Bayer Limited

Avelox 400 mg film-coated tablets

Each film-coated tablet contains 400 mg moxifloxacin as hydrochloride.

Excipient: The film-coated tablet contains lactose monohydrate (see section 4.4).

For a full list of excipients, see section 6.1.

Film-coated tablet

Dull red tablets marked with “M400” on one side and “BAYER” on the reverse.

Avelox 400 mg film-coated tablets are indicated for the treatment of the following bacterial infections in patients of 18 years and older caused by bacteria susceptible to moxifloxacin (see sections 4.4, 4.8 and 5.1). Moxifloxacin should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections or when these have failed:

- Acute bacterial sinusitis (adequately diagnosed)

- Acute exacerbations of chronic bronchitis (adequately diagnosed)

- Community acquired pneumonia, except severe cases

- Mild to moderate pelvic inflammatory disease (i.e. infections of female upper genital tract, including salpingitis and endometritis), without an associated tubo-ovarian or pelvic abscess.

Avelox 400 mg film-coated tablets are not recommended for use in monotherapy of mild to moderate pelvic inflammatory disease but should be given in combination with another appropriate antibacterial agent (e.g. a cephalosporin) due to increasing moxifloxacin resistance of Neisseria gonorrhoeae unless moxifloxacin-resistant Neisseria gonorrhoeae can be excluded (see sections 4.4 and 5.1).

Avelox 400 mg film-coated tablets may also be used to complete a course of therapy in patients who have shown improvement during initial treatment with intravenous moxifloxacin for the following indications:

- Community-acquired pneumonia

- Complicated skin and skin structure infections

Avelox 400 mg film-coated tablets should not be used to initiate therapy for any type of skin and skin structure infection or in severe community-acquired pneumonia.

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

Dosage (adults)

One 400 mg film-coated tablet once daily.

Renal/hepatic impairment

No adjustment of dosage is required in patients with mild to severely impaired renal function or in patients on chronic dialysis i.e. haemodialysis and continuous ambulatory peritoneal dialysis (see section 5.2 for more details).

There is insufficient data in patients with impaired liver function (see section 4.3).

Other special populations

No adjustment of dosage is required in the elderly and in patients with low bodyweight.

Children and adolescents

Moxifloxacin is contraindicated in children and adolescents (< 18 years). Efficacy and safety of moxifloxacin in children and adolescents have not been established (see section 4.3).

Method of administration

The film-coated tablet should be swallowed whole with sufficient liquid and may be taken independent of meals.

Duration of administration

Avelox 400 mg film-coated tablets should be used for the following treatment durations:

Avelox 400 mg film-coated tablets have been studied in clinical trials for up to 14 days treatment.

The recommended dose (400 mg once daily) and duration of therapy for the indication being treated should not be exceeded.

- Hypersensitivity to moxifloxacin, other quinolones or to any of the excipients.

- Pregnancy and lactation (see section 4.6).

- Patients below 18 years of age.

- Patients with a history of tendon disease/disorder related to quinolone treatment.

Both in preclinical investigations and in humans, changes in cardiac electrophysiology have been observed following exposure to moxifloxacin, in the form of QT prolongation. For reasons of drug safety, moxifloxacin is therefore contraindicated in patients with:

- Congenital or documented acquired QT prolongation

- Electrolyte disturbances, particularly in uncorrected hypokalaemia

- Clinically relevant bradycardia

- Clinically relevant heart failure with reduced left-ventricular ejection fraction

- Previous history of symptomatic arrhythmias

Moxifloxacin should not be used concurrently with other drugs that prolong the QT interval (see also section 4.5).

Due to limited clinical data, moxifloxacin is also contraindicated in patients with impaired liver function (Child Pugh C) and in patients with transaminases increase > 5fold ULN.

Prolongation of QTc interval and potentially QTc-prolongation-related clinical conditions

Moxifloxacin has been shown to prolong the QTc interval on the electrocardiogram in some patients. In the analysis of ECGs obtained in the clinical trial program, QTc prolongation with moxifloxacin was 6 msec ± 26 msec, 1.4% compared to baseline. As women tend to have a longer baseline QTc interval compared with men, they may be more sensitive to QTc-prolonging medications. Elderly patients may also be more susceptible to drug-associated effects on the QT interval.

