of vancomycin can lead to an overgrowth of non-sensitive bacteria and fungi. Close observation of the patient is essential. Appropriate measures must be taken if superinfection occurs during treatment.
The onset of reversible neutropenia has been reported (see section 4.8). Periodic blood counts must be performed in patients receiving prolonged treatments with vancomycin or concomitant treatment with medicinal products which can cause neutropenia.
Anaesthetic induced myocardial depression may be enhanced by vancomycin. During anaesthesia, doses must be well diluted and administered slowly with close cardiac monitoring. Position changes should be delayed until the infusion is completed to allow for postural adjustment.
Use in the elderly:
Because of its ototoxicity and nephrotoxicity, vancomycin should be used with caution in patients
with renal insufficiency or previous hearing loss. The elderly are particularly at risk. Doses should be titrated on the basis of serum levels. Blood levels should be monitored and renal function tests performed regularly. The elderly are particularly susceptible to auditory damage and should be given serial tests for auditory function if over the age of 60. Concurrent or sequential use of other neurotoxic substances should be avoided.
Use in infants/children:
Vancomycin should be used with particular care in premature infants and children, because of their renal immaturity and the possible increase in the serum concentration of vancomycin. The blood concentrations of vancomycin should therefore be monitored carefully. The concomitant use of vancomycin and anaesthetic agents in children has been associated with erythema and anaphylactoid reactions. If the administration of vancomycin is required for
surgical prophylaxis, it is advisable to administer the anaesthetic agents after completion of the vancomycin infusion (see section 4.8).
Regular monitoring of the blood levels of vancomycin is indicated in longer-term use, particularly in patients with renal dysfunction or impaired faculty of hearing as well as in concurrent administration of nephrotoxic or ototoxic substances, respectively.
4.5 Interaction with other medicinal products and other forms of interaction
Other _potentially nephrotoxic or ototoxic medications
Concurrent or sequential administration of vancomycin with other potentially neurotoxic or/and nephrotoxic active substances particularly gentamycin, amphotericin B, streptomycin, neomycin, kanamycin, amikacin, tobramycin, viomycin, bacitracin, polymyxin B, colistin and cisplatin may potentiate the nephrotoxicity and/or ototoxicity of vancomycin and consequently requires careful monitoring of the patient.
Because of synergic action (e.g. with gentamycin) in these cases the maximum dose of vancomycin has to be restricted to 500 mg every 8 hours.
Anaesthetics
Concurrent administration of vancomycin and anaesthetic agents has been associated with erythema, histamine like flushing and anaphylactoid reactions. This may be reduced if the vancomycin is administered over 60 minutes before anaesthetic induction.
Muscle relaxants
If vancomycin is administered during or directly after surgery, the effect (neuromuscular blockade) of muscle relaxants (such as succinylcholine) concurrently used can be enhanced and prolonged.
4.6 Pregnancy and lactation
Pregnancy:
No sufficient safety experience is available regarding vancomycin during human pregnancy. Reproduction toxicological studies on animals do not suggest any effects on the development of the embryo, foetus or gestation period (see section 5.3).
However, vancomycin penetrates the placenta and a potential risk of embryonal and neonatal ototoxicity and nephrotoxicity cannot be excluded. Therefore vancomycin should be given in pregnancy only if clearly needed and after a careful risk/benefit evaluation.
Lactation:
Vancomycin is excreted in human milk and should be therefore used in lactation period only if other antibiotics have failed. Vancomycin should be cautiously given to breast-feeding mothers because of potential adverse reactions in the infant (disturbances in the intestinal flora with diarrhoea, colonisation with yeast-like fungi and possibly sensibilisation).
Considering the importance of this medicine for nursing mother, the decision should to stop breastfeeding should be considered.
4.7 Effects on ability to drive and use machines
Vancomycin has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
The most common adverse reactions are phlebitis and pseudo-allergic reactions in connection with too rapid intravenous use (by infusion) of vancomycin.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The adverse reactions listed below is defined using the following MedDRA convention and system organ class database:
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).
Blood and the lymphatic system disorder:
Rare (> 10,000 to <1/1,000): Trombocytopenia, neutropenia, agranulocytoses,
eosinophilia.
Immune system disorders:
Rare (> 10,000 to <1/1,000): Anaphylactic reactions, hypersensitivity
reactions.
Ear and labyrinth disorders:
Uncommon (> 1,000 to <1/1 00): Transient or permanent loss of hearing.
Rare (> 10,000 to <1/1,000): Tinnitus, dizziness.
Cardiac disturbances
Very rare (<1/10,000): Cardiac arrest
Vascular disorders:
Common (>1/100 to <1/10): Decrease in blood pressure,
thrombophlebitis.
Vasculitis.
Rare (> 10,000 to <1/1,000):
Respiratory, thoracic and medistinal disorders: Common (>1/100 to <1/10): Dyspnoea, stridor.
Gastrointestinal Disorders:
Rare(> 10,000 to <1/1,000): Nausea.
