SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Caramet 50 mg/200 mg CR Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 50 mg carbidopa (as monohydrate) and 200 mg levodopa

For a full list of excipients see section 6.1

3    PHARMACEUTICAL FORM

Prolonged-release tablet

Orange-brown, round, biconvex prolonged-release tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Idiopathic Parkinson’s disease

4.2    Posology and method of administration

The daily dose of Caramet 50 mg/200 mg CR Tablets should be carefully titrated. Patients should be closely monitored during the dose adjustment phase, particularly regarding the occurrence of or increase in nausea and abnormal involuntary movements such as dyskinesias, chorea and dystonia.

Intake of any previously administered antiparkinsonian medicinal product, apart from levodopa, can be continued during administration of Caramet 50 mg/200 mg CR Tablets, although a dose reduction of such medicinal products may be necessary.

As carbidopa prevents a loss of effect in levodopa due to pyridoxine, Caramet 50 mg/200 mg CR Tablets can also be taken by patients who are concurrently receiving pyridoxine (vitamin B₆).

Precaution:

In order to maintain the prolonged-release effect of the medicinal product, the prolonged-release tablets may only be taken whole and may not be divided.

Intake of food, especially protein-rich food, may influence the absorption of levodopa. Therefore the prolonged-release tablets should be taken 30 minutes before a meal.

Initial dose

Patients not previously treated with levodopa

The recommended initial dose is one prolonged-release tablet of Caramet 50 mg/200 mg CR Tablets, twice daily. The initial dose should not exceed 600 mg levodopa/day. An interval of at least 6 hours should be allowed between individual doses.

An interval of at least 2-4 days should be allowed between dose adjustments.

Depending upon the severity of disease, a period of up to 6 months may be required before optimal treatment results are seen.

Dosage recommendation for patients previously treated with non-prolonged-release, immediate-release levodopa/decarboxylase inhibitors

When changing to Caramet 50 mg/200 mg CR Tablets, the initial dose should not exceed approximately 10% more levodopa/day, if higher doses are required (over 900 mg daily).

At least 12 hours should be allowed between the last intake of levodopa plus decarboxylase inhibitor and the first dose of Caramet 50 mg/200 mg CR Tablets.

The interval between the individual doses should be increased by 30%-50% to 4-12 hours.

Dosages may be required which are a maximum of 30% above the previous levodopa dose.

When changing from immediate-release levodopa/carbidopa tablets to prolonged-release tablets, see table.

Levodopa/ Caramet 50 mg/200 mg CR Tablets Carbidopa

Daily dose of Daily dose of Number of prolonged-

levodopa (mg) 300-400 500-600 700-800 900-1000 1100-1200 1300-1400 1500-1600

Patients who have previously received levodopa as monotherapy

An interval of at least 12 hours should be allowed between the last intake of levodopa and the first dose of Caramet 50 mg/200 mg CR Tablets. In patients with mild to moderate disease, the recommended initial dose is 1 prolonged-release tablet of Caramet 50 mg/200 mg CR Tablets twice daily.

Dose adjustment

Once the dosage has been established, the dose or the dosing interval can be increased or decreased, depending upon the patient’s response to treatment.

In most patients, a daily dose of 2-8 prolonged-release tablets of Caramet 50 mg/200 mg CR Tablets is sufficient. The prolonged-release tablets should be taken in divided doses at intervals of 4-12 hours during the day.

Higher doses (up to 12 prolonged-release tablets) have also been given at shorter intervals (less than 4 hours), but this is generally not recommended.

The lowest dose should be taken at the end of the day, if the intervals between the individual doses are less than 4 hours or if various dosage strengths are used throughout the day.

Compared with immediate-release levodopa/carbidopa, the usual effect of the first morning dose may be delayed by up to one hour in some patients.

Intervals of at least 3 days should be allowed between dose adjustments.

Maintenance dose

Regular routine examinations are recommended, as Parkinson’s disease is progressive. A subsequent dose adjustment of Caramet 50 mg/200 mg CR Tablets may become necessary.