Medication that can reduce potassium levels should be used with caution in patients receiving moxifloxacin.

Moxifloxacin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients), such as acute myocardial ischaemia or QT prolongation as this may lead to an increased risk for ventricular arrhythmias (incl. torsade de pointes) and cardiac arrest (see also section 4.3). The magnitude of QT prolongation may increase with increasing concentrations of the drug. Therefore, the recommended dose should not be exceeded.

The benefit of moxifloxacin treatment especially in infections with a low degree of severity should be balanced with the information contained in the warnings and precautions section.

If signs of cardiac arrhythmia occur during treatment with moxifloxacin, treatment should be stopped and an ECG should be performed.

Hypersensitivity / allergic reactions

Hypersensitivity and allergic reactions have been reported for fluoroquinolones including moxifloxacin after first administration. Anaphylactic reactions can progress to a life-threatening shock, even after the first administration. In these cases moxifloxacin should be discontinued and suitable treatment (e.g. treatment for shock) initiated.

Severe liver disorders

Cases of fulminant hepatitis potentially leading to liver failure (including fatal cases) have been reported with moxifloxacin (see section 4.8). Patients should be advised to contact their doctor prior to continuing treatment if signs and symptoms of fulminant hepatic disease develop such as rapidly developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy.

Liver function tests/investigations should be performed in cases where indications of liver dysfunction occur.

Serious bullous skin reactions

Cases of bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with moxifloxacin (see section 4.8). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

Patients predisposed to seizures

Quinolones are known to trigger seizures. Use should be with caution in patients with CNS disorders or in the presence of other risk factors which may predispose to seizures or lower the seizure threshold. In case of seizures, treatment with moxifloxacin should be discontinued and appropriate measures instituted.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesias, hypoaesthesias, dysaesthesias, or weakness have been reported in patients receiving quinolones. Patients under treatment with moxifloxacin should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop (see section 4.8).

Psychiatric reactions

Psychiatric reactions may occur even after the first administration of quinolones, including moxifloxacin. In very rare cases depression or psychotic reactions have progressed to suicidal thoughts and self-endangering behaviour such as suicide attempts (see section 4.8). In the event that the patient develops these reactions, moxifloxacin should be discontinued and appropriate measures instituted. Caution is recommended if moxifloxacin is to be used in psychotic patients or in patients with history of psychiatric disease.

Antibiotic-associated diarrhoea incl. colitis

Antibiotic-associated diarrhoea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, has been reported in association with the use of broad spectrum antibiotics including moxifloxacin and may range in severity from mild diarrhoea to fatal colitis. Therefore it is important to consider this diagnosis in patients who develop serious diarrhoea during or after the use of moxifloxacin. If AAD or AAC is suspected or confirmed, ongoing treatment with antibacterial agents, including moxifloxacin, should be discontinued and adequate therapeutic measures should be initiated immediately. Furthermore, appropriate infection control measures should be undertaken to reduce the risk of transmission. Drugs inhibiting peristalsis are contraindicated in patients who develop serious diarrhoea.

Patients with myasthenia gravis

Moxifloxacin should be used with caution in patients with myasthenia gravis because the symptoms can be exacerbated.

Tendon inflammation, tendon rupture

Tendon inflammation and rupture may occur with quinolone therapy including moxifloxacin, particularly in elderly patients and in those treated concurrently with corticosteroids. At the first sign of pain or inflammation, patients should discontinue treatment with moxifloxacin, rest the affected limb(s) and consult their doctor immediately in order to initiate appropriate treatment (e.g. immobilisation) for the affected tendon. Tendon inflammation and rupture may occur even up to several months after discontinuing quinolone therapy including moxifloxacin.

Patients with renal impairment

Elderly patients with renal disorders should use moxifloxacin with caution if they are unable to maintain adequate fluid intake, because dehydration may increase the risk of renal failure.

Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).

