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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Azithromycin 250mg Film-Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Azithromycin 250mg Film-Coated Tablets contain 250mg azithromycin (anhydrous), equivalent to 250mg azithromycin base.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

White to off-white film-coated oval shaped biconvex tablet debossed with W 961 on one side and plain on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of the following bacterial infections induced by micro-organisms susceptible to azithromycin (see sections 4.4 and 5.1):

-    Acute bacterial sinusitis (adequately diagnosed)

-    Acute bacterial otitis media (adequately diagnosed)

-    Pharyngitis, tonsillitis

-    Acute exacerbation of chronic    bronchitis (adequately diagnosed)

-    Community acquired pneumonia

-    Skin and soft tissue infections

-    Uncomplicated Chlamydia trachomatis urethritis and cervicitis

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

4.2 Posology and method of administration

This medicine should be taken in a single daily dose. The tablets should be swallowed whole and may be taken with or without food. The length of treatment for various infectious diseases is set out below.

Children and adolescents with a body weight above 45 kg, adults and the elderly:

The total dosage of azithromycin is 1500 mg, staggered over three days (500 mg once daily). Alternatively, the dosage may be staggered over five days (500 mg as a single dose on the first day, and then 250 mg once daily).

In the case of uncomplicated Chlamydia trachomatis urethritis and cervicitis, the dosage is 1000 mg as a single oral dose.

Children and adolescents with a body weight below 45 kg:

Azithromycin <> tablets are not suitable for these patients. Other pharmaceutical forms of azithromycin may be used, such as suspensions.

Elderly patients:

Dose adjustment is not required for the elderly.

Patients with renal impairment:

Dose adjustment is not required in patients with mild to moderate renal impairment (GFR 10-80 ml/min) (see section 4.4).

Patients with hepatic impairment:

Dose adjustment is not required for patients with mild to moderate hepatic dysfunction (see section 4.4).

4.3 Contraindications

The use of azithromycin is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any excipient 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 angioedema 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.

Renal failure:

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 ml/min). 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).

Hepatic failure:

Since 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) Liver function tests/investigations should be performed in cases where signs and symptoms of liver dysfunction occur such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy.

When severe liver impairment occurs, the treatment with azithromycin should be ceased.

Ergot alkaloids and Azithromycin:

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 coadministered. (see section 4.5).

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 repolarization (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 substances known to prolong QT interval such as antiarrhythmics of classes IA and III, cisapride and terfenadine.

-    With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesemia.

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

Pneumococcal infections:

As for other macrolides, high resistance rates of Streptococcus pneumoniae (> 30 %) have been reported for azithromycin in some European countries (see section 5.1). This should be taken into account when treating infections caused by Streptococcus pneumoniae.

Due to cross-resistance existing among macrolides, in areas with a high incidence of erythromycin resistance, it is especially important to take into consideration the evolution of the pattern of susceptibility to azithromycin and other antibiotics (see section 5.1).

Superinfections:

Attention should be paid to possible symptoms of superinfections caused by non-sensitive causal agents such as fungi. A superinfection may require an interruption of the azithromycin treatment and initiation of adequate measures.

Neurological or psychiatric diseases:

Azithromycin should be administered with caution to patients suffering from neurological or psychiatric diseases.

Pseudomembranous colitis:

After the use of macrolide antibiotics pseudomembranous colitis has been reported. This diagnosis should therefore be considered for patients who suffer from diarrhoea after start of the treatment with azithromycin. Should pseudomembranous colitis be induced by azithromycin, then anti-peristaltics should be contraindicated.

Clostridium difficile associated diarrhea:

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Long term use:

There is no experience regarding the safety and efficacy of long term use of azithromycin for the mentioned indications. In case of rapid recurrent infections, treatment with another antibiotic should be considered.

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).

This medicine is not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.

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

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, coadministration 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):

Coadministration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 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.

Ergotamine:

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 special precautions for use).

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

Atorvastatin:

Coadministration 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 post-marketing period of potentiated anticoagulation subsequent to coadministration 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.

Cyclosporin:

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 cyclosporin, the resulting cyclosporin C_max and AUC_0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

Efavirenz:

Coadministration 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:

Coadministration 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 coadministration of fluconazole, however, a clinically insignificant decrease in C_max (18%) of azithromycin was observed.

Indinavir:

Coadministration 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 5 days.

