4.1. Therapeutic indications

Stalevo is indicated for the treatment of adult patients with Parkinson's disease and end-of-dose motor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment.

4.2. Posology and method of administration

Posology

The optimum daily dose must be determined by careful titration of levodopa in each patient. The daily dose should be preferably optimised using one of the seven available tablet strengths (50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg, 150 mg/37.5 mg/200 mg, 175 mg/43.75 mg/200 mg or 200 mg/50 mg/200 mg levodopa/carbidopa/entacapone).

Patients should be instructed to take only one Stalevo tablet per dose administration. Patients receiving less than 70-100 mg carbidopa a day are more likely to experience nausea and vomiting. While the experience with total daily dose greater than 200 mg carbidopa is limited, the maximum recommended daily dose of entacapone is 2 000 mg and therefore the maximum dose is 10 tablets per day for the Stalevo strengths of 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg and 150 mg/37.5 mg/200 mg. Ten tablets of Stalevo 150 mg/37.5 mg/200 mg equals 375 mg of carbidopa a day. According to this daily carbidopa dose, the maximum recommended daily dose of Stalevo 175 mg/43.75 mg/200 mg is 8 tablets per day and Stalevo 200 mg/50 mg/200 mg dose is 7 tablets per day.

Usually Stalevo is to be used in patients who are currently treated with corresponding doses of standard release levodopa/DDC inhibitor and entacapone.

How to transfer patients taking levodopa/DDC inhibitor (carbidopa or benserazide) preparations and entacapone tablets to Stalevo

a. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa in doses equal to Stalevo tablet strengths can be directly transferred to corresponding Stalevo tablets.

For example, a patient taking one tablet of 50 mg/12.5 mg of levodopa/carbidopa with one tablet of entacapone 200 mg four times daily can take one 50 mg/12.5 mg/200 mg Stalevo tablet four times daily in place of their usual levodopa/carbidopa and entacapone doses.

b. When initiating Stalevo therapy for patients currently treated with entacapone and levodopa/carbidopa in doses not equal to Stalevo tablets (50 mg/12.5 mg/200 mg or 75 mg/18.75 mg/200 mg or 100 mg/25 mg/200 mg or 125 mg/31.25 mg/200 mg or 150 mg/37.5 mg/200 mg or 175 mg/43.75 mg/200 mg or 200 mg/50 mg/200 mg), Stalevo dosing should be carefully titrated for optimal clinical response. At the initiation, Stalevo should be adjusted to correspond as closely as possible to the total daily dose of levodopa currently used.

c. When initiating Stalevo in patients currently treated with entacapone and levodopa/benserazide in a standard release formulation, the dosing of levodopa/benserazide should be discontinued in the previous night, and Stalevo should be started in the next morning. The starting dose of Stalevo should provide either the same amount of levodopa or slightly (5-10%) more.

How to transfer patients not currently treated with entacapone to Stalevo

Initiation of Stalevo may be considered at corresponding doses to current treatment in some patients with Parkinson's disease and end-of-dose motor fluctuations, who are not stabilised on their current standard release levodopa/DDC inhibitor treatment. However, a direct switch from levodopa/DDC inhibitor to Stalevo is not recommended for patients who have dyskinesias or whose daily levodopa dose is above 800 mg. In such patients it is advisable to introduce entacapone treatment as a separate treatment (entacapone tablets) and adjust the levodopa dose if necessary, before switching to Stalevo.

Entacapone enhances the effects of levodopa. It may therefore be necessary, particularly in patients with dyskinesia, to reduce levodopa dose by 10-30% within the first days to first weeks after initiating Stalevo treatment. The daily dose of levodopa can be reduced by extending the dosing intervals and/or by reducing the amount of levodopa per dose, according to the clinical condition of the patient.

Dose adjustment during the course of the treatment

When more levodopa is required, an increase in the frequency of doses and/or the use of an alternative strength of Stalevo should be considered, within the dose recommendations.

When less levodopa is required, the total daily dose of Stalevo should be reduced either by decreasing the frequency of administration by extending the time between doses, or by decreasing the strength of Stalevo at an administration.

If other levodopa products are used concomitantly with a Stalevo tablet, the maximum dose recommendations should be followed.

Discontinuation of Stalevo therapy: If Stalevo treatment (levodopa/carbidopa/entacapone) is discontinued and the patient is transferred to levodopa/DDC inhibitor therapy without entacapone, it is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms.

Paediatric population: The safety and efficacy of Stalevo in children aged below 18 years have not been established. No data are available.

Elderly: No dose adjustment of Stalevo is required for elderly.

