SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

{Product name} 25 mg film-coated tablets {Product name} 100 mg film-coated tablets {Product name} 150 mg film-coated tablets {Product name} 200 mg film-coated tablets {Product name} 300 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 25 mg, 100 mg, 150 mg, 200 mg or 300 mg quetiapine (as quetiapine fumarate). Excipient: lactose monohydrate.

25 mg 100 mg 150 mg 200 mg 300 mg Lactose monohydrate 4.50 mg 18.00 mg 27.00 mg 36.00 mg 54.00 mg

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

The 25 mg tablets are round, pale red film-coated tablets with bevelled edge. The 100 mg tablets are round, yellow-brown film-coated tablets. The 150 mg tablets are round, white film-coated tablets with bevelled edge. The 200 mg tablets are round, white film-coated tablets. The 300 mg tablets are capsule-shaped, white film-coated tablets.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of schizophrenia. Treatment of moderate to severe manic episodes. Quetiapine has not been proved to prevent recurrence of manic or depressive episodes (see section 5.1).

4.2 Posology and method of administration

{Product name} should be administered twice daily with or without food.

Adults: For the treatment of schizophrenia the total daily dose for the first four days of treatment is 50 mg on the first day, 100 mg on the second day, 200 mg on the third day and 300 mg on the fourth day of the treatment.

From the fourth day onwards the dose should be titrated to the usual effective dose range of 300 – 450 mg/day. Depending on the clinical response and tolerability of the individual patient to the drug, the dose may be adjusted to 150 – 750 mg/day.

For the treatment of manic episodes associated with bipolar disorder the total daily dosage for the first four days of therapy is 100 mg on the first day, 200 mg on the second day, 300 mg on the third day and 400 mg on the fourth day.

Further dosage adjustments increased up to the maximum of 800 mg/day by day six should be in increments of a maximum of 200 mg daily. Depending on the clinical response and tolerability of the individual patient to the drug, the dose may be adjusted to 200 – 800 mg/day. The usual effective dose is in the range of 400 – 800 mg/day.

Use in elderly patients: Like other antipsychotics, {Product name} should be used with caution in the elderly, especially during the initial dosing period. Depending on the clinical response and tolerability of the individual patient the dose-titration period can be longer and the daily dose can be lower than in younger patients. Quetiapine’s average plasma clearance was reduced by 30-50% in elderly compared to younger patients.

Children and adolescents: The safety and efficacy of {Product name} have not been evaluated in children and adolescents.

Renal impairment: Adjustment of dose is not necessary for patients with renal impairment.

Hepatic impairment: Quetiapine is extensively metabolised by the liver. Therefore {Product name} should be used with caution in patients with known hepatic impairment. Patients with hepatic impairment should be started on 25 mg/day. The dose should, dependent on the patients clinical response and tolerability, be increased daily in increments of 25 – 50 mg/day to an effective dose.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azole-antifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated. See also section 4.5.

4.4 Special warnings and precautions for use

Cardiovascular disease {Product name} should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or some other conditions predisposing to hypotension. Quetiapine may induce orthostatic hypotension, especially during the initial dose-titration period. If this happens a reduction in dose or a gradual dose-titration should be considered.

Seizures In controlled clinical trials, there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. Like other antipsychotics, caution is recommended when treating patients with a history of seizures.

Extrapyramidale symptoms In controlled clinical trials the incidence of extrapyramidale symptoms was not different from placebo within the recommended therapeutic dose-interval.

Tardive dyskinesia

If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of {Product name} medication should be considered (See section 4.8).

Neuroleptic malignant syndrome Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine. (see section 4.8). Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability and increased creatine phosphokinase. In such an event, {Product name} should be discontinued and appropriate medical treatment initiated.

Interactions See also section 4.5.

Concomitant use of {Product name} with potent hepatic enzyme inducers, such as carbamazepine or phenytoin, may substantially decrease plasma concentrations of quetiapine, which can influence the efficacy of {Product name} treatment. {Product name} therapy in patients using hepatic enzyme inducers should only be initiated after weighing the benefits of {Product name} treatment against the risks of discontinuing the hepatic enzyme inducer therapy. It is important that any changes in the use of hepatic enzyme inducers are gradual. If necessary, the hepatic enzyme inducer should be replaced with a non-inducing agent (e.g. sodium valproate). The concomitant use of other neuroleptics should be avoided.

