Trileptal^® 60 mg/ml Oral Suspension.

1 ml of the oral suspension contains 60 mg oxcarbazepine.

Excipients: Each ml also contains 0.30 mg propylparahydroxybenzoate (E216), 1.20 mg methylparahydroxybenzoate (E218), 250 mg sorbitol 70 % liquid (non crystallising) and 0.9 mg ethanol.

For a full list of excipients, see section 6.1.

Oral suspension.

Off-white to slightly reddish brown oral suspension.

Trileptal is indicated for the treatment of partial seizures with or without secondarily generalised tonic-clonic seizures.

Trileptal is indicated for use as monotherapy or adjunctive therapy in adults and in children of 6 years of age and above.

In mono- and adjunctive therapy, treatment with Trileptal is initiated with a clinically effective dose given in two divided doses. The dose may be increased depending on the clinical response of the patient. When other antiepileptic medicinal products are replaced by Trileptal, the dose of the concomitant antiepileptic medicinal product(s) should be reduced gradually on initiation of Trileptal therapy. In adjunctive therapy, as the total antiepileptic medicinal product load of the patient is increased, the dose of concomitant antiepileptic medicinal product(s) may need to be reduced and/or the Trileptal dose increased more slowly (see section 4.5).

Trileptal can be taken with or without food.

The prescription for Trileptal oral suspension should be given in millilitres (see conversion table below which gives the milligram dose in millilitres). The prescribed dose in millilitres is rounded to the nearest 0.5 ml.

The doses given in the table below are only applicable to patients aged 6 years and above. These doses are to be administered twice a day.

Before taking Trileptal oral suspension, the bottle should be shaken well and the dose prepared immediately afterwards. The prescribed amount of oral suspension should be withdrawn from the bottle using the oral syringe supplied. Trileptal oral suspension may be swallowed directly from the syringe or can be mixed in a small glass of water just prior to administration. After each use, the bottle should be closed and the outside of the syringe wiped with a dry, clean tissue.

Trileptal oral suspension and Trileptal film-coated tablets may be interchanged at equal doses.

The following dosing recommendations apply to all patients, in the absence of impaired renal function (see section 5.2). Drug plasma level monitoring is not necessary to optimise Trileptal therapy.

Adults

Monotherapy

Trileptal should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses. If clinically indicated, the dose may be increased by a maximum of 600 mg/day increments at approximately weekly intervals from the starting dose to achieve the desired clinical response. Therapeutic effects are seen at doses between 600 mg/day and 2,400 mg/day.

Controlled monotherapy trials in patients not currently being treated with antiepileptic medicinal products showed 1,200 mg/day to be an effective dose; however, a dose of 2,400 mg/day has been shown to be effective in more refractory patients converted from other antiepileptic medicinal products to Trileptal monotherapy.

In a controlled hospital setting, dose increases up to 2,400 mg/day have been achieved over 48 hours.

Adjunctive therapy

Trileptal should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses. If clinically indicated, the dose may be increased by a maximum of 600 mg/day increments at approximately weekly intervals from the starting dose to achieve the desired clinical response. Therapeutic responses are seen at doses between 600 mg/day and 2,400 mg/day.

Daily doses from 600 to 2,400 mg/day have been shown to be effective in a controlled adjunctive therapy trial, although most patients were not able to tolerate the 2,400 mg/day dose without reduction of concomitant antiepileptic medicinal products, mainly because of CNS-related adverse events. Daily doses above 2,400 mg/day have not been studied systematically in clinical trials.

Elderly

Adjustment of the dose is recommended in the elderly with compromised renal function (see 'Patients with renal impairment'). For patients at risk of hyponatraemia see section 4.4.

Children

In mono- and adjunctive therapy, Trileptal should be initiated with a dose of 8-10 mg/kg/day given in 2 divided doses. In adjunctive therapy, therapeutic effects were seen at a median maintenance dose of approximately 30 mg/kg/day. If clinically indicated, the dose may be increased by a maximum of 10 mg/kg/day increments at approximately weekly intervals from the starting dose, to a maximum dose of 46 mg/kg/day, to achieve the desired clinical response (see section 5.2).

Trileptal is recommended for use in children of 6 years of age and above. Safety and efficacy have been evaluated in controlled clinical trials involving approximately 230 children aged less than 6 years (down to 1 month). Trileptal is not recommended in children aged less than 6 years since safety and efficacy have not been adequately demonstrated.

All the above dosing recommendations (adults, elderly and children) are based on the doses studied in clinical trials for all age groups. However, lower initiation doses may be considered where appropriate.

