1. Name Of The Medicinal Product
Doribax
2. Qualitative And Quantitative Composition
Each vial contains doripenem monohydrate equivalent to 500mg doripenem.
The medicinal product does not contain any excipients.
3. Pharmaceutical Form
Powder for solution for infusion (powder for infusion)
White to slightly yellowish off-white crystalline powder
4. Clinical Particulars
4.1 Therapeutic Indications
Doribax is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1):
• Nosocomial pneumonia (including ventilator–associated pneumonia)
• Complicated intra-abdominal infections
• Complicated urinary tract infections
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology And Method Of Administration
The recommended dose and administration by infection is shown in the following table:
Posology
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The usual treatment duration of doripenem therapy is 5-14 days and should be guided by the severity, site of the infection and the patient's clinical response. Doripenem was given for up to 14 days in clinical studies and the safety of longer durations of therapy has not been established. After commencing treatment with intravenous doripenem, a switch to appropriate oral therapy to complete the treatment course is possible once clinical improvement has been established.
Dose in paediatric patients
Doribax is not recommended for use in children below 18 years of age due to a lack of safety and efficacy data.
Dose in patients with impaired renal function
In patients with mild renal impairment (i.e. creatinine clearance (CrCl) is > 50 to < 80 ml/min), no dose adjustment is necessary. In patients with moderate renal impairment (CrCl > 30 to < 50 ml/min), the dose of Doribax should be 250mg every 8 hours (see section 6.6). In patients with severe renal impairment (CrCl < 30ml/min), the dose of Doribax should be 250mg every 12 hours (see section 6.6). Due to limited clinical data and an expected increased exposure to doripenem and its metabolite (doripenem-M-1), Doribax should be used with caution in patients with severe renal impairment (see section 5.2).
Dose in patients on dialysis
Doribax dosing and administration recommendations for patients on continuous renal replacement therapies are shown in the following table.
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Dosing recommendations for pathogens with MIC > 1 mg/l have not been established for continuous renal replacement therapy due to the potential for accumulation of doripenem and doripenem-M-1 metabolite (see sections 4.4 and 5.2). Close safety monitoring is advised for patients on continuous renal replacement therapy, due to limited clinical data and an expected increased exposure to doripenem-M-1 metabolite (see section 4.4).
There is insufficient information to make dose adjustment recommendations in patients on dialysis. (see section 5.2).
Dose in elderly patients (
No dose adjustment is necessary in elderly patients, except in cases of moderate to severe renal impairment (see Dose in patients with impaired renal function above and section 5.2).
Dose in patients with impaired hepatic function
No dose adjustment is necessary.
Method of administration
Doribax is to be reconstituted and then further diluted (see section 6.6) prior to administration by intravenous infusion over a period of 1 or 4 hours.
4.3 Contraindications
• Hypersensitivity to the active substance
• 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
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have occurred in patients receiving beta-lactam antibiotics. Before therapy with Doribax is started, careful inquiry should be made concerning a previous history of hypersensitivity reactions to other active substances in this class or to beta-lactam antibiotics. Doribax should be used with caution in patients with such a history. Should a hypersensitivity reaction to Doribax occur, it should be discontinued immediately and appropriate measures taken. Serious acute hypersensitivity (anaphylactic) reactions require immediate emergency treatment.
Seizures have infrequently been reported during treatment with other carbapenems.
Pseudomembranous colitis due to Clostridium difficile has been reported with Doribax and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of Doribax (see section 4.8).
Administration of doripenem, like other antibiotics, has been associated with emergence and selection of strains with reduced susceptibility. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken. Prolonged use of Doribax should be avoided.
The concomitant use of doripenem and valproic acid/sodium valproate is not recommended (see section 4.5).
When Doribax was used investigationally via inhalation, pneumonitis occurred. Therefore, Doribax should not be administered by this route.
The exposure to the metabolite doripenem-M-1 in patients on continuous renal replacement therapy may be increased to levels where no in vivo safety data are presently available. The metabolite lacks target pharmacological activity but other possible pharmacological effects are unknown. Therefore, close safety monitoring is advised. (see sections 4.2 and 5.2)
Description of the patient population treated in clinical studies
In two clinical trials of patients with nosocomial pneumonia (N=979), 60% of the clinically-evaluable Doribax-treated patients had ventilator-associated pneumonia (VAP). Of these, 50% had late-onset VAP (defined as that occurring after five days of mechanical ventilation), 54% had an APACHE (Acute Physiology And Chronic Health Evaluation) II score >15 and 32% received concomitant aminoglycosides (76% for more than 3 days).