Hepatic impairment: It is advised that Stalevo should be administered cautiously to patients with mild to moderate hepatic impairment. Dose reduction may be needed (see section 5.2). For severe hepatic impairment see section 4.3.

Renal impairment: Renal impairment does not affect the pharmacokinetics of entacapone. No particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with renal insufficiency, therefore Stalevo therapy should be administered cautiously to patients in severe renal impairment including those receiving dialysis therapy (see section 5.2).

Method of administration

Each tablet is to be taken orally either with or without food (see section 5.2). One tablet contains one treatment dose and the tablet may only be administered as whole tablets.

4.3. Contraindications

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

- Severe hepatic impairment.

- Narrow-angle glaucoma.

- Pheochromocytoma.

- Coadministration of Stalevo with non-selective monoamine oxidase (MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine).

- Coadministration with a selective MAO-A inhibitor and a selective MAO-B inhibitor (see section 4.5).

- A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic rhabdomyolysis.

4.4. Special warnings and precautions for use

- Stalevo is not recommended for the treatment of drug-induced extrapyramidal reactions.

- Stalevo therapy should be administered cautiously to patients with ischemic heart disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal or endocrine disease, history of peptic ulcer disease or history of convulsions.

- In patients with a history of myocardial infarction who have residual atrial nodal or ventricular arrhythmias; cardiac function should be monitored with particular care during the period of initial dose adjustments.

- All patients treated with Stalevo should be monitored carefully for the development of mental changes, depression with suicidal tendencies, and other serious antisocial behaviour. Patients with past or current psychosis should be treated with caution.

- Concomitant administration of antipsychotics with dopamine receptor-blocking properties, particularly D2 receptor antagonists should be carried out with caution, and the patient carefully observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms.

- Patients with chronic wide-angle glaucoma may be treated with Stalevo with caution, provided the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in intra-ocular pressure.

- Stalevo may induce orthostatic hypotension. Therefore Stalevo should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension.

- Entacapone in association with levodopa has been associated with somnolence and episodes of sudden sleep onset in patients with Parkinson's disease and caution should therefore be exercised when driving or operating machines (see section 4.7).

- In clinical studies, dopaminergic adverse reactions, e.g. dyskinesia, were more common in patients who received entacapone and dopamine agonists (such as bromocriptine), selegiline or amantadine compared to those who received placebo with this combination. The doses of other antiparkinsonian medicinal products may need to be adjusted when Stalevo treatment is substituted for a patient currently not treated with entacapone.

- Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been observed rarely in patients with Parkinson's disease. Therefore, any abrupt dose reduction or withdrawal of levodopa should be carefully observed, particularly in patients who are also receiving neuroleptics. NMS, including rhabdomyolysis and hyperthermia, is characterised by motor symptoms (rigidity, myoclonus, tremor), mental status changes (e.g., agitation, confusion, coma), hyperthermia, autonomic dysfunction (tachycardia, labile blood pressure) and elevated serum creatine phosphokinase. In individual cases, only some of these symptoms and/or findings may be evident. The early diagnosis is important for the appropriate management of NMS. A syndrome resembling the neuroleptic malignant syndrome including muscular rigidity, elevated body temperature, mental changes and increased serum creatine phosphokinase has been reported with the abrupt withdrawal of antiparkinsonian agents. Neither NMS nor rhabdomyolysis have been reported in association with entacapone treatment from controlled trials in which entacapone was discontinued abruptly. Since the introduction of entacapone into the market, isolated cases of NMS have been reported, especially following abrupt reduction or discontinuation of entacapone and other concomitant dopaminergic medicinal products. When considered necessary, the replacement of Stalevo with levodopa and DDC inhibitor without entacapone or other dopaminergic treatment should proceed slowly and an increase in levodopa dose may be necessary.

- If general anaesthesia is required, therapy with Stalevo may be continued for as long as the patient is permitted to take fluids and medicinal products by mouth. If therapy has to be stopped temporarily, Stalevo may be restarted as soon as oral medicinal products can be taken at the same daily dose as before.

- Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during extended therapy with Stalevo.

- For patients experiencing diarrhoea, a follow-up of weight is recommended in order to avoid potential excessive weight decrease. Prolonged or persistent diarrhoea appearing during use of entacapone may be a sign of colitis. In the event of prolonged or persistent diarrhoea, the drug should be discontinued and appropriate medical therapy and investigations considered.

- 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, 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 Stalevo. Review of treatment is recommended if such symptoms develop.

- Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with carbidopa/levodopa. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS (see also section 4.8).

- For patients who experience progressive anorexia, asthenia and weight decrease within a relatively short period of time, a general medical evaluation including liver function should be considered.

- Levodopa/carbidopa may cause false positive result when a dipstick is used to test for urinary ketone and this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may give false negative results for glycosuria.