Prevention of photosensitivity reactions

Quinolones have been shown to cause photosensitivity reactions in patients. However, studies have shown that moxifloxacin has a lower risk to induce photosensitivity. Nevertheless patients should be advised to avoid exposure to either UV irradiation or extensive and/or strong sunlight during treatment with moxifloxacin.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with a family history of, or actual glucose-6-phosphate dehydrogenase deficiency are prone to haemolytic reactions when treated with quinolones. Therefore, moxifloxacin should be used with caution in these patients.

Patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Patients with pelvic inflammatory disease

For patients with complicated pelvic inflammatory disease (e.g. associated with a tubo-ovarian or pelvic abscess), for whom an intravenous treatment is considered necessary, treatment with Avelox 400 mg film-coated tablets is not recommended.

Pelvic inflammatory disease may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae. Therefore in such cases empirical moxifloxacin should be co-administered with another appropriate antibiotic (e.g. a cephalosporin) unless moxifloxacin-resistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.

Patients with special cSSSI

Clinical efficacy of intravenous moxifloxacin in the treatment of severe burn infections, fasciitis and diabetic foot infections with osteomyelitis has not been established.

Interference with biological tests

Moxifloxacin therapy may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth causing false negative results.

Patients with MRSA infections

Moxifloxacin is not recommended for the treatment of MRSA infections. In case of a suspected or confirmed infection due to MRSA, treatment with an appropriate antibacterial agent should be started (see section 5.1).

Paediatric population

Due to adverse effects on the cartilage in juvenile animals (see section 5.3) the use of moxifloxacin in children and adolescents < 18 years is contraindicated (see section 4.3).

Interactions with medicinal products

An additive effect on QT interval prolongation of moxifloxacin and other medicinal products that may prolong the QTc interval cannot be excluded. This might lead to an increased risk of ventricular arrhythmias, including torsade de pointes. Therefore co-administration of moxifloxacin with any of the following medicinal products is contraindicated (see also section 4.3):

- anti-arrhythmics class IA (e.g. quinidine, hydroquinidine, disopyramide)

- anti-arrhythmics class III (e.g. amiodarone, sotalol, dofetilide, ibutilide)

- antipsychotics (e.g. phenothiazines, pimozide, sertindole, haloperidol, sultopride)

- tricyclic antidepressive agents

- certain antimicrobial agents (sparfloxacin, erythromycin IV, pentamidine, antimalarials particularly halofantrine)

- certain antihistaminics (terfenadine, astemizole, mizolastine)

- others (cisapride, vincamine IV, bepridil, diphemanil).

An interval of about 6 hours should be left between administration of agents containing bivalent or trivalent cations (e.g. antacids containing magnesium or aluminium, didanosine tablets, sucralfate and agents containing iron or zinc) and administration of moxifloxacin.

Concomitant administration of charcoal with an oral dose of 400 mg moxifloxacin leads to a pronounced prevention of drug absorption and a reduced systemic availability of the drug by more than 80%. Therefore, the concomitant use of these two drugs is not recommended (except for overdose cases, see also section 4.9).

After repeated dosing in healthy volunteers, moxifloxacin increased C_max of digoxin approximately 30% without affecting AUC or trough levels. No precaution is required for use with digoxin.

In studies conducted in diabetic volunteers, concomitant administration of oral moxifloxacin with glibenclamide resulted in a decrease of approximately 21% in the peak plasma concentrations of glibenclamide. The combination of glibenclamide and moxifloxacin could theoretically result in a mild and transient hyperglycaemia. However, the observed pharmacokinetic changes for glibenclamide did not result in changes of the pharmacodynamic parameters (blood glucose, insulin). Therefore no clinically relevant interaction was observed between moxifloxacin and glibenclamide.

Changes in INR

A large number of cases showing an increase in oral anticoagulant activity have been reported in patients receiving antibiotics, especially fluoroquinolones, macrolides, tetracyclines, cotrimoxazole and some cephalosporins. The infectious and inflammatory conditions, age and general status of the patient appear to be risk factors. Under these circumstances, it is difficult to evaluate whether the infection or the antibiotic therapy cause the INR (international normalised ratio) disorder. A precautionary measure would be to more frequently monitor the INR. If necessary, the oral anticoagulant dosage should be adjusted as appropriate. Even if during an interaction study performed in healthy volunteers between moxifloxacin and warfarin, negative results have been observed, the precautionary measures as above stated should apply to warfarin as for other anticoagulants.