In two clinical trials of patients with complicated intra-abdominal infections (N=962) the most common anatomical site of infection in microbiologically-evaluable Doribax-treated patients was the appendix (62%). Of these, 51% had generalised peritonitis at baseline. Other sources of infection included colon perforation (20%), complicated cholecystitis (5%) and infections at other sites (14%). Eleven percent had an APACHE II score of >10, 9.5% had post-operative infections, 27% had single or multiple intra-abdominal abscesses and 4% had concurrent bacteraemia at baseline.
In two clinical trials of patients with complicated urinary tract infections (N=1179), 52% of microbiologically-evaluable Doribax-treated patients had complicated lower urinary tract infections and 48% had pyelonephritis, of which 16% were complicated. Overall, 54% of patients had a persistent complication, 9% had concurrent bacteraemia and 23% were infected with a levofloxacin resistant uropathogen at baseline.
The experience in patients who are severely immunocompromised, receiving immunosuppressive therapy, and patients with severe neutropenia is limited since this population was excluded from phase 3 trials.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Doripenem undergoes little to no Cytochrome P450 (CYP450) mediated metabolism. Based on in vitro studies it is not expected that doripenem will inhibit or induce the activities of CYP450. Therefore, no CYP450-related drug interactions are to be expected (see section 5.2).
It has been shown that co-administration of doripenem and valproic acid significantly reduces serum valproic acid levels below the therapeutic range. The lowered valproic acid levels can lead to inadequate seizure control. In an interaction study, the serum concentrations of valproic acid were markedly reduced (AUC was reduced by 63%) following co-administration of doripenem and valproic acid. The interaction had a fast onset. Since patients were administered only four doses of doripenem, a further decrease of valproic acid levels with longer concomitant administration cannot be excluded.
Decreases in valproic acid levels have also been reported when co-administered with other carbapenem agents, achieving a 60 -100 % decrease in valproic acid levels in about two days. Therefore alternative antibacterial or supplemental anticonvulsant therapies should be considered.
Probenecid competes with doripenem for renal tubular secretion and reduces the renal clearance of doripenem. In an interaction study, the mean doripenem AUC increased by 75% following co-administration with probenecid. Therefore, co-administration of probenecid with Doribax is not recommended. An interaction with other medicinal products eliminated by renal tubular secretion cannot be excluded.
4.6 Pregnancy And Lactation
For doripenem, limited clinical data on exposed pregnancies are available. Animal studies are insufficient with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential risk for humans is unknown. Doribax should not be used during pregnancy unless clearly necessary.
It is unknown whether doripenem is excreted in human breast milk. A study in rats has shown that doripenem and its metabolite are transferred to milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Doribax should be made taking into account the benefit of breast-feeding to the child and the benefit of Doribax therapy to the woman.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects of Doribax on the ability to drive and use machines have been performed. Based on reported adverse drug reactions, it is not anticipated that Doribax will affect the ability to drive and use machines.
4.8 Undesirable Effects
In 3,142 adult patients (1817 of which received Doribax) evaluated for safety in phase II and phase III clinical trials, adverse reactions due to Doribax 500 mg every 8 hours occurred at a rate of 32%. Doribax was discontinued because of adverse drug reactions in 0.1% of patients overall. Adverse drug reactions that led to Doribax discontinuation were nausea (0.1%), diarrhoea (0.1%), pruritus (0.1%), vulvomycotic infection (0.1%), hepatic enzyme increased (0.2 %) and rash (0.2%). The most common adverse reactions were headache (10%), diarrhoea (9%) and nausea (8%).
Adverse drug reactions identified during clinical trials and post-marketing experience with Doribax are listed below by frequency category. Frequency categories are defined as follows: Very common (
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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4.9 Overdose
In a Phase I study in healthy subjects receiving doripenem 2 g infused over 1 hour every 8 hours for 10 to 14 days, the incidence of rash was very common (5 of 8 subjects). The rash resolved within 10 days after doripenem administration was discontinued. In the event of overdose, Doribax should be discontinued and general supportive treatment given until renal elimination takes place. Doribax can be removed by continuous renal replacement therapy or haemodialysis (see section 5.2). However, no information is available on the use of either of these therapies to treat overdose.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antibacterials for systemic use. Carbapenems, ATC code: J01DH04.