Methylprednisolone:

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

Midazolam:

In healthy volunteers, coadministration 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:

Coadministration 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:

Coadministration 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 (500mg daily for 3 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, coadministration of azithromycin 500 mg on Day 1 and 250 mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole:

Coadministration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with azithromycin 1200 mg on Day 7 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.

CYP3A4 substrates:

Even though azithromycin does not appear to inhibit the enzyme CYP3A4, caution is advised when combining the medicinal product with quinidine, cyclosporine, cisapride, astemizole, terfenadine, ergot alkaloids, pimozide or other medicinal products with a narrow therapeutic index predominantly metabolised by CYP3A4.

Cisapride:

Cisapride is metabolized in the liver by the enzyme CYP 3A4. Because macrolides inhibit this enzyme, concomitant administration of cisapride may cause the increase of QT interval prolongation, ventricular arrhythmias and torsade de pointes.

Astemizol and, Alfentanil:

No data are available on interactions with astemizol, and alfentanil. Caution should be exercised with concomitant use of these agents and azithromycin in view of the described potentation of its effect during concomitant use of the macrolide antibiotic erythromycin.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well controlled studies on the use of azithromycin by pregnant women. Limited human data do not suggest an increase in the risk of birth defects. Azithromycin crosses the placenta in limited amounts.

Animal data do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Azithromycin should only be used during pregnancy when the benefit clearly outweighs the risk.

Lactation

Limited data indicate that azithromycin passes into breast milk in limited amounts. A risk to the suckling infant cannot be excluded. Azithromycin should not be used in the treatment of a lactating woman unless the potential benefits justify the potential risks to the infant.

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

No data are available regarding the influence of azithromycin on a patient's ability to drive or operate machinery. Side effects such as dizziness, which can affect the ability to drive or operate machinery can occur with azihtromycin.

4.8 Undesirable effects

The table below lists the adverse reactions identified through clinical trial experience and post-marketing 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 > 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 < 1/10,00 0	not known frequency cannot be estimated from available data
Infections and infestations
		Candidiasis Oral candidiasis Vaginal infection			Pseudomembranous colitis (see 4.4)
B		ood and lympha	tic system disorders
		Leukopenia Neutropenia			Thrombocytopen ia, Haemolytic anaemia
Immune sysl			tem disorders
		Angioedema Hypersensitivit y			Anaphylactic reaction (see section 4.4.)
Metabolism and nutrition disorders
	anorexia
Psychiatric disorders
		Nervousness	Agitation		Aggression Anxiety
Nervous syst			tem disorders
	Dizziness Headache Paraesthesi a Dysgeusia	Hypoaesthesia Somnolence Insomnia			Syncope, Convulsion, Psychomotor hyperactivity, Anosmia, Ageusia, Parosmia, Exacerbation or aggravation of myasthenia gravis (see 4.4)
Eye disorders
	Visual impairmen

	t
Ear and labyrinth disorders
	Deafness	Hearing impaired, tinnitus	Vertigo
Cardiac disorders
		palpitations			Torsades de pointes (see Section 4.4) Arrhythmia including ventricular tachycardia.
Vascular disorders
					Hypotension
Gastrointestinal disorders
Diarrhoea 5 Abdomin al pain, Nausea, Flatulenc e	Vomiting Dyspepsia	Gastritits Constipation			Pancreatitis, Tongue and teeth discoloration
Hepatobiliary disorders
		Hepatitis	Hepatic function abnormal		Hepatic failure (see 4.4), which has rarely resulted in death, Hepatitis fulminant, Hepatic necrosis, Jaundice cholestatic
Skin and subcutaneous tissue disorders
	Rash, Pruritis	Stevens- Johnson syndrome, Photosensitivit y reaction, Urticaria	allergic reactions including angioneurot ic oedema,		Toxic epidermal necrolysis, Erythema multiforme
Musculoskeletal and 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
	Lymphocy te count decreased, eosinophil count increased, blood bicarbonat e decreased	Aspartate aminotransfera se increased, alanine aminotransfera se increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormal			Electrocardiogra m QT prolonged (see section 4.4)

Reporting of suspected adverse reactions

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

4.9 Overdose

Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, macrolides ATC code: J01FA10

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.

Mode of action:

The mechanism of action of azithromycin is based upon the suppression of bacterial protein synthesis, by binding to the ribosomal 50S sub-unit and thus inhibiting the translocation of peptides.

PK/PD relationship:

For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin.