Clinical studies have shown that there are no interactions following concomitant administration of moxifloxacin with: ranitidine, probenecid, oral contraceptives, calcium supplements, morphine administered parenterally, theophylline, cyclosporine or itraconazole.

In vitro studies with human cytochrome P450 enzymes support this data. Considering these results a metabolic interaction via cytochrome P450 enzymes is unlikely.

Interaction with food

Moxifloxacin has no clinically relevant interaction with food including dairy products.

Pregnancy

The use of moxifloxacin during pregnancy is contraindicated. The safety of moxifloxacin in human pregnancy has not been evaluated. Reversible joint injuries are described in children receiving some quinolones, however this effect has not been reported as occurring on exposed foetuses. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Lactation

The use of moxifloxacin during breast feeding is contraindicated. As with other quinolones, moxifloxacin has been shown to cause lesions in the cartilage of the weight bearing joints of immature animals. Preclinical data indicate that moxifloxacin passes into milk.

No studies on the effects of moxifloxacin on the ability to drive and use machines have been performed. However, fluoroquinolones including moxifloxacin may result in an impairment of the patient's ability to drive or operate machinery due to CNS reactions (e.g. dizziness; acute, transient loss of vision, see section 4.8) or acute and short lasting loss of consciousness (syncope, see section 4.8). Patients should be advised to see how they react to moxifloxacin before driving or operating machinery.

Adverse reactions based on all clinical trials with moxifloxacin 400 mg (oral and sequential therapy) sorted by frequencies are listed below:

Apart from nausea and diarrhoea all adverse reactions were observed at frequencies below 3%.

There have been very rare cases of the following side effects reported following treatment with other fluoroquinolones, which might possibly also occur during treatment with moxifloxacin: hypernatraemia, hypercalcaemia, haemolytic anaemia, rhabdomyolysis, photosensitivity reactions, peripheral neuropathy (see section 4.4).

No specific countermeasures after accidental overdose are recommended. In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Concomitant administration of charcoal with a dose of 400 mg oral moxifloxacin will reduce systemic availability of the drug by more than 80%. The use of charcoal early during absorption may be useful to prevent excessive increase in the systemic exposure to moxifloxacin in cases of oral overdose.

Pharmacotherapeutic group: Quinolone antibacterials, fluoroquinolones, ATC code: J01 MA 14

Mechanism of action

Moxifloxacin has in vitro activity against a wide range of Gram-positive and Gram-negative pathogens.

The bactericidal action of moxifloxacin results from the inhibition of both type II topoisomerases (DNA gyrase and topoisomerase IV) required for bacterial DNA replication, transcription and repair. It appears that the C8-methoxy moiety contributes to enhanced activity and lower selection of resistant mutants of Gram-positive bacteria compared to the C8-H moiety. The presence of the bulky bicycloamine substituent at the C-7 position prevents active efflux, associated with the norA or pmrA genes seen in certain Gram-positive bacteria.

Pharmacodynamic investigations have demonstrated that moxifloxacin exhibits a concentration dependent killing rate. Minimum bactericidal concentrations (MBC) were found to be in the range of the minimum inhibitory concentrations (MIC).

Effect on the intestinal flora in humans

The following changes in the intestinal flora were seen in volunteers following oral administration of moxifloxacin: Escherichia coli, Bacillus spp., Enterococcus spp., and Klebsiella spp. were reduced, as were the anaerobes Bacteroides vulgatus, Bifidobacterium spp., Eubacterium spp., and Peptostreptococcus spp.. For Bacteroides fragilis there was an increase. These changes returned to normal within two weeks.

Mechanism of resistance

Resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not interfere with the antibacterial activity of moxifloxacin. Other resistance mechanisms such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may also effect susceptibility to moxifloxacin.

In vitro resistance to moxifloxacin is acquired through a stepwise process by target site mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Moxifloxacin is a poor substrate for active efflux mechanisms in Gram-positive organisms.

Cross-resistance is observed with other fluoroquinolones. However, as moxifloxacin inhibits both topoisomerase II and IV with similar activity in some Gram-positive bacteria, such bacteria may be resistant to other quinolones, but susceptible to moxifloxacin.