Mechanism of action
Doripenem is a synthetic carbapenem antibacterial agent.
Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death.
In vitro doripenem showed little potential to antagonise or be antagonised by other antibacterial agents. Additive activity or weak synergy with amikacin and levofloxacin has been seen for Pseudomonas aeruginosa and for gram-positive bacteria with daptomycin, linezolid, levofloxacin, and vancomycin.
Pharmacokinetic/pharmacodynamic relationship
Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of doripenem exceeds the minimum inhibitory concentration (%T>MIC) of the infecting organism has been shown to best correlate with efficacy in pre-clinical pharmacokinetic/pharmacodynamic (PK/PD) studies. Monte Carlo simulations using pathogen susceptibility results from completed phase 3 trials and population PK data indicated that the %T>MIC target of 35% was achieved in greater than 90% of patients with nosocomial pneumonia, complicated urinary tract infections and complicated intra-abdominal infections, for all degrees of renal function.
Extending the infusion time of Doribax to 4 hours maximises the %T>MIC for a given dose and is the basis for the option to administer 4-hour infusions in patients with nosocomial pneumonia including ventilator-associated pneumonia. In seriously ill patients or those with an impaired immune response, a 4-hour infusion time may be more suitable when the MIC of doripenem for the known or suspected pathogen(s) has been shown or is expected to be >0.5mg/l, in order to reach a target attainment of 50% T>MIC in at least 95% of the patients (see section 4.2). Monte Carlo simulations supported the use of 500mg 4-hour infusions every 8 hours in subjects with normal renal function for target pathogens with doripenem MICs
Mechanisms of resistance
Bacterial resistance mechanisms that effect doripenem include active substance inactivation by carbapenem-hydrolysing enzymes, mutant or acquired PBP's, decreased outer membrane permeability and active efflux. Doripenem 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 doripenem. Methicillin-resistant staphylococci should always be considered as resistant to doripenem. As with other antimicrobial agents, including carbapenems, doripenem has been shown to select for resistant bacterial strains.
Breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:
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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.
Localised clusters of infections due to carbapenem-resistant organisms have been reported in the European Union. The information below gives only approximate guidance on the probability as to whether the micro-organism will be susceptible to doripenem or not.
Commonly susceptible species:
Gram positive aerobes
Enterococcus faecalis*$
Staphylococcus aureus (methicillin susceptible strains only)*^
Staphylococcus spp. (methicillin susceptible strains only)^
Streptococcus pneumoniae*
Streptococcus spp.
Gram negative aerobes
Citrobacter diversus
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae*
Haemophilus influenzae*
Escherichia coli*
Klebsiella pneumoniae*
Klebsiella oxytoca
Morganella morganii
Proteus mirabilis*
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Salmonella spp.
Serratia marcescens
Shigella spp.
Anaerobes
Bacteroides fragilis*
Bacteroides caccae*
Bacteroides ovatus
Bacteroides uniformis*
Bacteroides thetaiotaomicron*
Bacteroides vulgatus*
Bilophila wadsworthia
Peptostreptococcus magnus
Peptostreptococcus micros*
Porphyromonas spp.
Prevotella spp.
Sutterella wadsworthenis
Species for which acquired resistance may be a problem:
Acinetobacter baumannii*
Acinetobacter spp.
Burkholderia cepacia$+
Pseudomanas aeruginosa*
Inherently resistant organisms:
Gram -positive aerobes
Enterococcus faecium
Gram negative aerobes
Stenotrophomonas maltophilia
Legionella spp.
*species against which activity has been demonstrated in clinical studies
$species that show natural intermediate susceptibility
+species with >50% acquired resistance in one or more Member State
^all methicillin-resistant staphylococci should be regarded as resistant to doripenem
5.2 Pharmacokinetic Properties
The mean Cmax and AUC0- of doripenem in healthy subjects across studies following administration of 500mg over 1 hour are approximately 23 μg/ml and 36 μg.h/ml, respectively. The mean Cmax and AUC0- of doripenem in healthy subjects across studies following administration of 500mg and 1g over 4 hours are approximately 8 μg/ml and 17 μg/ml, and 34 μg.h/ml and 68 μg.h/ml, respectively. There is no accumulation of doripenem following multiple intravenous infusions of either 500mg or 1g administered every 8 hours for 7 to 10 days in subjects with normal renal function.