Patients with hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. Trileptal has not been studied in patients with severe hepatic impairment, therefore, caution should be exercised when dosing severely impaired patients (see section 5.2).

Patients with renal impairment

In patients with impaired renal function (creatinine clearance less than 30 ml/min) Trileptal therapy should be initiated at half the usual starting dose (300 mg/day) and increased, in at least weekly intervals, to achieve the desired clinical response (see section 5.2).

Dose escalation in renally impaired patients may require more careful observation.

Hypersensitivity to the active substance or to any of the excipients.

Hypersensitivity

Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and reports of anaphylaxis have been received in the post-marketing period. Cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of Trileptal. If a patient develops these reactions after treatment with Trileptal, the drug should be discontinued and an alternative treatment started.

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25-30 % of these patients may experience hypersensitivity reactions (e.g. severe skin reactions) with Trileptal (see section 4.8).

Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients without history of hypersensitivity to carbamazepine. Such reactions can affect the skin, liver, blood and lymphatic system or other organs, either individually or together in the context of a systemic reaction (see section 4.8). In general, if signs and symptoms suggestive of hypersensitivity reactions occur (see section 4.8), Trileptal should be withdrawn immediately.

Dermatological effects

Serious dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme, have been reported very rarely in association with Trileptal use. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and very rarely be fatal. Trileptal associated cases occurred in both children and adults. The median time to onset was 19 days. Several isolated cases of recurrence of the serious skin reaction when rechallenged with Trileptal were reported. Patients who develop a skin reaction with Trileptal should be promptly evaluated and Trileptal withdrawn immediately unless the rash is clearly not drug related. In case of treatment withdrawal, consideration should be given to replacing Trileptal with other antiepileptic drug therapy to avoid withdrawal seizures. Trileptal should not be restarted in patients who discontinued treatment due to a hypersensitivity reaction (see section 4.3).

Hyponatraemia

Serum sodium levels below 125 mmol/l, usually asymptomatic and not requiring adjustment of therapy, have been observed in up to 2.7 % of Trileptal treated patients. Experience from clinical trials shows that serum sodium levels returned towards normal when the Trileptal dosage was reduced, discontinued or the patient was treated conservatively (e.g. restricted fluid intake). In patients with pre-existing renal conditions associated with low sodium or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics, desmopressin) as well as NSAIDs (e.g. indometacin), serum sodium levels should be measured prior to initiating therapy. Thereafter, serum sodium levels should be measured after approximately two weeks and then at monthly intervals for the first three months during therapy, or according to clinical need. These risk factors may apply especially to elderly patients. For patients on Trileptal therapy when starting on sodium-lowering medicinal products, the same approach for sodium checks should be followed. In general, if clinical symptoms suggestive of hyponatraemia occur on Trileptal therapy (see section 4.8), serum sodium measurement may be considered. Other patients may have serum sodium assessed as part of their routine laboratory studies.

All patients with cardiac insufficiency and secondary heart failure should have regular weight measurements to determine occurrence of fluid retention. In case of fluid retention or worsening of the cardiac condition, serum sodium should be checked. If hyponatraemia is observed, water restriction is an important counter-measurement. As oxcarbazepine may, very rarely, lead to impairment of cardiac conduction, patients with pre-existing conduction disturbances (e.g. atrioventricular-block, arrhythmia) should be followed carefully.

Hepatic function

Very rare cases of hepatitis have been reported, which in most of the cases resolved favourably. When a hepatic event is suspected, liver function should be evaluated and discontinuation of Trileptal should be considered.

Hematological effects

Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients treated with Trileptal during post-marketing experience (see section 4.8).

Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.

Suicidal behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for oxcarbazepine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Hormonal contraceptives

Female patients of childbearing age should be warned that the concurrent use of Trileptal with hormonal contraceptives may render this type of contraceptive ineffective (see section 4.5). Additional non-hormonal forms of contraception are recommended when using Trileptal.

Alcohol

Caution should be exercised if alcohol is taken in combination with Trileptal therapy, due to a possible additive sedative effect.

Withdrawal

As with all antiepileptic medicinal products, Trileptal should be withdrawn gradually to minimise the potential of increased seizure frequency.

Other

Trileptal oral suspension contains ethanol, less than 100 mg per dose. It contains parabenes which may cause allergic reactions (possibly delayed). It contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance.

Enzyme induction

Oxcarbazepine and its pharmacologically active metabolite (the monohydroxy derivative, MHD) are weak inducers in vitro and in vivo of the cytochrome 450 enzymes CYP3A4 and CYP3A5 responsible for the metabolism of a very large number of drugs, for example, immunosuppressants (e.g. ciclosporin, tacrolimus), oral contraceptives (see below), and some other antiepileptic medicinal products (e.g. carbamazepine) resulting in a lower plasma concentration of these medicinal products (see table below summarizing results with other antiepileptic medicinal products).