Hyperglycaemia Hyperglycaemia or exacerbation of pre-existing diabetes has been reported in very rare cases during treatment with quetiapine. Appropriate clinical monitoring is recommended in diabetic patients and in patients with risk factors for the development of diabetes mellitus (see also section 4.8).

QT-prolongation In clinical studies and by use according to the product infromation, quetiapine was not associated with prolongation of absolute QT-intervals. However OT-prolongation was observed after overdosage (see 4.9). Like with other antipsychotics, caution is necessary when {Product name} is prescribed in combination with drugs known to prolong the QT interval (see section 4.5). This precaution is especially important for use in the elderly, in patients with congenital prolongation of the QT interval, as well as in congestive heart failure, cardiac hypertrophia, hypokalemia, or hypomagnesaemia.

Acute withdrawal reactions Acute withdrawal symptoms including nausea, vomiting and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.

Elderly patients with dementia-related psychosis Quetiapine is not approved for the treatment of patients with dementia-related psychosis.

An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Quetiapine should be used with caution in patients with risk factors for stroke.

In a meta-analysis of atypical antipsychotic drugs, it has been reported that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. However in two 10-week placebo-controlled quetiapine studies in the same patient population (n=710; mean age: 83 years; range: 56-99 years) the incidence of mortality in quetiapine-treated patients was 5.5% versus 3.2% in the placebo group. The patients in these trials died from a variety of causes that were consistent with expectations for this population. These data do not establish a causal relationship between quatipine treatment and death in elderly patients with dementia.

Other information Only limited information is available on concomitant use of quetiapine and valproate or lithium in the treatment of moderate and severe manic episodes; however, combination therapy was well-tolerated (see sections 4.8 and 5.1). Data indicated an additive effect in week 3 of treatment. Another study did not show an additive effect after 6-week treatment. There is no information on combination therapy for more than 6 weeks.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.

4.5 Interaction with other medicinal products and other forms of interaction

Due to the primary central nervous system effects of quetiapine, {Product name} should be used with caution in combination with other centrally acting drugs and alcohol.

Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for the cytochrome P450-mediated metabolism of quetiapine. In a trial in healthy volunteers, concomitant administration of quetiapine with ketoconazole (a CYP 3A4 inhibitor) induced a 5- to 8-fold increase in the quetiapine AUC level. Therefore, concomitant use of quetiapine with potent CYP 3A4 inhibitors is contraindicated. It is also not recommended to take quetiapine together with grapefruit juice.

It was observed in a pharmacokinetic multiple dose study that administration of carbamazepine (a known hepatic enzyme inducer) during treatment with quetiapine significantly increased the clearance of quetiapine. This increase in clearance reduced the systemic quetiapine exposure (as measured by AUC) to an average of 13% compared to that in those receiving quetiapine only. As a consequence of this interaction, lower plasma concentrations can occur which may affect the efficacy of {Product name} treatment. Concomitant administration of quetiapine and phenytoin (another microsomal enzyme inducer) caused increases in the clearance of quetiapine, of approximately 450%. {Product name} therapy in patients using hepatic enzyme inducers should only be initiated after weighing the benefits of {Product name} therapy against the risks of discontinuing the hepatic enzyme inducer therapy. It is important that any changes in the use of hepatic enzyme inducers are gradual. If necessary, the hepatic enzyme inducer should be replaced with a non-inducing agent (e.g. sodium valproate) (see also section 4.4). The pharmacokinetics of quetiapine was not significantly altered in concomitant administration of antidepressants, imipramine (known CYP 2D6 inhibitor) or fluoxetine (known CYP 3A4 and CYP 2D6 inhibitor). The pharmacokinetics of quetiapine was not significantly altered in concomitant administration of antipsychotics, risperidone or haloperidol. However, concomitant use of quetiapine and thioridazine increased the clearance of quetiapine, by an average of 70%.

The pharmacokinetics of quetiapine remained unchanged in concomitant administration of cimetidine.

The pharmacokinetics of lithium was not altered following co-administration with quetiapine.

When co-administered the pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent.

Formal interaction studies of commonly used cardio vascular drugs have not been completed.

Caution is advised with the concomitant treatment of other medicinal products that can prolong the QT-interval. Caution is advised when quetiapine is co-administered with other medicinal products that may cause electrolyte disturbances e.g. thiazide diuretics (hypokalaemia), as they increase the risk of malignant arrhythmia.