Doripenem single dose pharmacokinetics after a 4-hour infusion in adults with cystic fibrosis are consistent with those in adults without cystic fibrosis. Adequate and well controlled studies to establish the safety and efficacy of doripenem in patients with cystic fibrosis have not been conducted.
Distribution
The average binding of doripenem to plasma proteins was approximately 8.1% and is independent of plasma concentrations. The volume of distribution at steady state is approximately 16.8L, similar to extracellular fluid volume in man. Doripenem penetrates well into several body fluids and tissues, such as uterine tissue, retroperitoneal fluid, prostatic tissue, gallbladder tissue and urine.
Metabolism
Metabolism of doripenem to a microbiologically inactive ring-opened metabolite occurs primarily via dehydropeptidase-I. Doripenem undergoes little to no Cytochrome P450 (CYP450) mediated metabolism. In vitro studies have determined that doripenem does not inhibit or induce the activities of CYP isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 or 3A4.
Elimination
Doripenem is primarily eliminated unchanged by the kidneys. Mean plasma terminal elimination half-life of doripenem in healthy young adults is approximately 1-hour and plasma clearance is approximately 15.9 l/hour. Mean renal clearance is 10.3 l/hour. The magnitude of this value, coupled with the significant decrease in the elimination of doripenem seen with concomitant probenecid administration, suggests that doripenem undergoes glomerular filtration, tubular secretion and re-absorption. In healthy young adults given a single 500mg dose of Doribax, 71% and 15% of the dose was recovered in urine as unchanged active substance and ring-opened metabolite, respectively. Following the administration of a single 500mg dose of radiolabeled doripenem to healthy young adults, less than 1% of the total radioactivity was recovered in faeces. The pharmacokinetics of doripenem are linear over a dose range of 500 mg to 2 g when intravenously infused over 1 hour and 500 mg to 1 g when intravenously infused over 4 hours.
Renal insufficiency
Following a single 500mg dose of Doribax, doripenem AUC increased 1.6-fold, 2.8-fold, and 5.1-fold in subjects with mild (CrCl 51-79 ml/min), moderate (CrCl 31-50 ml/min), and severe renal impairment (CrCl
Doribax dosage adjustment is necessary in patients receiving continuous renal replacement therapy (see section 4.2). In a study where 12 subjects with end stage renal disease received a single 500 mg dose of doripenem as a 1-hour i.v. infusion, the systemic exposure to doripenem and doripenem-M-1 were increased compared with healthy subjects. The amount of doripenem and doripenem-M-1 removed during a 12-hour CVVH session was approximately 28% and 10% of the dose, respectively; and during a 12-hour CVVHDF session was approximately 21% and 8% of the dose, respectively. Dosing recommendations for patients on continuous renal replacement therapy were developed to achieve doripenem systemic exposures similar to subjects with normal renal function who receive doripenem 500 mg as a 1-hour infusion, to maintain doripenem concentrations above a minimum inhibitory concentration of 1 mg/l for at least 35% of the dosing interval, and to maintain doripenem and doripenem-M-1 metabolite exposures below those observed with a 1-hour infusion of 1 g doripenem every 8 hours in healthy subjects. These dosing recommendations were derived by modeling data from subjects with end stage renal disease receiving continuous renal replacement therapy, and take into consideration the potential increases in non-renal clearance of carbapenems in patients with acute renal insufficiency compared to patients with chronic renal impairment. Doripenem-M-1 had a slow elimination in the patient group and the half-life (and AUC) has not been satisfactorily determined. Therefore, it may not be excluded that the exposure obtained in patients receiving continuous renal replacement therapy will be higher than estimated and thus higher than metabolite exposures observed with a 1-hour infusion of 1 g doripenem every 8 hours in healthy subjects. The in vivo consequences of the increased exposures to the metabolite are unknown as data on pharmacological activity, except for antimicrobiological activity, are lacking (see section 4.4). If the doripenem dose is increased beyond the recommended dose for continuous renal replacement therapy, the systemic exposure of the doripenem-M-1 metabolite is even further increased. The clinical consequences of such an increase in exposure are unknown.