In vitro, oxcarbazepine and MHD are weak inducers of UDP-glucuronyl transferases (effects on specific enzymes in this family are not known). Therefore, in vivo oxcarbazepine and MHD may have a small inducing effect on the metabolism of medicinal products which are mainly eliminated by conjugation through the UDP-glucuronyl transferases. When initiating treatment with Trileptal or changing the dose, it may take 2 to 3 weeks to reach the new level of induction.

In case of discontinuation of Trileptal therapy, a dose reduction of the concomitant medications may be necessary and should be decided upon by clinical and/or plasma level monitoring. The induction is likely to gradually decrease over 2 to 3 weeks after discontinuation.

Hormonal contraceptives: Trileptal was shown to have an influence on the two components, ethinylestradiol (EE) and levonorgestrel (LNG), of an oral contraceptive. The mean AUC values of EE and LNG were decreased by 48-52 % and 32-52% respectively. Therefore, concurrent use of Trileptal with hormonal contraceptives may render these contraceptives ineffective (see section 4.4). Another reliable contraceptive method should be used.

Enzyme inhibition

Oxcarbazepine and MHD inhibit CYP2C19. Therefore, interactions could arise when co-administering high doses of Trileptal with medicinal products that are metabolised by CYP2C19 (e.g. phenytoin). Phenytoin plasma levels increased by up to 40 % when Trileptal was given at doses above 1,200 mg/day (see table below summarizing results with other anticonvulsants). In this case, a reduction of co-administered phenytoin may be required (see Section 4.2).

Antiepileptic medicinal products

Potential interactions between Trileptal and other antiepileptic medicinal products were assessed in clinical studies. The effect of these interactions on mean AUCs and C_min are summarised in the following table.

Summary of antiepileptic medicinal product interactions with Trileptal

* Preliminary results indicate that oxcarbazepine may result in lower lamotrigine concentrations, possibly of importance in children, but the interaction potential of oxcarbazepine appears lower than seen with concomitant enzyme inducing drugs (carbamazepine, phenobarbitone, and phenytoin).

Strong inducers of cytochrome P450 enzymes (i.e. carbamazepine, phenytoin and phenobarbitone) have been shown to decrease the plasma levels of MHD (29-40 %) in adults; in children 4 to 12 years of age, MHD clearance increased by approximately 35% when given one of the three enzyme-inducing antiepileptic medicinal products compared to monotherapy. Concomitant therapy of Trileptal and lamotrigine has been associated with an increased risk of adverse events (nausea, somnolence, dizziness and headache). When one or several antiepileptic medicinal products are concurrently administered with Trileptal, a careful dose adjustment and/or plasma level monitoring may be considered on a case by case basis, notably in paediatric patients treated concomitantly with lamotrigine.

No autoinduction has been observed with Trileptal.

Other medicinal product interactions

Cimetidine, erythromycin, viloxazine, warfarin and dextropropoxyphene had no effect on the pharmacokinetics of MHD.

The interaction between oxcarbazepine and MAOIs is theoretically possible based on a structural relationship of oxcarbazepine to tricyclic antidepressants.

Patients on tricyclic antidepressant therapy were included in clinical trials and no clinically relevant interactions have been observed.

The combination of lithium and oxcarbazepine might cause enhanced neurotoxicity.

Pregnancy

Risk related to epilepsy and antiepileptic medicinal products in general:

It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3% in the general population. In the treated population, an increase in malformations has been noted with polytherapy, however, the extent to which the treatment and/or the illness is responsible has not been elucidated.

Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

Risk related to oxcarbazepine:

Clinical data on exposure during pregnancy are still insufficient to assess the teratogenic potential of oxcarbazepine. In animal studies, increased embryo mortality, delayed growth and malformations were observed at maternally toxic dose levels (see section 5.3).

Taking these data into consideration:

• If women receiving Trileptal become pregnant or plan to become pregnant, the use of this product should be carefully re-evaluated. Minimum effective doses should be given, and monotherapy whenever possible should be preferred at least during the first three months of pregnancy.

• Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.

• During pregnancy, an effective antiepileptic oxcarbazepine treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

Monitoring and prevention:

Antiepileptic medicinal products may contribute to folic acid deficiency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. As the efficacy of this supplementation is not proved, a specific antenatal diagnosis can be offered even for women with a supplementary treatment of folic acid.