Use of additional antiparkinsonian agents

Anticholinergic agents, dopamine agonists and amantadine can be administered concurrently with Caramet 50 mg/200 mg CR Tablets. A dose adjustment of Caramet 50 mg/200 mg CR Tablets may be necessary, if these medicinal products are given in addition to ongoing therapy with Caramet 50 mg/200 mg CR Tablets.

Therapy interruption

If the dose is reduced abruptly or if therapy with Caramet 50 mg/200 mg CR Tablets has to be discontinued, patients require careful monitoring. This particularly applies to patients receiving antipsychotic agents (see section 4.4).

If anaesthesia is required, Caramet 50 mg/200 mg CR Tablets can be administered for as long as the patient can take medicinal products. If therapy is temporarily discontinued, the usual dose can be given as soon as the patient is able to take medicinal products.

Use in children and adolescents

Safety of use has not been established in patients under 18 years of age. Treatment of children and adolescents below the age of 18 years is not recommended.

Use in elderly patients

There has been considerable experience with the use of levodopa/carbidopa in elderly patients. The above recommendations reflect clinical data derived from this experience.

Use in renal and hepatic impairment No dose adjustment is required.

4.3 Contraindications

-    Hypersensitivity to levodopa, carbidopa or any of the excipients

-    Narrow-angle glaucoma

-    Severe heart failure

-    Severe cardiac arrhythmia

-    Acute stroke

-    Mental confusion

-    Severe psychosis

Caramet 50 mg/200 mg CR Tablets may not be used if administration of a sympathomimetic agent is contraindicated.

Concurrent use of Caramet 50 mg/200 mg CR Tablets and non-selective monoamine oxidase (MAO) inhibitors and selective MAO-A inhibitors is contraindicated. Administration of these MAOIs should be discontinued at least 2 weeks before starting treatment with Caramet 50 mg/200 mg CR Tablets.

As levodopa can activate a malignant melanoma, Caramet 50 mg/200 mg CR Tablets may not be used in patients with suspicious and undiagnosed skin disorders or in patients with a history of melanoma.

4.4 Special warnings and precautions for use

When treatment with Caramet 50 mg/200 mg CR Tablets is started, patients pretreated with levodopa only should end the treatment 12 hours beforehand.

There has only been limited experience with levodopa/carbidopa prolonged-release tablets in patients not previously treated with levodopa.

In patients pre-treated with levodopa only, dyskinesias may occur, as carbidopa causes more levodopa to reach the brain, so that more dopamine is formed. The occurrence of dyskinesias may make a dose reduction necessary (see section 4.8).

Due to the pharmacokinetic profile of prolonged-release tablets containing levodopa/carbidopa, the effect on patients who suffer from early-morning dyskinesias may be delayed compared to the effect of immediate -release levodopa/carbidopa.

During treatment with levodopa/carbidopa prolonged-release tablets, the incidence of dyskinesias in patients in an advanced stage of motor fluctuations is higher than that associated with administration of immediate -release levodopa/carbidopa tablets (16.5% versus 12.2%).

As with levodopa only, Caramet 50 mg/200 mg CR Tablets may lead to involuntary movements and psychological disturbances.

If levodopa/carbidopa prolonged-release tablets are used, patients with a known history of severe involuntary movements and psychological disturbances, who have previously been treated with levodopa only or with immediate -release levodopa/carbidopa, require careful monitoring. These reactions are thought to be triggered by the increased availability of dopamine in the brain.

Administration of Caramet 50 mg/200 mg CR Tablets may lead to a recurrence of these symptoms, so that a dose reduction is required.

All patients should be closely monitored in case depression occurs, accompanied by suicidal tendencies. Treatment should be cautious in psychotic patients and in those with a known history of psychoses. If an existing psychosis worsens, Caramet 50 mg/200 mg CR Tablets should be discontinued.

Levodopa has been associated with drowsiness and sudden onset of sleep. There have been very rare reports of sudden onset of sleep during daily activities, in some cases without the patient being aware of it and with no advance warning signs. Patients must be informed of this possibility and advised to exercise caution if they intend to drive a vehicle or operate machinery during levodopa treatment.