The systemic exposures to doripenem and doripenem-M-1 are substantially increased in patients with end stage renal disease receiving haemodialysis compared with healthy subjects. In a study where six subjects with end stage renal disease received a single dose of 500mg doripenem by i.v. infusion, the amount of doripenem and doripenem-M-1 removed during 4-hour haemodialysis session was approximately (46% and 6%of the dose) , respectively. There is insufficient information to make dose adjustment recommendations in patients on intermittent haemodialysis or dialysis methods other than continuous renal replacement therapy (see section 4.2).
Hepatic impairment
The pharmacokinetics of doripenem in patients with hepatic impairment have not been established. As doripenem does not appear to undergo hepatic metabolism, the pharmacokinetics of Doribax are not expected to be affected by hepatic impairment.
Elderly
The impact of age on the pharmacokinetics of doripenem was evaluated in healthy elderly male and female subjects (66-84 years of age). Doripenem AUC increased 49% in elderly adults relative to young adults. These changes were mainly attributed to age-related changes in renal function. No dose adjustment is necessary in elderly patients, except in cases of moderate to severe renal insufficiency (see section 4.2).
Gender
The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male and female subjects. Doripenem AUC was 15% higher in females compared to males. No dose adjustment is recommended based on gender.
Race
The effect of race on doripenem pharmacokinetics was examined through a population pharmacokinetic analysis. No significant difference in mean doripenem clearance was observed across race groups and therefore, no dose adjustment is recommended for race.
5.3 Preclinical Safety Data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and genotoxicity. However, because of the design of the repeat dose toxicity studies and differences in pharmacokinetics in animals and humans, continuous exposure of animals was not assured in these studies.
No reproductive toxicity was observed in studies performed in rats and rabbits. However, these studies are of limited relevance because studies were performed with single daily dosing resulting in less than one tenth of daily doripenem exposure duration in animals.
6. Pharmaceutical Particulars
6.1 List Of Excipients
None
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.3.
6.3 Shelf Life
3 years.
Storage of reconstituted solutions: Upon reconstitution with sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for injection, Doribax suspension in the vial may be held for up to 1 hour below 30°C prior to transfer and dilution in the infusion bag.
Following dilution in the infusion bag with sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml (5%) solution for injection, Doribax infusions stored at room temperature or under refrigeration should be completed according to the times in the following table:
Time by which reconstitution, dilution and infusion must be completed for Doribax infusion solutions
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* Once removed from the refrigerator, infusions should be completed within the room temperature stability time, provided the total refrigeration time, time to reach room temperature and infusion time does not exceed refrigeration stability time.
+ Dextrose 50 mg/ml (5%) solution for injection should not be used for infusion durations greater than 1 hour.
Chemical and physical in-use stability has been demonstrated for the times and solutions shown in the above table.
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°C-8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
For storage conditions of the reconstituted medicinal product, and infusion solutions see section 6.3.
6.5 Nature And Contents Of Container
Clear 20 ml Type I glass vial.
The medicinal product is supplied in cartons containing 10 vials.
6.6 Special Precautions For Disposal And Other Handling
Each vial is for single use only.
Doribax is reconstituted and then further diluted prior to infusion.
Preparation of 500 mg dose of solution for infusion using the 500 mg vial
1. Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for injection to the 500 mg vial and shake it to form a suspension.
2. Inspect the suspension visually for foreign matter. Note: the suspension is not for direct infusion.
3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing 100 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml (5%) solution for injection and mix to complete dissolution. Infuse all of this solution to administer a 500 mg dose of doripenem.
Preparation of 250 mg dose of solution for infusion using the 500mg vial
1. Add 10ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for injection to the 500mg vial and shake it to form a suspension.
2. Inspect the suspension visually for foreign matter. Note: the suspension is not for direct infusion.
3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing 100ml either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml (5%) solution for injection and mix to complete dissolution.
4. Remove 55ml of this solution from the infusion bag and discard. Infuse all of the remaining solution to administer a 250 mg dose of doripenem.
Doribax solutions for infusion range from clear, colourless solutions to solutions that are clear and slightly yellow. Variations in colour within this range do not affect the potency of the product.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Janssen-Cilag International NV
Turnhoutseweg, 30
B-2340 Beerse
Belgium
8. Marketing Authorisation Number(S)
EU/1/08/467/001
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 25th July 2008
10. Date Of Revision Of The Text
08/2011
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.
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