Data from a limited number of women indicate that plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that clinical response should be monitored carefully in women receiving Trileptal treatment during pregnancy to ensure that adequate seizure control is maintained. Determination of changes in MHD plasma concentrations should be considered. If dosages have been increased during pregnancy, postpartum MHD plasma levels may also be considered for monitoring.

In the newborn child:

Bleeding disorders in the newborn caused by antiepileptic agents have been reported. As a precaution, vitamin K₁ should be administered as a preventive measure in the last few weeks of pregnancy and to the newborn.

Lactation

Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-to-plasma concentration ratio of 0.5 was found for both. The effects on the infant exposed to Trileptal by this route are unknown. Therefore, Trileptal should not be used during breast-feeding.

The use of Trileptal has been associated with adverse reactions such as dizziness or somnolence (see section 4.8). Therefore, patients should be advised that their physical and/ or mental abilities required for operating machinery or driving a car might be impaired.

The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue occurring in more than 10% of patients.

The undesirable effect profile by body system is based on AEs from clinical trials assessed as related to Trileptal. In addition, clinically meaningful reports on adverse experiences from named patient programs and post-marketing experience were taken into account.

Frequency estimate* :- very common: 1/10; common: 1/100 - < 1/10; uncommon: 1/1,000 - < 1/100; rare: 1/10,000 - < 1/1,000; very rare: < 1/10,000; unknown: cannot be estimated from the available data.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* according to CIOMS III frequency classification

^† Very rarely clinically significant hyponatraemia (sodium <125 mmol/l) can develop during Trileptal use. It generally occurred during the first 3 months of treatment with Trileptal, although there were patients who first developed a serum sodium <125 mmol/l more than 1 year after initiation of therapy (see section 4.4).

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Trileptal. The mechanism by which Trileptal affects bone metabolism has not been identified.

Isolated cases of overdose have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment. Symptoms of overdose include somnolence, dizziness, nausea, vomiting, hyperkinesia, hyponatraemia, ataxia and nystagmus. There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the medicinal product by gastric lavage and/or inactivation by administering activated charcoal should be considered.

Pharmacotherapeutic group: Antiepileptics

ATC code: N03A F 02

Pharmacodynamic effects

The pharmacological activity of oxcarbazepine is primarily exerted through the metabolite (MHD) (see section 5.2). The mechanism of action of oxcarbazepine and MHD is thought to be mainly based on blockade of voltage-sensitive sodium channels, thus resulting in stabilisation of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminishment of propagation of synaptic impulses. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may also contribute to the anticonvulsant effects. No significant interactions with brain neurotransmitter or modulator receptor sites were found.

Oxcarbazepine and its active metabolite (MHD), are potent and efficacious anticonvulsants in animals. They protected rodents against generalised tonic-clonic and, to a lesser degree, clonic seizures, and abolished or reduced the frequency of chronically recurring partial seizures in Rhesus monkeys with aluminum implants. No tolerance (i.e. attenuation of anticonvulsive activity) against tonic-clonic seizures was observed when mice and rats were treated daily for 5 days or 4 weeks, respectively, with oxcarbazepine or MHD.

Absorption

Following oral administration of Trileptal tablets, oxcarbazepine is completely absorbed and extensively metabolised to its pharmacologically active metabolite (MHD).

After single dose administration of 600 mg Trileptal oral suspension to healthy male volunteers under fasted conditions, the mean C_max value of MHD was 24.9 μmol/l, with a corresponding median t_max of 6 hours.

In a mass balance study in man, only 2 % of total radioactivity in plasma was due to unchanged oxcarbazepine, approximately 70 % was due to MHD, and the remainder attributable to minor secondary metabolites which were rapidly eliminated.

Food has no effect on the rate and extent of absorption of oxcarbazepine, therefore, Trileptal can be taken with or without food.

Distribution

The apparent volume of distribution of MHD is 49 litres.

Approximately 40 % of MHD, is bound to serum proteins, predominantly to albumin. Binding was independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.

Oxcarbazepine and MHD cross the placenta. Neonatal and maternal plasma MHD concentrations were similar in one case.

Biotransformation

Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for the pharmacological effect of Trileptal. MHD is metabolised further by conjugation with glucuronic acid. Minor amounts (4 % of the dose) are oxidised to the pharmacologically inactive metabolite (10, 11-dihydroxy derivative, DHD).

Elimination

Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95 % of the dose appears in the urine, with less than 1 % as unchanged oxcarbazepine. Faecal excretion accounts for less than 4 % of the administered dose. Approximately 80 % of the dose is excreted in the urine either as glucuronides of MHD (49 %) or as unchanged MHD (27 %), whereas the inactive DHD accounts for approximately 3 % and conjugates of oxcarbazepine account for 13 % of the dose.