In vitro Susceptibility Data

EUCAST clinical MIC breakpoints for moxifloxacin (31.01.2006):

Clinical and Laboratory Standards Institute™ (CLSI), formerly NCCLS breakpoints are presented in the below table for MIC testing (mg/l) or disc diffusion testing (zone diameter [mm]) using a 5-µg moxifloxacin disc.

Clinical and Laboratory Standards Institute™ (CLSI) MIC and disc diffusion breakpoints for Staphylococcus spp. and fastidious organisms (M100-S17, 2007) and MIC breakpoints for anaerobes (M11-A7, 2007):

The prevalence of acquired resistance may vary geographically and with time for selected species and local information of resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought where the local prevalence of resistance is such that utility of the agent in at least some types of infections is questionable.

Absorption and Bioavailability

Following oral administration moxifloxacin is rapidly and almost completely absorbed. The absolute bioavailability amounts to approximately 91%.

Pharmacokinetics are linear in the range of 50 - 800 mg single dose and up to 600 mg once daily dosing over 10 days. Following a 400 mg oral dose peak concentrations of 3.1 mg/l are reached within 0.5 - 4 h post administration. Peak and trough plasma concentrations at steady-state (400 mg once daily) were 3.2 and 0.6 mg/l, respectively. At steady-state the exposure within the dosing interval is approximately 30% higher than after the first dose.

Distribution

Moxifloxacin is distributed to extravascular spaces rapidly; after a dose of 400 mg an AUC of 35 m∙gh/l is observed. The steady-state volume of distribution (Vss) is approximately 2 l/kg. In vitro and ex vivo experiments showed a protein binding of approximately 40 - 42% independent of the concentration of the drug. Moxifloxacin is mainly bound to serum albumin.

The following peak concentrations (geometric mean) were observed following administration of a single oral dose of 400 mg moxifloxacin:

Metabolism

Moxifloxacin undergoes Phase II biotransformation and is excreted via renal and biliary/faecal pathways as unchanged drug as well as in the form of a sulpho-compound (M1) and a glucuronide (M2). M1 and M2 are the only metabolites relevant in humans, both are microbiologically inactive.

In clinical Phase I and in vitro studies no metabolic pharmacokinetic interactions with other drugs undergoing Phase I biotransformation involving cytochrome P450 enzymes were observed. There is no indication of oxidative metabolism.

Elimination

Moxifloxacin is eliminated from plasma with a mean terminal half life of approximately 12 hours. The mean apparent total body clearance following a 400 mg dose ranges from 179 to 246 ml/min. Renal clearance amounted to about 24 - 53 ml/min suggesting partial tubular reabsorption of the drug from the kidneys.

After a 400 mg dose, recovery from urine (approximately 19% for unchanged drug, approximately 2.5% for M1, and approximately 14% for M2) and faeces (approximately 25% of unchanged drug, approximately 36% for M1, and no recovery for M2) totalled to approximately 96%.

Concomitant administration of moxifloxacin with ranitidine or probenecid did not alter renal clearance of the parent drug.

Higher plasma concentrations are observed in healthy volunteers with low body weight (such as women) and in elderly volunteers.

The pharmacokinetic properties of moxifloxacin are not significantly different in patients with renal impairment (including creatinine clearance > 20 ml/min/1.73 m²). As renal function decreases, concentrations of the M2 metabolite (glucuronide) increase by up to a factor of 2.5 (with a creatinine clearance of < 30 ml/min/1.73 m²).

On the basis of the pharmacokinetic studies carried out so far in patients with liver failure (Child Pugh A, B), it is not possible to determine whether there are any differences compared with healthy volunteers. Impaired liver function was associated with higher exposure to M1 in plasma, whereas exposure to parent drug was comparable to exposure in healthy volunteers. There is insufficient experience in the clinical use of moxifloxacin in patients with impaired liver function.

Effects on the haematopoetic system (slight decreases in the number of erythrocytes and platelets) were seen in rats and monkeys. As with other quinolones, hepatotoxicity (elevated liver enzymes and vacuolar degeneration) was seen in rats, monkeys and dogs. In monkeys CNS toxicity (convulsions) occurred. These effects were seen only after treatment with high doses of moxifloxacin or after prolonged treatment.

