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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Azithromycin 200mg/5ml Powder for Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Azithromycin Powder for Oral Suspension contains 200mg azithromycin (anhydrous), equivalent to 200mg azithromycin base per 5ml on reconstitution.

Also contains approximately 3.83g of sucrose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for Oral Suspension.

A white to yellowish off-white mottled powder, which after reconstitution forms an off-white to buff coloured cherry flavoured suspension.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Azithromycin is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible microorganisms (see Section 5.1 Pharmacodynamic properties):

-    acute exacerbation of chronic bronchitis

-    community-acquired pneumonia

-    acute bacterial sinusitis

-    pharyngitis/tonsillitis (see section 4.4 regarding streptococcal infections)

-    acute bacterial otitis media

-    skin and soft tissue infections

-    uncomplicated urethritis and cervicitis due to Chlamydia trachomatis.

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

4.2 Posology and method of administration

Method of administration:

For oral use only.

Azithromycin is a white to yellowish off-white mottled powder, which after reconstitution forms an off-white to buff coloured cherry flavoured suspension.

Azithromycin Suspension should be given as a single daily dose and can be taken with food.

Children over 45 kg body weight and adults, including elderly patients: The total dose of azithromycin is 1500 mg which should be given over three days (500 mg once daily).

In uncomplicated urethritis and cervicitis due to Chlamydia trachomatis, the dose is 1000 mg as a single oral dose.

In children under 45 kg body weight:

Azithromycin Suspension should be used for children under 45 kg. There is no information on children less than 6 months of age.

The dose in children is 10mg/kg as a single daily dose for three days:

10mg/kg as a single daily dose for three days

5 ml (200 mg), once daily for three days. 7.5 ml (300 mg), once daily for three days.

36-45 kg (12-14 years): 10 ml (400 mg), once daily for three days.

Over 45 kg:    Dose as per adults.

Measure the dose as closely as possible using the 10 ml oral dosing syringe provided. The syringe is graduated in 0.25 ml divisions, providing 10 mg of azithromycin in every graduation.

See 'Nature and contents of container', Section 6.5, for appropriate pack size to use depending on age/body weight of child.

Renal failure:

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10 - 80 ml/min). Caution should be exercised when azithromycin is administered to patients with severe renal impairment (GFR < 10 ml/min) (see Section 4.4 - Special warnings and precautions for use and Section 5.2 Pharmacokinetic properties).

Hepatic failure:

Since azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment of such patients with azithromycin (see Section 4.4 Special warnings and precautions for use).

4.3 Contraindications

Azithromycin is contra-indicated in patients with a known hypersensitivity to azithromycin, erythromycin or any of the macrolide or ketolide antibiotics, or to any excipients thereof as (for example) listed in Section 6.1 (List of Excipients).

4.4 Special warnings and precautions for use

Allergic reactions

As with erythromycin and other macrolides, rare serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.

Hepatic impairment

Since the liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (see Section 4.8 Undesirable effects). Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products.

In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests/ investigations should be performed immediately. Azithromycin administration should be stopped if liver dysfunction has emerged.

Ergot alkaloids

In patients receiving ergot derivatives, ergotism has been precipitated by coadministration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administrated.

QT prolongation

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarisation (see Section 4.8 Undesirable effects); therefore caution is required when treating patients:

•    With congenital or documented QT prolongation

•    Currently receiving treatment with other active substance known to prolong QT interval such as antiarrhytmics of classes Ia and III, cisapride and terfenadine

•    With electrolyte disturbance, particularly in case of hypokalaemia and hypomagnesemia

•    With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

Superinfections

As with any antibiotic preparation, observation for signs of superinfection with nonsusceptible organisms including fungi is recommended.

Clostridium difficile associated diarrhoea (CDAD) and pseudomembranous colitis have been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea to fatal colitis. Strains of C. difficile producing hypertoxin A and B contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. Therefore, CDAD must be considered in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Discontinuation of therapy with azithromycin and the administration of specific treatment for C. difficile should be considered.