Oxcarbazepine is rapidly eliminated from the plasma with apparent half-life values between 1.3 and 2.3 hours. In contrast, the apparent plasma half-life of MHD averaged 9.3 ± 1.8 h.

Dose proportionality

Steady-state plasma concentrations of MHD are reached within 2 - 3 days in patients when Trileptal is given twice a day. At steady-state, the pharmacokinetics of MHD are linear and show dose proportionality across the dose range of 300 to 2,400 mg/day.

Special populations

Patients with hepatic impairment

The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900 mg oral dose. Mild to moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. Trileptal has not been studied in patients with severe hepatic impairment.

Patients with renal impairment

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Trileptal is administered as a single 300 mg dose, in renally impaired patients (creatinine clearance < 30 ml/min) the elimination half-life of MHD is prolonged by 60-90 % (16 to 19 hours) with a two fold increase in AUC compared to adults with normal renal function (10 hours).

Children

The pharmacokinetics of Trileptal were evaluated in clinical trials in paediatric patients taking Trileptal in the dose range 10-60 mg/kg/day. Weight-adjusted MHD clearance deceases as age and weight increases approaching that of adults. The mean weight clearance in children 4 to 12 years of age is approximately 40% higher that that of adults. Therefore MHD exposure in these children is expected to be about two-thirds that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, weight-adjusted MHD clearance is expected to reach that of adults.

Pregnancy

Data from a limited number of women indicate that MHD plasma levels may gradually decrease throughout pregnancy (see section 4.6).

Elderly

Following administration of single (300 mg) and multiple doses (600 mg/day) of Trileptal in elderly volunteers (60 - 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30 % - 60 % higher than in younger volunteers (18 - 32 years of age). Comparisons of creatinine clearances in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. No special dose recommendations are necessary because therapeutic doses are individually adjusted.

Gender

No gender related pharmacokinetic differences have been observed in children, adults, or the elderly.

Preclinical data indicated no special hazard for humans based on repeated dose toxicity, safety pharmacology and genotoxicity studies with oxcarbazepine and the pharmacologically active metabolite, monohydroxy derivative (MHD).

Evidence of nephrotoxicity was noted in repeated dose toxicity rat studies but not in dog or mice studies. As there are no reports of such changes in patients, the clinical relevance of this finding in rats remains unknown.

Immunostimulatory tests in mice showed that MHD (and to a lesser extent oxcarbazepine) can induce delayed hypersensitivity.

Animal studies revealed effects such as increases in the incidence of embryo mortality and some delay in antenatal and/or postnatal growth at maternally toxic dose levels. There was an increase in rat foetal malformations in one of the eight embryo toxicity studies, which were conducted with either oxcarbazepine or the pharmacologically active metabolite (MHD), at a dose which also showed maternal toxicity (see section 4.6).

In the carcinogenicity studies, liver (rats and mice), testicular and female genital tract granular cell (rats) tumours were induced in treated animals. The occurrence of liver tumours was most likely a consequence of the induction of hepatic microsomal enzymes; an inductive effect which, although it cannot be excluded, is weak or absent in patients treated with Trileptal. Testicular tumours may have been induced by elevated luteinizing hormone concentrations. Due to the absence of such an increase in humans, these tumours are considered to be of no clinical relevance. A dose-related increase in the incidence of granular cell tumours of the female genital tract (cervix and vagina) was noted in the rat carcinogenicity study with MHD. These effects occurred at exposure levels comparable with the anticipated clinical exposure. The mechanism for the development of these tumours has not been elucidated. Thus, the clinical relevance of these tumours is unknown.

Propyl parahydroxybenzoate (E 216)

Saccharin sodium

Sorbic acid (E 200)

Macrogol stearate 400

Methyl parahydroxybenzoate (E 218)

Yellow-plum-lemon flavour (containing ethanol)

Ascorbic acid (E 300)

Dispersible cellulose (containing microcrystalline cellulose and carmellose sodium)

Propylene glycol

Sorbitol 70% liquid (non-crystallising)

Water purified.

Not applicable.

3 years.

Use within 7 weeks after first opening the bottle.

This medicinal product does not require any special storage conditions.

Brown (amber) type III glass bottles containing 250 ml of oral suspension. The bottles have a child-resistant cap and are packed in a cardboard box together with a 10 ml polypropylene oral syringe and press-in bottle adaptor.

Pack size: 1 bottle

No special requirements.

Novartis Pharmaceuticals UK Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

United Kingdom

PL 00101/0631

13 November 2001 / 15 October 2009

20 April 2012