4.6 Pregnancy and lactation

The safety and efficacy of quetiapine in humans during pregnancy have not been studied. The animal studies have so far not shown harmful effects. Possible effects to the embryos eyes has not been investigated. Therefore, {Product name} should only be used during pregnancy when the benefits outweigh the potential risks. Withdrawal symptoms were observed in newborns if quetiapine was used during pregnancy.

The degree to which quetiapine is excreted into human milk is unknown. Therefore, breastfeeding should be avoided during use of {Product name}.

4.7 Effects on ability to drive and use machines

The effect of quetiapine in primarily seen in the central nervous system, quetiapine may affect activities where mental alertness is necesarry. Patients should therefore avoid driving or using machines until their individual susceptibility to this has been established.

4.8 Undesirable effects

The most commonly reported undesirable effects with quetiapine are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia.

Like other antipsychotics, the use of quetiapine has been associated with weight gain, syncope, neuroleptic malignant syndrome, leucopenia, neutropenia and peripheral edema.

The frequency of the undesirable effects is presented as follows: very common (> 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10 000 and < 1/1000), very rare (< 1/10 000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Investigations Common: Weight gain, elevation in serum transaminases (ALT or AST)4 Uncommon: Elevated serum gamma-GT4, elevated (non-fasting) serum triglyceride levels, elevation in total cholesterol. Cardiac disorders Common: Tachycardia5 Rare: QT-prolongation8, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia)8, sudden unexplained death8, cardiac arrest8, Torsade de pointes 8 Blood and lymphatic system disorders Common: Leucopenia3 Uncommon: Eosinophilia Very rare: Neutropenia3 Nervous system disorders Very common: Dizziness5, somnolence2, headache Common: Syncope5 Uncommon: Seizures1 Very rare: Tardive dyskinesia7 Respiratory, thoracic and mediastinal disorders Common: Rhinitis Gastrointestinal disorders Common: Dry mouth, constipation, dyspepsia Skin and subcutaneous tissue disorders Very rare: Angioedema7, Stevens-Johnson syndrome7 Metabolism and nutrition disorders Very rare: Hyperglycaemia1, 6, 7, diabetus mellitus1, 6, 7

Vascular system disorders Common: Orthostatic hypotension5 General disorders and administration site conditions Common: Mild asthenia, peripheral edema Rare: Neuroleptic malignant syndrome Immune system disorder Uncommon: Hypersensitivity. Hepato-biliary disorders Rare: Jaundice7 Very rare: Hepatitis7 Reproductive system and breast disorders Rare: Priapism 1. See section 4.4. 2. Somnolence may occur particularly during the first two weeks of treatment and generally resolves with the continued administration of quetiapine. 3. There are no reports from controlled clinical studies with quetiapine of persistent severe neutropenia or agranulocytosis. During post-marketing monitoring, leukopenia and/or neutropenia resolved when treatment with quetiapine was discontinued. Possible risk factors for leukopenia and/or neutropenia include pre-existing low white cell count and history of drug induced leukopenia and/or neutropenia. 4. In some patients receiving quetiapine, asymptomatic elevation of serum transaminase (ALT, AST) or gamma- GT levels have been observed. These elevations were usually reversible on continued quetiapine treatment. 5. Like other antipsychotics with adrenergic alpha1 receptor blocking activity, quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, particularly during the initial dose-titration period (see section 4.4.). 6. Hyperglycaemia or exacerbation of diabetes has been observed in very rare cases. 7. The frequency of the undesirable effects are based on post-marketing experience. 8. These effects are class effects of neuroleptics.

Use of quetiapine was associated with a slight dose-dependent reduction in thyroid hormone levels, particularly total T4 and free T4 levels. The reduction in total T4 and free T4 was maximal within the first two to four weeks of treatment with no further reduction during long-term treatment. In nearly all cases, discontinuation of quetiapine treatment was associated with reversal of the effects on total T4 and free T4 irrespective of the duration of the treatment. Smaller decreases in total T3 and reverse T3 (rT3) levels were seen only at higher doses. Levels of thyroxin-binding globulin (TBG) were unchanged and in general, no reciprocal increases in thyrotropin (thyroid-stimulating hormone, TSH) concentrations were observed. Quetiapine has not been shown to cause clinically significant hypothyroidism.

4.9 Overdose

There is limited experience with overdosage from clinical trials with quetiapine Estimated doses of quetiapine up to 20 g have been taken with no fatal outcomes and patients recovered without sequelae. In post-marketing surveillance, there have been very rare reports of overdosage with quetiapine alone resulting in death or coma or QT-prolongation.