Streptococcal infections:

Azithromycin is in general effective against streptococcus in the oropharynx, but no data are available that demonstrate the efficacy of azithromycin in preventing acute rheumatic fever.

Renal impairment:

In patients with severe renal impairment (GFR <10 ml/min) a 33% increase in systemic exposure to azithromycin was observed (see Section 5.2 Pharmacokinetic properties).

Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy (See Section 4.8).

Safety and efficacy for prevention or treatment of MAC in children have not been established.

Caution in diabetic patients: 5 ml of reconstituted suspension contains 3.82 g of sucrose.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

This product contains less then 100mg ethanol per 5ml. This product contains aspartame (E951), a source of phenylalanine, which may be harmful for people with phenylketonuria.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen, although peak serum concentrations were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously.

Cetirizine: In healthy volunteers, co-administration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.

Didanosine (Dideoxyinosine): Co-administration of 1200 mg/day azithromycin with 400 mg/day didanosine in six HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.

Digoxin: Some of the macrolide antibiotics have been reported to impair the microbial metabolism of digoxin in the gut in some patients. In patients receiving concomitant azithromycin, a related azalide antibiotic, and digoxin the possibility of raised digoxin levels should be borne in mind.

Zidovudine: Single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.

Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.

Ergot derivatives: Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended. (See Section 4.4 Special warnings and precautions for use).

Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.

Atorvastatin: Co-administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay).

Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.

Cimetidine: In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.

Coumarin-Type Oral Anticoagulants: In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. There have been reports received in the postmarketing period of potentiated anticoagulation subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.

Ciclosporin: In a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of ciclosporin, the resulting ciclosporin C_max and AUC0-5 were found to be significantly elevated (by 24% and 21% respectively), however no significant changes were seen in AUC₀.oo- Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, ciclosporin levels should be monitored and the dose adjusted accordingly.

Efavirenz: Co-administration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.

Fluconazole: Co-administration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in C_max (18%) of azithromycin was observed.

Indinavir: Co-administration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for five days.

Methylprednisolone: In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.

Midazolam: In healthy volunteers, co-administration of azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.

Nelfinavir: Co-administration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment is required.

Rifabutin: Co-administration of azithromycin and rifabutin did not affect the serum concentrations of either drug.

Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established (see Section 4.8. Undesirable effects).

Sildenafil: In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for three days) on the AUC and C_max, of sildenafil or its major circulating metabolite.

Terfenadine: Pharmacokinetic studies have reported no evidence of an interaction between azithromycin and terfenadine. There have been rare cases reported where the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred.

Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered to healthy volunteers.

Triazolam: In 14 healthy volunteers, co-administration of azithromycin 500 mg on Day one and 250 mg on Day two with 0.125 mg triazolam on Day two had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole: Co-administration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for seven days with azithromycin 1200 mg on Day seven had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal reproduction studies do not indicate harmful effects with respect to reproductive toxicity at doses which demonstrate some degree of toxicity (see section 5.3). There are, however, no adequate and well-controlled studies in pregnant women. The use of azithromycin should be considered during pregnancy if necessary.

Breast-feeding

There is insufficient information on the excretion of azithromycin or its metabolites in milk; however there are data which suggests that azithromycin passes into breast milk in limited amounts. A risk to the suckling child cannot be excluded A decision must be made whether to discontinue breast-feeding or to abstain from treatment with azithromycin taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Animal data do not suggest an effect of the treatment of azithromycin on male and female fertility. The effect on fertility in humans is unknown.

4.7 Effects on ability to drive and use machines

There is no evidence to suggest that Azithromycin suspension may have an effect on a patient's ability to drive or operate machinery.

Undesirable effects

Azithromycin Suspension is well tolerated with a low incidence of side effects.

The section below lists the adverse reactions identified through clinical trial experience and postmarketing surveillance by system organ class and frequency. Adverse reactions identified from post-marketing experience are included in italics. The frequency grouping is defined using the following convention: 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.