- Stalevo contains sucrose, and therefore patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

- Stalevo film-coated tablets contain less than 1 mmol (23 mg) sodium per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Other antiparkinsonian medicinal products: To date there has been no indication of interactions that would preclude concurrent use of standard antiparkinsonian medicinal products with Stalevo therapy. Entacapone in high doses may affect the absorption of carbidopa. However, no interaction with carbidopa has been observed with the recommended treatment schedule (200 mg of entacapone up to 10 times daily). Interactions between entacapone and selegiline have been investigated in repeated dose studies in Parkinson's disease patients treated with levodopa/DDC inhibitor and no interaction was observed. When used with Stalevo, the daily dose of selegiline should not exceed 10 mg.

Caution should be exercised when the following active substances are administered concomitantly with levodopa therapy.

Antihypertensives: Symptomatic postural hypotension may occur when levodopa is added to the treatment of patients already receiving antihypertensives. Dose adjustment of the antihypertensive agent may be required.

Antidepressants: Rarely, reactions including hypertension and dyskinesia have been reported with the concomitant use of tricyclic antidepressants and levodopa/carbidopa. Interactions between entacapone and imipramine and between entacapone and moclobemide have been investigated in single dose studies in healthy volunteers. No pharmacodynamic interactions were observed. A significant number of Parkinson's disease patients have been treated with the combination of levodopa, carbidopa and entacapone with several active substances including MAO-A inhibitors, tricyclic antidepressants, noradrenaline reuptake inhibitors such as desipramine, maprotiline and venlafaxine and medicinal products that are metabolised by COMT (e.g. catechol-structured compounds, paroxetine). No pharmacodynamic interactions have been observed. However, caution should be exercised when these medicinal products are used concomitantly with Stalevo (see sections 4.3 and 4.4).

Other active substances: Dopamine receptor antagonists (e.g. some antipsychotics and antiemetics), phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking these medicinal products with Stalevo should be carefully observed for loss of therapeutic response.

Due to entacapone's affinity to cytochrome P450 2C9 in vitro (see section 5.2), Stalevo may potentially interfere with active substances whose metabolism is dependent on this isoenzyme, such as S-warfarin. However, in an interaction study with healthy volunteers, entacapone did not change the plasma levels of S-warfarin, while the AUC for R-warfarin increased on average by 18% [CI90 11-26%]. The INR values increased on average by 13% [CI90 6-19%]. Thus, a control of INR is recommended when Stalevo is initiated for patients receiving warfarin.

Other forms of interactions: Since levodopa competes with certain amino acids, the absorption of Stalevo may be impaired in some patients on high protein diet.

Levodopa and entacapone may form chelates with iron in the gastrointestinal tract. Therefore, Stalevo and iron preparations should be taken at least 2-3 hours apart (see section 4.8).

In vitro data: Entacapone binds to human albumin binding site II which also binds several other medicinal products, including diazepam and ibuprofen. According to in vitro studies, significant displacement is not anticipated at therapeutic concentrations of the medicinal products. Accordingly, to date there has been no indication of such interactions.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of the combination of levodopa/carbidopa/entacapone in pregnant women. Studies in animals have shown reproductive toxicity of the separate compounds (see section 5.3). The potential risk for humans is unknown. Stalevo should not be used during pregnancy unless the benefits for the mother outweigh the possible risks to the foetus.

Breast-feeding

Levodopa is excreted in human breast milk. There is evidence that breast-feeding is suppressed during treatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but is not known whether they are excreted in human breast milk. The safety of levodopa, carbidopa or entacapone in the infant is not known. Women should not breast-feed during treatment with Stalevo.

Fertility

No adverse reactions on fertility were observed in preclinical studies with entacapone, carbidopa or levodopa alone. Fertility studies in animals have not been conducted with the combination of entacapone, levodopa and carbidopa.

4.7. Effects on ability to drive and use machines

Stalevo may have a major influence on the ability to drive and use machines. Levodopa, carbidopa and entacapone together may cause dizziness and symptomatic orthostatism. Therefore, caution should be exercised when driving or using machines.

Patients being treated with Stalevo and presenting with somnolence and/or sudden sleep onset episodes must be instructed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes have resolved (see section 4.4).