Moxifloxacin, like other quinolones, was genotoxic in in vitro tests using bacteria or mammalian cells. Since these effects can be explained by an interaction with the gyrase in bacteria and - at higher concentrations - by an interaction with the topoisomerase II in mammalian cells, a threshold concentration for genotoxicity can be assumed. In in vivo tests, no evidence of genotoxicity was found despite the fact that very high moxifloxacin doses were used. Thus, a sufficient margin of safety to the therapeutic dose in man can be provided. Moxifloxacin was non-carcinogenic in an initiation-promotion study in rats.

Many quinolones are photoreactive and can induce phototoxic, photomutagenic and photocarcinogenic effects. In contrast, moxifloxacin was proven to be devoid of phototoxic and photogenotoxic properties when tested in a comprehensive programme of in vitro and in vivo studies. Under the same conditions other quinolones induced effects.

At high concentrations, moxifloxacin is an inhibitor of the rapid component of the delayed rectifier potassium current of the heart and may thus cause prolongations of the QT interval. Toxicological studies performed in dogs using oral doses of 90 mg/kg leading to plasma concentrations 16 mg/l caused QT prolongations, but no arrhythmias. Only after very high cumulative intravenous administration of more than 50fold the human dose (> 300 mg/kg), leading to plasma concentrations of 200 mg/l (more than 40fold the therapeutic level), reversible, non-fatal ventricular arrhythmias were seen.

Quinolones are known to cause lesions in the cartilage of the major diarthrodial joints in immature animals. The lowest oral dose of moxifloxacin causing joint toxicity in juvenile dogs was four times the maximum recommended therapeutic dose of 400 mg (assuming a 50 kg bodyweight) on a mg/kg basis, with plasma concentrations two to three times higher than those at the maximum therapeutic dose.

Toxicity tests in rats and monkeys (repeated dosing up to six months) revealed no indication regarding an oculotoxic risk. In dogs, high oral doses ( 60 mg/kg) leading to plasma concentrations 20 mg/l caused changes in the electroretinogram and in isolated cases an atrophy of the retina.

Reproductive studies performed in rats, rabbits and monkeys indicate that placental transfer of moxifloxacin occurs. Studies in rats (p.o. and i.v.) and monkeys (p.o.) did not show evidence of teratogenicity or impairment of fertility following administration of moxifloxacin. A slightly increased incidence of vertebral and rib malformations was observed in foetuses of rabbits but only at a dose (20 mg/kg i.v.) which was associated with severe maternal toxicity. There was an increase in the incidence of abortions in monkeys and rabbits at human therapeutic plasma concentrations. In rats, decreased foetal weights, an increased prenatal loss, a slightly increased duration of pregnancy and an increased spontaneous activity of some male and female offspring was observed at doses which were 63 times the maximum recommended dose on a mg/kg basis with plasma concentrations in the range of the human therapeutic dose.

Tablet core:

Microcrystalline cellulose

Croscarmellose sodium

Lactose monohydrate

Magnesium stearate

Film coat:

Hypromellose

Macrogol 4000

Ferric oxide (E172)

Titanium dioxide (E171)

Not applicable.

5 years

Polypropylene/aluminium blisters

Do not store above 25°C.

Store in the original package in order to protect from moisture.

Aluminium/aluminium blisters

Store in the original package in order to protect from moisture.

Cartons containing colourless or white opaque polypropylene/aluminium blisters:

The film-coated tablets are available in packs of 5, 7, and 10 tablets.

Hospital packs containing 25 (5 x 5), 50 (5 x 10), 70 (7 x 10) film-coated tablets or bundled containing 80 (5 x 16) or 100 (10 x 10) film-coated tablets.

Aluminium/aluminium blisters, pack size one tablet in a carton.

Not all pack sizes may be marketed.

No special requirements.

Bayer Limited,

The Atrium,

Blackthorn Road,

Dublin 18

PA1410/27/1

Date of first authorisation: 10th December 1999

Date of last renewal: 30th November 2008

July 2011