Very rare(<1/10,000) Pseudomembranous enterocolitis.
Skin and subcutaneous tissue disorders:
Common (>1/100 to <1/10): Exanthema and mucosal inflammation,
prurutus, urticaria.
Very rare (<1/10, 000): Exfoliative dermatitis, Stevens-Johnson
syndrome, Lyell’s syndrome, vasculitis, IgA induced bullous dermatitis
Renal and urinary disorders:
Common (>1/100 to <1/10): Renal insufficiency manifested primarily by
increased serum creatinine or serum urea concentrations.
Rare(> 10,000 to <1/1,000): Interstitial nephritis, acute renal failure.
General disorders and administration site conditions:
Common (>1/100 to <1/10): Redness of the upper body and the face. Pain
and spasm of the chest and back muscels. Rare(> 10,000 to <1/1,000): Drug fever, shivering.
During or shortly after rapid infusion anaphylactic reactions may occur. The reactions abate when administration is stopped, generally between 20 minutes and 2 hours after having stopped administration.
Ototoxicity has primarily been reported in patients given high doses, or concomitant treatment with other ototoxic medicinal products, or had preexisting reduction in kidney function or hearing.
4.9 Overdose
Toxicity due to overdose has been reported. 500 mg IV to a child, 2 year of age, resulted in lethal intoxication. Administration of a total of 56 g during 10 days to an adult resulted in lethal intoxication. In certain risk constellations (e. g. in case of severe renal impairment) high serum levels and oto- and nephrotoxic effects can occur.
Measures in case of overdosage
• A specific antidote is not known.
• High concentrations can be effectively reduced by hemodialysis using polysulfone membranes or by hemofiltration or hemoperfusion using polysulfone resin.
• Furthermore, in case of overdosage a symptomatic treatment under maintenance of the renal function is necessary.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC classification
Pharmacotherapeutic group: Glycopeptide antibacterials ATC code: J01XA01 Mode of action
Vancomycin is a glycopeptide antibiotic. Vancomycin has a bactericidal effect on proliferating germs by inhibiting the biosynthesis of the cell wall. In addition, it impairs the permeability of the bacterial cell membrane and RNA synthesis
PK/PD relationship
Vancomycin activity is considered to be time-dependent - that is, antimicrobial activity depends on the duration that the drug level exceeds the minimum inhibitory concentration (MIC) of the target organism.
Mechanism of resistance:
Acquired resistance to glycopeptides is based on acquisition of various van gene complexes and alteration of the D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-D-serine which bind vancomycin poorly, because a critical site for hydrogen bonding is missing. This form of resistance is especially seen in Enterococcus faecium.
The reduced susceptibility or resistance to vancomycin in Staphylococcus is not well understood. Several genetic elements and multiple mutations are required.
Cross-resistance with teicoplanin has been reported.
Susceptibility:
Vancomycin is active against gram-positive bacteria. Gram-negative bacteria are resistant.
The MIC breakpoints separating susceptible from resistant organisms are as follows:
EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommendations Susceptible Resistant
Staphylococcus spp. < 2 mg/L >2 mg/L
Enterococcus spp. <4 mg/L > 4 mg/L
Streptococcus spp < 2 mg/L > 2 mg/L
Streptococcus pneumoniae < 2 mg/L > 2 mg/L
Gram-positive anaerobes < 2 mg/L < 2 mg/L
Non species related* < 2 mg/L > 4 mg/L
* Non-species related breakpoints 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 that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended.
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.
Classes
Commonly susceptible species Gram positive
Enterococcus faecalis.
Staphylococcus aureus Staphylococcus coagulase negative Staphylococcus epidermidis Streptococcus spp.
Streptococcus pneumoniae
Species for which acquire d resistance may be a problem
Enterococcus faecium Streptococcus bovis Streptococcus viridans Inherently resistant Gram negative bacteria Chlamydia spp.
Mycobacteria Mycoplasma spp.
Rickettsia spp.
5.2 Pharmacokinetic properties
Vancomycin is not significantly absorbed from the normal gastro-intestinal tract.
Distribution: Following intravenous administration, vancomycin is distributed to almost all tissues and diffuses in pleural, pericardial, ascitic and synovial fluid as well as in the cardiac muscle and in heart valves. Comparable high concentrations are achieved as in blood plasma. Data about the vancomycin concentrations in bone (spongiosa, compacta) vary widely. The apparent distribution volume in steady state is stated to be 0.43 (up to 0.9) L/kg. In non-inflamed meninges vancomycin passes the blood-brain barrier only to a low extent. Vancomycin is bound to plasma proteins at 30 to 55 % and even higher.
Elimination: Vancomycin is metabolized only to a low extent. After parenteral administration it is excreted almost completely as microbiologically active substance (approx. 75-90% within 24 hours) through glomerular filtration via the kidneys. Biliary excretion is insignificant (less than 5% of a dose).