Mechanism of resistance:

Generally, the resistance of different bacterial species to macrolides has been reported to occur by three mechanisms associated with target site alteration, antibiotic modification, or altered antibiotic transport (efflux). The efflux in streptococci is conferred by the mef genes and results in a macrolide-restricted resistance (M phenotype). Target modification is controlled by erm encoded methylases.

A complete cross resistance exists among erythromycin, azithromycin, other macrolides and lincosamides for Streptococcus pneumoniae, beta-haemolytic streptococcus of group A, Enterococcus spp. and Staphylococcus aureus, including methicillin resistant Staphylococcus aureus (MRSA). Penicillin susceptible Streptococcus pneumoniae are more likely to be susceptible to azithromycin than are penicillin resistant strains of Streptococcus pneumoniae. Methicillin resistant Staphylococcus aureus (MRSA) is less likely to be susceptible to azithromcyin than methicillin susceptible Staphylococcus aureus (MSSA).

The induction of significant resistance in both in vitro and in vivo models is <1 dilution rise in MICs for Streptococcus pyogenes, Haemophilus influenzae, and Enterobacterciae after nine sub lethal passages of active substance and three dilution increase for Staphylococcus aureus and development of in vitro resistance due to mutation is rare.

Breakpoints

Azithromycin susceptibility breakpoints for typical bacterial pathogens: 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

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information provides only an

Distribution:

Orally administered azithromycin is widely distributed over the whole body.

Pharmacokinetic studies have shown considerably higher azithromycin concentrations in the tissues (up to 50 times the maximum concentration observed in the plasma) than in the plasma. This indicates that the substance is extensively bound in the tissues (steady-state volume of distribution approximately 31 l/kg).

With the recommended dosage no accumulation in the serum/plasma occurs. Accumulation does occur in the tissues where the levels are much higher than in the serum/plasma. Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC₉₀ for likely pathogens after a single dose of 500 mg.

In experimental in-vitro and in-vivo studies, azithromycin accumulates in phagocytes; release is promoted by active phagocytosis. In animal models this process appeared to contribute to the accumulation of azithromycin in tissue. The binding of azithromycin to plasma proteins is variable, and varies from 52 % at 0.05 ^g/ml to 18 % at 0.5 ^g/ml, depending on the serum concentration.

Metabolism and Excretion:

The terminal plasma elimination half-life follows the tissue depletion half-life of 2 to 4 days.

Approximately 12 % of an intravenously administered dose is excreted in unchanged form with the urine over a period of 3 days; the major proportion in the first 24 hours. Concentrations of up to 237 ^g/ml azithromycin, 2 days after a 5-day course of treatment, have been found in human bile.Ten metabolites have been identified (formed by N- and O-demethylation, by hydroxylation of the desosamine and aglycone rings, and by splitting of the cladinose conjugate). Investigations suggests that the metabolites do not play a role in the microbiological activity of azithromycin.

Pharmacokinetics in Special populations:

Renal Insufficiency:

Following a single oral dose of azithromycin 1 g, mean C_ma_xand 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_ma_xand AUC_0-120 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 pg/l in those aged 6-15 years. The half-life 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 40 times the proposed clinical dose, phospholipidosis (intracellular phospholipids 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 of dosing; however, the clinical relevance of this finding is unknown.

Electrophysiological investigations have shown that azithromycin prolongs the QT interval.

Mutagenic potential:

At cytotoxic concentrations (240 pg/mL), azithromycin caused an increase in mutant frequency in a mouse lymphoma assay. However, overall, 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 foetal ossification was observed at 50 to 200 mg/kg/day, while a reduction in maternal weight gain was noted at 100 and 200 mg/kg/day. In rat peri- and post-natal studies, mild retardations in physical and reflex development were noted.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Microcrystalline cellulose Maize starch Croscarmellose sodium Magnesium trisilicate (E553a) Magnesium stearate Colloidal silicon dioxide (E551) Hydroxypropyl cellulose (E463) Sodium lauryl sulphate

Film-coating:

Opadry Y-1-7000 white: Hypromellose (E464)

Titanium dioxide (E171) Polyethylene glycol 400

6.2 Incompatibilities

None known.

6.3 Shelf life

24 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Aluminium/PVC blister packs in a cardboard carton. Pack size: 2, 3, 4, 6, 9, 12 and 24 film-coated tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 29831/0537

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/07/2013

10 DATE OF REVISION OF THE TEXT

27/06/2014