In general, the signs have been those from an exaggeration of the drug’s known pharmacological effects, i.e. drowsiness, sedation, tachycardia and hypotension.

There is no specific antidote to quetiapine. In cases of severe intoxication, the possibility of multiple drug involvement should be considered and intensive care procedures are recommended: maintaining the patient’s airway, ensuring adequate oxygenation and ventilation as well as monitoring and support of the cardiovascular system. Although inhibition of absorption in overdosage has not been investigated, gastric lavage (after intubation in unconscious patients) and administration of medicinal charcoal together with laxative should be considered. Close medical supervision and monitoring should be continued until the patient recovers.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: diazepines, oxazepines and thiazepines, ATC code: N05AH04.

Mechanism of action: Quetiapine is an atypical antipsychotic agent which interacts with a broad range of neurotransmitter receptors. Quetiapine has affinity for serotonin (5-HT2) and dopamine D1- and D2-receptors in the brains. Quetiapine exhibits a higher affinity for serotonin (5-HT2) receptors than for dopamine D2- receptors, which is believed to contribute to quetiapin’s antipsychotic characteristics and its low potential to cause extra-pyramidal side-effects (EPS). Quetiapine also has high affinity for histaminergic and adrenergic α1-receptors, with a lower affinity for adrenergic α2-receprors, but no appreciable affinity for cholinergic muscarinic or benzodiazepine receptors. Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It reverses the effects of dopamine agonists, measured either behaviorally or neurophysiologically, and elevates dopamine metabolites concentrations, a neuro-chemical sign of D2-receptor blocking.

Pharmacodynamic effects: In the preclinical studies predictive of EPS quetiapine had a profile different from the traditional antipsychotics. Quetiapine does not increase the sensitivity of dopamine D2-receptors even after long- term treatment. Quetiapine causes only weak catalepsy at effective dopamine D2-receptor blocking doses. Quetiapine has a selective effect on limbic system, because after long-term treatment depolarisation inhibition is generated in the mesolimbic, but not in the nigrostriatal neurons containing dopamine. Quetiapine causes very little dystonia tendency in patients sensitive to haloperidol or in non-treated Cebus-monkeys after short- or long-term treatment. The results of these studies predict that quetiapine has very little potential for EPS. It is assumed that medicines which generate less EPS would also less likely cause tardive dyskinesia (see section 4.8).

Clinical efficacy: The results of three placebo-controlled clinical trials, using a variable dose range of quetipine in schizophrenic patients showed no difference between quetiapine and placebo in the incidence of EPS or use of concomitant anticholinergics. The results of a placebo-controlled, fixed-dose clinical trial, using a dose range of quetiapine of 75 to 750 mg/day, showed no difference between quetiapine and placebo in the incidence of EPS or use of concomitant anticholinergics.

In four placebo-controlled clinical trials, evaluating doses of quetiapine up to 800 mg/day for the treatment of moderate or severe mania episodes (two as monotherapy and two as adjunct therapy to lithium or valproate), there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics.

Absence of EPS- induction is considered to be a characteristic for atypical antipsychotics. Contrary to many other atypical antipsychotics, quetiapine does not produce sustained elevations in prolactin, which is one of the characteristics of atypical antipsychotic substances. In a placebo- controlled, multiple fixed-dose clinical trial on schizophrenic partients, there were no differences in prolactin levels at study completion between quetiapine (across the recommended dose range) and placebo.

In two clinical trials, quetiapine used as monotherapy was shown to be more effective than placebo when in reducing manic symptoms in patients suffering from moderate or severe manic episodes. Measurements were made after three- and 12 weeks treatment periods. There are not available results from long-term monitoring of the efficacy of quetiapine in preventing manic or depressive episodes appearing later. There is only a limited amount of information available of the concomitant use of quetiapine and valproate or lithium after three- or six- weeks treatment periods in the treatment of moderate or severe manic episodes. However, the concomitant use was found to be well tolerated. The results of these studies showed an additive effect of the medications during the third week of treatment. Another study did not show an additive effect during the sixth week of treatment. There is no information available on the concomitant use of quetiapine and valproate or lithium beyond six weeks. The mean daily dosage of quetiapine during the last week of treatment period was 600 mg/day in patients responding to therapy, and approximately 85% of these patients received daily dosage of 400 to 800 mg.