Patients in whom drowsiness and/or sudden onset of sleep has occurred may not drive a vehicle or operate machinery. In addition, a dose reduction or discontinuation of treatment should be considered.

Caramet 50 mg/200 mg CR Tablets should be used with caution in patients with severe cardiovascular or pulmonary diseases, bronchial asthma, severe renal and hepatic disease, endocrine disturbance, cushing’s syndrome or a history of ulcers, haematemesis or convulsions.

Levodopa/carbidopa should be used with caution in patients who have recently experienced myocardial infarction and who have residual atrial, nodal or ventricular arrhythmias. In such patients, cardiac function should be very carefully monitored at the beginning of treatment and when any dose adjustments are made.

Patients with chronic wide-angle glaucoma can be treated cautiously with Caramet 50 mg/200 mg CR Tablets , provided that intraocular pressure is well controlled. Patients should be carefully monitored during treatment for any changes in ocular pressure.

If treatment of Parkinson’s disease with medicinal products is withdrawn abruptly, a symptom complex has been described which resembles neuroleptic malignant syndrome, accompanied by muscular rigidity, raised body temperature, psychological changes and a rise in serum creatine phosphokinase. Patients thus require close monitoring if the carbidopa/levodopa dose is abruptly reduced or the medicinal product is withdrawn, particularly if there is concurrent administration of antipsychotic agents.

Use of levodopa/carbidopa is not recommended in the treatment of pharmacogenic extrapyramidal reactions or Huntington’s chorea.

During long-term treatment, hepatic and renal function, haematopoietic organs function and the cardiovascular system should be regularly checked.

To date, the safety and efficacy of levodopa/carbidopa have not been established in neonates and children. Use in patients below 18 years of age is not recommended. Laboratory tests

Levodopa and carbidopa have caused abnormalities in numerous laboratory tests. This may also occur with Caramet 50 mg/200 mg CR Tablets. This includes increased values in liver function tests, such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactate dehydrogenase, bilirubin, blood urea, creatinine, uric acid and a positive Coombs test.

Reduced values of haemoglobin and haematocrit, increased blood glucose and leukocytes, bacteria and blood in the urine have been observed.

If test strips are used to test for ketonuria, carbidopa/levodopa may give false-positive results for ketone bodies. This reaction is not changed by boiling the urine sample. False-negative results may also occur with the use of glucose-oxidase methods of testing for glucosuria.

Cases of falsely diagnosed pheochromo-cytoma in patients on carbidopa-levodopa therapy have been reported very rarely.

A close monitoring is necessary in patients with history of orthostatic hypotension, especially at the beginning of the treatment. A treatment could be necessary in case of symptomatic orthostatic hypotension.

Care should be taken with concurrent administration of reserpine and a close watch kept for any signs of potentiation, antagonism and unusual adverse reactions.

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido and hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa, including levodopa/carbidopa. Review of treatment is recommended if such symptoms develop.

4.5 Interaction with other medicinal products and other forms of interaction

Caution is advised if Caramet 50 mg/200 mg CR Tablets are used concurrently with the following medicinal products:

Antihypertensive agents

When levodopa with a decarboxylase inhibitor has been added to an existing dosage regimen with certain antihypertensive agents, symptomatic orthostatic dysregulation has occurred. During the titration phase of treatment with Caramet 50 mg/200 mg CR Tablets, a dose adjustment of the antihypertensive agents may be required.

Antidepressants

In rare cases, adverse effects, e.g., hypertension and dyskinesia, occurred when carbidopa/levodopa was administered concurrently with tricyclic antidepressants (see section 4.3 for patients receiving non-selective MAO- and selective MAO-A inhibitors).

Caramet 50 mg/200 mg CR Tablets may be used concurrently only with the recommended dose of a selective MAO-B inhibitor (e.g., selegiline HCl). The risk of orthostatic hypotension may otherwise be increased

Anticholinergic agents

Anticholinergic agents can work synergistically with levodopa, in order to improve tremor. Concurrent use can, however, cause a worsening of involuntary motor disorders. Anticholinergic agents may impair the effect of levodopa, due to a delayed absorption. A dose adjustment of levodopa may be required.