In patients with normal renal function the half-life in serum is about 4-6 (5-11) hours, in children 2.2-3 hours. In impaired renal function, the half-life of vancomycin may be considerably prolonged (up to 7.5 days). Due to ototoxicity of vancomycin therapy-adjuvant monitoring of the plasma concentrations is indicated in such cases.
Mean plasma concentrations after i.v. infusion of 1000 mg vancomycin over 60 minutes were about 63 mg/L at the end of the infusion, about 23 mg/L after 2 hours and about 8 mg/L after 11 hours.
The clearance of vancomycin from plasma correlates nearly with the glomerular filtration rate.
The total systemic and renal clearance of vancomycin can be reduced in elderly patients.
As studies in anephric patients showed, the metabolic clearance seems to be very low.
No vancomycin metabolites have been identified so far in humans.
If vancomycin is given during a peritoneal dialysis via the intraperitoneal route, approx. 60% reaches the systemic circulation during 6 hours. After i.p. administration of 30 mg/kg BW, serum levels of approx. 10 mg/l are achieved.
Vancomycin diffuses readily across the placenta and is distributed into cord blood.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.
Limited data on mutagenic effects show negative results, long-term studies in animals regarding a carcinogenic potential are not available. In teratogenicity studies, where rats and rabbits received doses approximately corresponding to the human dose based on body surface (mg/m2), no direct or indirect teratogenic effects were observed.
Animal studies of the use during the perinatal/postnatal period and regarding effects on fertility are not available.
6 PHARMACEUTICAL PARTICULARS
List of excipients
6.1
Hydrochloric acid (for pH adjustment) .
6.2 Incompatibilities
Vancomycin solution has a low pH that may cause chemical or physical instability when it is mixed with other compounds. Mixing with alkaline solutions should be avoided. Each parenteral solution should be checked visually for precipitation and discolouration prior to use.
Mixtures of solutions of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible. The likelihood of precipitation increases with higher concentrations of vancomycin. It is recommended to adequately flush the intravenous lines between the administrations of these antibiotics. It is also recommended to dilute solutions of vancomycin to 5 mg/mL or less.
Although intravitreal injection is not an approved route of administration for vancomycin, precipitation has been reported after intravitreal injection of vancomycin and ceftazidime for endophthalmitis using different syringes and needles. The precipitates dissolved gradually, with complete clearing of the vitreous cavity over two months and with improvement of visual acuity.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Powder as packaged for sale 500 mg vial: 3 years After reconstitution /dilution
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage items and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8° C.
6.4 Special precautions for storage
Powder:
Store below 25°C. Keep the vial in the outer carton to protect from light.
After reconstitution /dilution: For storage conditions of the reconstituted/diluted medicinal product, see section 6.3.
Prior to administration, parenteral medicinal products should be inspected visually for particulate matter and discolouration whenever solution or container permits.
6.5 Nature and contents of container
Colourless, glass (Type I) vials of 19 ml, closed with rubber (Type I) closures and sealed with aluminium caps and a blue plastic flip-off top.
Pack Sizes: 1, 5, 10 and 20.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The powder must be reconstituted and the resulting concentrate must then be diluted prior to use.
Preparation of the reconstituted concentrate
At the time of use, the content of each 500 mg vial is dissolved in 10 ml of sterile water for injections. One ml of reconstituted solution contains 50 mg of vancomycin.
For storage conditions of the reconstituted medicinal product, see section 6.3. Preparation of final diluted Solution for Infusion
Reconstituted solutions containing 50 mg/ml of vancomycin should be further diluted depending on the method of administration.
Suitable diluents are:
5% Glucose Injection (50 mg/ml) or 0.9% Sodium Chloride Injection (9 mg/ml).
Intermittent infusion:
The concentration of vancomycin in Solution for infusion should not exceed 5 mg/ml.
The desired dose should be administered intravenously, by slow infusion at a rate of no more than 10 mg/minute, for at least 60 minutes or even longer.
If administered over a shorter period of time or in higher concentrations, there is the possibility of inducing marked hypotension in addition to thrombophlebitis. Rapid administration may also produce flushing and a transient rash over the neck and shoulders
Continuous infusion:
This should be used only if treatment with an intermittent infusion is not possible. Dilute 1 g to 2 g of dissolved vancomycin in a sufficient amount of the above suitable diluent and administer it in the form of a drip infusion, so that the patient will receive the prescribed daily dose in 24 hours.
For storage conditions of the diluted medicinal product, see section 6.3
Before administration, the reconstituted and diluted solutions should be inspected visually for particulate matter and discoloration. Only clear, and colourless solution free from particles should be used.
Disposal
Vials are for single use only. Unused product must be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Noridem Enterprises Ltd.
Evagorou & Makariou Mitsi Building 3 Suit. 115, 1065 Nicosia Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 24598/0015 PA 1122/008/001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/03/2011
10
DATE OF REVISION OF THE TEXT
01/03/2011