The results of clinical trials have shown that quetiapine is effective when administered twice a day, although the pharmacokinetic half-life of quetiapine is approximately seven hours. This is also supported by the results of a positron emission tomography (PET) study, which showed that the effect of quetiapine in 5-HT2- and D2-receptors lasts twelve hours. The efficacy and safety have not been studied in daily dosages exceeding 800 mg/day.

The long-term efficacy of quetiapine in preventing recurrence of disease has not been verified in blinded clinical trials. Open studies in schizophrenia patients have shown that quetiapine maintains clinical improvement with continued use in patients who responded to the medication already in the beginning of the treatment period. This finding indicates long-term efficacy of quetiapine.

5.2 Pharmacokinetic properties

Quetiapine is well absorbed and extensively metabolised following oral administration. The principal human plasma metabolites do not have significant pharmacological activity. The bioavailability of quetiapine is not significantly affected by administration with food. The elimination half-life of quetiapine is approximately 7 hours. Quetiapine is approximately 83% bound to plasma proteins.

The pharmacokinetics of quetiapine are linear, and do not differ between men and women.

The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.

The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1,73 m2), but the individual clearance values are within the range for normal subjects.

Quetiapine is extensively metabolised by the liver, with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled quetiapine. Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces. The mean plasma clearance of quetiapine is reduced by approximately 25% in individuals with hepatic impairment (stable alcoholic cirrhosis). Because quetiapine is extensively metabolised by the liver, higher plasma concentrations can be expected in patients with hepatic impairment, and consequently adjustments of the daily dosage might be necessary (see section, 4.2.).

In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine.

Quetiapine and several of its metabolites were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities, but only at concentrations at least 10- to 50-fold higher than those observed in the usual effective dose range of 300 to 450mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug. Animal studies have established that quetiapine can induce P450 enzymes. However, a specific interaction study in psychotic patients showed no increase in the cytochrome P450 activity after administration of quetiapine.

5.3 Preclinical safety data

Prolonged administration of quetiapine was associated with an anticipated central nervous system effects in rats, dogs and monkeys at exposure levels similar to or greater than the clinical exposure. In mice, rats and monkeys, reversible morphological and functional effects on the liver, consistent with hepatic enzyme induction were seen. Thyroid follicular cell hypertrophy and concomitant decrease in T3 plasma levels occurred in rats and monkeys. A decrease in haemoglobin concentrations and a decrease in the number of red- and white blood cells were also detected in Cynomolgus monkeys. Pigmentation of a number of tissues, particularly of the thyroid gland, was not associated with any morphological or functional effects and the relevance of this finding to human risk is unknown. Posterior triangular cataracts seen in dogs were consistent with the inhibition of cholesterol biosynthesis in the lens. No cataracts were observed in Cynomolgus monkeys nor in rodents; however blurred lens in female monkeys was detected at a dose 5.5 times the maximum human dose. Monitoring in clinical studies did not reveal drug-related corneal opacities in man. There was no evidence of genotoxicity in a series of in vitro and in vivo mutagenicity studies. In the carcinogenicity studies the incidence of mammary adenocarcinomas was increased in female rats at exposure levels similar to or greater than the clinical exposure, secondary to prolonged hyperprolactinaemia. In male rats and mice, there was an increased incidence of thyroid follicular cell benign adenomas, consistent with known rodent-specific mechanisms resulting from enhanced hepatic thyroxine clearance. Quetiapine had no teratogenic effects in rats and rabbits at doses corresponding to 0.3-2.4 and 0.6-2.4 times the maximum human dose, respectively. The possible relevance of adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to or greater than the clinical exposure levels with the possible relevance of this finding to human risk is unknown.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The core of tablet: Lactose monohydrate Calcium hydrogen phosphate, dihydrate Microcrystalline cellulose (E460) Povidone Sodium starch glycolate (type A) Magnesium stearate The film-coating: Hypromellose Titanium dioxide (E171) Macrogol 4000 Yellow iron oxide (E172) - only in 25 mg and 100 mg tablets Red iron oxide (E172) - only in 25 mg tablets

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

HDPE tablet container: Shelf life after the first opening is 3 months.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister pack (PVC/Al): 6 (only 25 mg tablets), 10, 20, 30, 30 x 1, 50, 60, 90, 100, 100 x 1, 120 (only 150 mg and 300 mg tablets), 180 (only 150 mg and 300 mg tablets) or 240 (only 150 mg and 300 mg tablets) tablets in a box. Polyethylene (HDPE) plastic container: 250 tablets (only 100 mg and 200 mg). Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: Date of last renewal:

10. DATE OF REVISION OF THE TEXT