Other medicinal products

Neuroleptics (except clozapine) may attenuate the therapeutic effect of levodopa.

This combination is not recommended. If necessary the lowest dose of both medicaments should be used. Benzodiazepines and isoniazid may attenuate the therapeutic effect of levodopa. The positive effect of levodopa on Parkinson’s disease is impaired by phenytoin and papaverine. Patients taking these medicinal products concurrently with Caramet 50 mg/200 mg CR Tablets should be carefully monitored due to the possibility of a poorer therapeutic response.

Concurrent use of selegiline and Caramet 50 mg/200 mg CR Tablets may trigger severe orthostatic dysregulation (see section 4.3).

COMT inhibitors (tolcapone, entacapone)

Concurrent use of COMT (catechol-O-methyltransferase) inhibitors and Caramet 50 mg/200 mg CR Tablets may increase the bioavailability of levodopa. The dose of levodopa/carbidopa may have to be adjusted.

Amantadine works synergistically with levodopa and may enhance the undesirable effects of levodopa. A dose adjustment of Caramet 50 mg/200 mg CR Tablets may be required.

Metoclopramide accelerates gastric emptying and may increase the bioavailability of levodopa/carbidopa.

Sympathomimetic agents may potentiate the adverse cardiovascular effects of levodopa.

Concurrent administration of iron sulphate and levodopa/carbidopa reduces the bioavailability of levodopa with approximately 50 %, most likely because of chelate formation. The bioavailability of carbidopa is also decreased by approximately 75 %. Products containing iron sulphate and levodopa/carbidopa should be administered separately with the longest possible time interval.

As levodopa competes with certain amino acids, levodopa absorption may be impaired in some patients who are on a high-protein diet.

The effects of antacids and levodopa/carbidopa on the bioavailability of levodopa have not been investigated.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are insufficient data available on the use of Caramet 50 mg/200 mg CR Tablets in pregnant women. The results of animal studies have shown teratogenicity (see section 5.3). The potential risk to embryo or the foetus is not known.

Caramet 50 mg/200 mg CR Tablets should not be used during pregnancy unless the benefits for the mother outweigh the possible risks to the foetus. It is preferable to delay the administration of levodopa after the first trimester; in case of no possibility to delay the beginning of treatment or no alternative, prenatal monitoring is necessary. Women of child-bearing age must use reliable contraceptive methods. Lactation

Significant amounts of levodopa are excreted into the breast milk. Women should avoid breast-feeding during treatment with Caramet 50 mg/200 mg CR Tablets.

4.7 Effects on ability to drive and use machines

No data is available relating to the effect of this medicinal product on the ability to drive. Adverse effects, such as drowsiness and light-headedness, may influence the ability to drive or operate machinery.

Patients receiving levodopa treatment who report drowsiness and/or sudden onset of sleep, must be instructed to avoid driving. Any other activities which require full concentration should be avoided (e.g., operating vehicles or machinery), as patients are otherwise putting themselves and others at risk of injury or death.

This applies until these recurrent episodes or the drowsiness have subsided (see section 4.4).

4.8 Undesirable effects

In controlled, clinical trials involving patients with moderate to severe motor fluctuations, no undesirable effects occurred with levodopa/carbidopa which were due to the pharmaceutical form with delayed release of the active substance.

The adverse reactions considered at least possibly related to treatment are listed below by body system organ class and absolute frequency. Frequencies are defined as very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare (>1/10 000 to <1/1000); very rare (<1/10 000).

Disturbances of the haematopoietic system

Rare: leukopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia Very rare: agranulocytosis

Metabolic and nutritional disorders Common: anorexia

Uncommon: weight loss or gain Psychological disturbances

Common: hallucinations, confusion, light-headedness, nightmares, drowsiness, exhaustion, insomnia, depression, very rarely with attempted suicide, euphoria, dementia, psychotic episodes, increased drive

Rare: agitation, fear, thought disorders, disorientation, headache, increased libido, torpor, convulsions

Levodopa/carbidopa has been associated with drowsiness and, to date, very rarely with extreme daytime drowsiness and sudden onset of sleep.