Adverse reactions possibly or probably related to azithromycin based on clinical trial experience and post-marketing surveillance:

	Very common	Common	Uncommon	Rare	Not Known
Infections and Infestations			Candidiasis, Oral candidiasis Vaginal infection		Pseudomembranous colitis (See Section 4.4)
Blood and Lymphatic System Disorders			Leukopenia Neutropenia		Thrombocytopenia Haemolytic anaemia
Immune System Disorders			Angioedema Hypersensitivity		Anaphylactic reaction (See Section 4.4)
Metabolism and Nutrition Disorders		Anorexia
Psychiatric Disorders			Nervousness	Agitation	Aggression Anxiety
Nervous System Disorders		Dizziness Headache Paraesthesia Dysgeusia	Hypoaesethesia Somnolence Insomnia		Syncope Convulsion Psychomotor hyperactivity Anosmia Ageusia Parosmia Exacerbation of myasthenia gravis (See Section 4.4)
Eye Disorders		Visual impairment
Ear and Labyrinth Disorders		Deafness	Hearing impaired Tinnitus	Vertigo
Cardiac Disorders			Palpitations		Torsades de pointes (See Section 4.4)

					Arrhythmia (See Section 4.4) including ventricular tachycardia
Vascular Disorders					Hypotension
Gastrointestinal Disorders	Diarrhoea Abdominal pain Nausea Flatulence	Vomiting Dyspepsia	Gastritis Constipation		Pancreatitis Tongue discolouration
Hepatobiliary Disorders			Hepatitis	Hepatic function abnormal	Hepatic failure (See Section 4.4), which has rarely resulted in death, hepatitis fulminant, hepatic necrosis, jaundice cholestatic
Skin and Subcutaneous Tissue Disorders		Pruritus Rash	Stevens-Johnson syndrome Photosensitivity reaction Urticaria		Toxic epidermal necrolysis Erythema multiforme
Musculoskeletal, Connective Tissue Disorders		Arthralgia
Renal and Urinary Disorders					Renal failure acute Nephritis interstitial
General disorders and Administration Site Conditions		Fatigue	Chest pain Oedema Malaise Asthenia
Investigations		Lymphocyte count decreased Eosinophil count increased Blood bicarbonate	Aspartate aminotransferase increased Alanine aminotransferase increased Blood bilirubin		Electrocardiogram QT prolonged (See Section 4.4)

4.9 Overdose

Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea. In the event of overdose, the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use ATC code: J01FA10

Mode of action:

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is constructed by adding a nitrogen atom to the lactone ring of erythromycin A. The mechanism of action of azithromycin is based upon the suppression of bacterial protein synthesis by means of binding to the ribosomal 50s sub-unit and inhibition of peptide translocation.

Mechanism of resistance:

Resistance to azithromycin may be inherent or acquired. There are three main mechanisms of resistance in bacteria: target site alteration, alteration in antibiotic transport and modification of the antibiotic.

Complete cross resistance exists among Streptococcus pneumoniae, betahaemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.

Breakpoints

EUCAST:

-    Staphylococcus spp.: susceptible < 1 mg/l; resistant > 2 mg/l

-    Haemophilus spp.: susceptible < 0.12 mg/l; resistant > 4 mg/l

-    Streptococcus pneumoniae and Streptococcus A, B, C, G: susceptible < 0.25 mg/l; resistant > 0.5 mg/l

-    Moraxella catarrhalis: < 0.5 mg/l; resistant > 0.5 mg/l

-    Neisseria gonorrhoeae: < 0.25 mg/l; resistant > 0.5 mg/l

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.

Table: Antibacterial spectrum of Azithromycin Commonly susceptible species Aerobic Gram-positive microorganisms

Staphylococcus aureus Methycillin-susceptible

Streptococcus pneumoniae Penicillin-susceptible

Streptococcus pyogenes (Group A)

Aerobic Gram-negative microorganisms

Haemophilus influenzae Haemophilus parainfluenzae

Legionella pneumophila

Moraxella catarrhalis

Pasteurella multocida

Anaerobic microorganisms

Clostridium perfringens

mean volume of distribution at steady state (VVss) has been calculated to be 31.1 l/kg.

Elimination

The terminal plasma elimination half-life closely reflects the elimination half-life from tissues of 2-4 days.