Disturbances of the nervous system and the sensory organs

Common: dyskinesias (during use of levodopa/carbidopa prolonged-release tablets, dyskinesias have been observed more frequently than with use of immediate-release levodopa/carbidopa dosage forms), chorea, dystonia, extrapyramidal and motor disturbances.

An (on-off episodes) bradykinesia may occur some months or years after beginning treatment with levodopa and is probably associated with progression of the disease. Adjustment of the dosage regimen and dosing interval may be required.

Uncommon: ataxia, increased tremor of the hands

Rare: neuroleptic malignant syndrome, paraesthesias, falling, gait abnormalities,

trismus

Eye disorders

Rare: blurred vision, blepharospasm, activation of a latent Horner’s syndrome, diplopia, pupil dilation, gaze spasms Blepharospasm can be an early symptom of overdose.

Disturbances of cardiac function Common: palpitations, irregular heart beat Disturbances of vascular function

Common: orthostatic dysregulation, tendency to fainting, syncope

Uncommon: hypertension

Rare: phlebitis

Respiratory disturbances

Uncommon: hoarseness, chest pain

Rare: dyspnoea, disturbed normal breathing

Gastrointestinal disturbances

Common: nausea, vomiting, dry mouth, bitter taste

Uncommon: constipation, diarrhoea, hypersalivation, dysphagia, flatulence Rare: dyspepsia, gastrointestinal pain, dark discolouration of the saliva, bruxism, hiccups, gastrointestinal bleeding, burning sensation on the tongue, duodenal ulcers Skin and subcutaneous tissue disorders Uncommon: oedema

Rare: angioedema, urticaria, pruritus, flushing, hair loss, exanthema, increased

sweating, dark discolouration of the sweat, activation of malignant melanoma (see

section 4.3), Schoenlein-Henoch disease

Disturbances of musculoskeletal function

Uncommon: myospasm

Renal and lower urinary tract dysfunction

Uncommon: dark discolouration of the urine

Rare: urinary retention, urinary incontinence, priapism

Other disturbances

Uncommon: feeling of weakness, malaise, “flare ups”

Impulse control disorders

Pathological gambling, increased libido and hypersexuality, compulsive spending or buying, binge eating or compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including carbidopa+levodopa.(see section 4.4 “Special warnings and precautions for use”).

4.9 Overdose

Management of acute overdose of levodopa/carbidopa is generally the same as that of an acute overdose of levodopa only, although pyridoxine is not suitable for attenuating the effect of levodopa/carbidopa.

Using ECG monitoring, the patient should be carefully observed for the possible development of cardiac arrhythmias. If required, appropriate antiarrhythmic therapy should be given.

The possibility that the patient may have taken other medicinal products together with Caramet 50 mg/200 mg CR Tablets should be borne in mind.

To date, there has been no experience with dialysis; hence its benefit in the management of overdose is not known.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: dopaminergic agents; dopa and dopa derivatives ATC-Code: N04BA02

Levocarb-TEVA prolonged-release tablets is a combination of carbidopa, an inhibitor of aromatic amino acid decarboxylation, and levodopa, the metabolic precursor of dopamine, in the form of a tablet with polymer-based delayed release of the active agent for use in the treatment of Parkinson’s disease.

Levodopa/carbidopa prolonged-release tablets are particularly suitable for shortening the off-phase in patients pre-treated with immediate-release levodopa/decarboxylase inhibitors and in whom dyskinesias and motor fluctuations have occurred.

Motor fluctuations may occur in patients with Parkinson’s disease who have been treated with levodopa. These are characterised by end-of-dose wearing off, dyskinesia at the time of peak plasma concentrations and akinesia. The advanced form of motor fluctuations (on-off phenomenon) is characterised by an unpredictable change from mobility to immobility. Although the causes of motor fluctuations have not yet been fully established, it has been confirmed that they can be reduced by treatment regimens which ensure constant levodopa plasma concentrations.