Approximately 12% of an intravenously administered dose of azithromycin is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also in bile, ten metabolites were detected, which were formed through N- and O-demethylation, hydroxylation of desosamine - and aglycone rings and cleavage of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of azithromycin are not microbiologically active.

Pharmacokinetics in Special populations:

Renal Insufficiency:

Following a single oral dose of azithromycin 1 g, mean C_max and AUC_0-120 increased by 5.1 % and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 ml/min) compared with normal renal function (GFR>80ml/min). In subjects with severe renal impairment, the mean C_max and AUC_0-i₂₀ increased 61% and 35% respectively compared to normal.

Hepatic insufficiency:

In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.

Elderly:

The pharmacokinetics of azithromycin in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations (increased by 30-50%) were observed, no significant accumulation occurred.

In elderly volunteers (>65 years), higher (29 %) AUC values were always observed after a 5-day course than in younger volunteers (<45 years). However, these differences are not considered to be clinically relevant; no dose adjustment is therefore recommended.

Infants, toddlers, children and adolescents:

Pharmacokinetics has been studied in children aged 4 months - 15 years taking capsules, granules or suspension. At 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the C_max achieved is slightly lower than in adults, with 224 pg/l in children aged

0.6-5 years and after 3 days dosing, and 383 jag/l in those aged 6-15 years. The halflife of 36 h in the older children was within the expected range for adults.

5.3 Preclinical safety data

In animal studies, following repeated administration of azithromycin to adults (mouse, rat, dog) and neonates (rat and dog) at up to 40 times the proposed clinical dose, phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas). The effect has been shown to be reversible after cessation ofdosing; howeverthe clinical significance of these findings are unknown.

Electrophysiological investigations have shown that azithromycin prolongs the QT interval.

Mutagenic potential:

At cytotoxic concentrations (240 qg/mL), azithromycin caused an increase in mutant frequency in a mouse lymphoma assay. However, overall the in vitro and in vivo data do not suggest a potential to cause genotoxicity.

Carcinogenic potential:

Long-term studies in animals have not been performed to evaluate carcinogenic potential as the drug is indicated for short-term treatment.

Reproductive toxicity:

Azithromycin was not teratogenic in the mouse and rat. In the rat, delayed ossification was observed at 50 to 200 mg/kg/day, while a reduction inmaternal weight gain was noted at 100 and 200mg/kg/day. In rat peri- and post natal studies, mild retardations in physical and reflex development were noted.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sucrose

Hydroxypropylcellulose (E463)

Trisodium phosphate anhydrous (E339)

Xanthan gum (E415)

Sucralose (E955)

Colloidal anhydrous silica (E551)

Cherry flavour 501027 AP0551 Banana flavour 501013 AP0551

Masking flavour 501482 TP0424 (contains sugar and aspartame) Banana durarome flavour 501392 TDI0991 (contains sugar and ethanol)

6.2 Incompatibilities

None known.

6.3 Shelf life

Unopened: 24 months

Once reconstituted with water, Azithromycin Suspension has an in-use shelf life of 10 days.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

600 mg powder (15 ml) pack (recommended for use in children up to 7 years (25 kg)):

Reconstitute with 9 ml of water to give 15 ml suspension.

900 mg powder (22.5 ml) pack (recommended for use in children aged from 8-11 years (26-35 kg)):

Reconstitute with 12 ml of water to give 22.5 ml suspension.

1200 mg powder (30 ml) pack (recommended for use in children aged from 12-14 years (36-45 kg)).

Reconstitute with 15 ml of water to give 30 ml suspension.

After reconstitution the powder forms an off-white to buff coloured cherry flavoured suspension.

All packs of powder are contained in a 60ml HDPE bottle with a child resistant closure in a carton box. All packs contain a 10 ml oral dosing syringe with detachable adaptor.

6.6 Special precautions for disposal

Before dispensing the syringe adaptor should be detached from the syringe and inserted into the bottle neck and the cap replaced.

7    MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 29831/0479

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/05/2013

10    DATE OF REVISION OF THE TEXT

10/05/2013