In the brain, levodopa is decarboxylated to dopamine, thereby having a positive effect on the symptoms of Parkinson’s disease. Carbidopa, which cannot cross the blood-brain barrier, only inhibits the extracerebral decarboxylation of levodopa, so that more levodopa is available for transport to the brain and for subsequent conversion to dopamine.

Therefore it is normally not necessary to administer high doses of levodopa at frequent intervals.

Gastrointestinal and cardiovascular undesirable effects, particularly those caused by dopamine formation in extracerebral tissues, can be partially or completely avoided by the administration of lower doses.

In clinical studies, patients with motor fluctuations taking levodopa/carbidopa in prolonged-release formulation experienced shorter off-phases than those receiving immediate -release levodopa/carbidopa tablets. The reduction in the off-phase was relatively small (approx. 10%) and the frequency of dyskinesias slightly increased after use of levodopa/carbidopa prolonged-release tablets compared with treatment with immediate -release levodopa/carbidopa tablets.

In patients without motor fluctuations, levodopa/carbidopa prolonged-release tablets, under controlled conditions with longer dosing intervals, had the same therapeutic advantages as immediate -release levodopa/carbidopa tablets. There was no overall improvement in other parkinsonian symptoms.

5.2 Pharmacokinetic properties

Absorption

The pharmacokinetics of levodopa after administration of levodopa/carbidopa 200 mg/50 mg prolonged-release formulation were investigated in young, healthy volunteers. Following administration of levodopa/carbidopa 200 mg/50 mg prolonged-release formulation, peak levodopa plasma levels were reached after approx. 2 hours, compared with 0.75 hours with immediate-release tablets containing levodopa and carbidopa.

Mean peak levodopa plasma levels were reduced by 60% during use of levodopa/carbidopa 200 mg/50 mg prolonged-release formulation compared with immediate -release tablets containing levodopa and carbidopa.

In-vivo absorption of levodopa after administration of levodopa/carbidopa 200 mg/50 mg prolonged-release formulation was continuous over a period of 4-6 hours. In these studies, levodopa plasma concentrations fluctuated within narrower limits than with immediate-release tablets containing levodopa and carbidopa.

Intake of food, especially protein-rich food, may influence the absorption of levodopa.

Therefore the prolonged-release tablets should be taken 30 min before a meal.

Concurrent food intake resulted in a 50% reduction of the AUC and a 40% reduction in the C_max for carbidopa. These lower plasma levels of carbidopa have no clinical significance.

Distribution

Levodopa is co-administered with carbidopa, a decarboxylase inhibitor, which increases the bioavailability and decreases clearance for levodopa. Clearance and volume of distribution for levodopa is 0.3 l/hour/kg and 0.9-1.6 l/kg respectively when given together with a decarboxylase inhibitor. The protein binding of levodopa in plasma is negligible. Levodopa is not accumulated in plasma.

Metabolism and elimination

The elimination half life for levodopa is approximately 1-2 hours. Levodopa is eliminated completely through metabolism and the metabolites formed are excreted mainly in the urine. Four metabolic pathways are known, the decarboxylase stage being predominant for levodopa administered without any enzyme inhibitor. When levodopa is co-administered with carbidopa the decarboxylase enzyme is inhibited so that metabolism via catechol-O-methyl-transferase (COMT) becomes the dominant metabolic pathway.

5.3 Preclinical safety data

Animal studies with regard to the pharmacological safety and toxicity after repeated administration, mutagenicity studies and carcinogenicity investigations showed no particular risk for humans. In reproductive toxicity studies both levodopa and the combination of carbidopa/levodopa have caused visceral and skeletal malformations in rabbits.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Fumaric acid Hypromellose Sodium stearyl fumarate Silica colloidal anhydrous Quinoline yellow (E104)

Coating:

Hypromellose Iron oxide yellow (E172) Iron oxide red (E172) Titanium dioxide (E171) Macrogol 6000

6.2    Incompatibilities

Not applicable

6.3    Shelf life

4 years

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

Aluminium/Aluminium blister pack with 20, 25, 30, 60 and 100 prolonged-release tablets.

Not all package sizes may be marketed

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

TEVA UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0925

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/09/2006

10 DATE OF REVISION OF THE TEXT

21/12/2012