4.8. Undesirable effects

a. Summary of the safety profile

The most frequently reported adverse reactions with Stalevo are dyskinesias occurring in approximately 19% of patients; gastrointestinal symptoms including nausea and diarrhoea occurring in approximately 15% and 12% of patients, respectively; muscle, musculoskeletal and connective tissue pain occurring in approximately 12% of patients; and harmless reddish-brown discolouration of urine (chromaturia) occurring in approximately 10% of patients. Serious events of gastrointestinal haemorrhage (uncommon) and angioedema (rare) have been identified from the clinical trials with Stalevo or entacapone combined with levodopa/DDC inhibitor. Serious hepatitis with mainly cholestatic features, rhabdomyolysis and neuroleptic malignant syndrome may occur with Stalevo although no cases have been identified from the clinical trial data.

b. Tabulated list of adverse reactions

The following adverse reactions, listed in Table 1, have been accumulated both from a pooled data of eleven double-blind clinical trials consisting of 3 230 patients (1 810 treated with Stalevo or entacapone combined with levodopa/DDC inhibitor, and 1 420 treated with placebo combined with levodopa/DDC inhibitor or cabergoline combined with levodopa/ DDC inhibitor), and from the post-marketing data since the introduction of entacapone into the market for the combination use of entacapone with levodopa/DDC inhibitor.

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10 000 to <1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data, since no valid estimate can be derived from clinical trials or epidemiological studies).

Table 1. Adverse reactions

Blood and lymphatic system disorders

Common:

Anaemia

Uncommon:

Thrombocytopenia

Metabolism and nutrition disorders

Common:

Weight decreased*, decreased appetite*

Psychiatric disorders

Common:

Depression, hallucination, confusional state*, abnormal dreams*, anxiety, insomnia

Uncommon:

Psychosis, agitation*

Not known:

Suicidal behaviour, Dopamine dysregulation syndrome

Nervous system disorders

Very common:

Dyskinesia*

Common:

Parkinsonism aggravated (e.g. bradykinesia)*, tremor, on and off phenomenon, dystonia, mental impairment (e.g. memory impairment, dementia), somnolence, dizziness*, headache

Not known:

Neuroleptic malignant syndrome*

Eye disorders

Common:

Blurred vision

Cardiac disorders

Common:

Ischemic heart disease events other than myocardial infarction (e.g. angina pectoris)**, irregular heart rhythm

Uncommon:

Myocardial infarction**

Vascular disorders

Common:

Orthostatic hypotension, hypertension

Uncommon:

Gastrointestinal haemorrhage

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea

Gastrointestinal disorders

Very common:

Diarrhoea*, nausea*

Common:

Constipation*, vomiting*, dyspepsia, abdominal pain and discomfort*, dry mouth*

Uncommon:

Colitis*, dysphagia

Hepatobiliary disorders

Uncommon:

Hepatic function test abnormal*

Not known:

Hepatitis with mainly cholestatic features (see section 4.4)*

Skin and subcutaneous tissue disorders

Common:

Rash*, hyperhidrosis

Uncommon:

Discolourations other than urine (e.g. skin, nail, hair, sweat)*

Rare:

Angioedema

Not known:

Urticaria*

Musculoskeletal and connective tissue disorders

Very common:

Muscle, musculoskeletal and connective tissue pain*

Common:

Muscle spasms, arthralgia

Not known:

Rhabdomyolysis*

Renal and urinary disorders

Very common:

Chromaturia*

Common:

Urinary tract infection

Uncommon:

Urinary retention

General disorders and administration site conditions

Common:

Chest pain, peripheral oedema, fall, gait disturbance, asthenia, fatigue

Uncommon:

Malaise

*Adverse reactions that are mainly attributable to entacapone or are more frequent (by the frequency difference of at least 1% in the clinical trial data) with entacapone than levodopa/DDC inhibitor alone. See section c.

**The incidence rates of myocardial infarction and other ischemic heart disease events (0.43% and 1.54%, respectively) are derived from an analysis of 13 double-blind studies involving 2 082 patients with end-of-dose motor fluctuations receiving entacapone.

c. Description of selected adverse reactions

Adverse reactions that are mainly attributable to entacapone or are more frequent with entacapone than levodopa/DDC inhibitor alone are indicated with an asterisk in Table 1, section 4.8b. Some of these adverse reactions relate to the increased dopaminergic activity (e.g. dyskinesia, nausea and vomiting) and occur most commonly at the beginning of the treatment. Reduction of levodopa dose decreases the severity and frequency of these dopaminergic reactions. Few adverse reactions are known to be directly attributable to the active substance entacapone including diarrhoea and reddish-brown discolouration of urine. Entacapone may in some cases cause also discolouration of e.g. skin, nail, hair and sweat. Other adverse reactions with an asterisk in Table 1, section 4.8b are marked based on either their more frequent occurring (by the frequency difference of at least 1%) in the clinical trial data with entacapone than levodopa/DDCI alone or the individual case safety reports received after the introduction of entacapone into the market.

Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship to levodopa/carbidopa therapy has not been established.

Impulse control disorders: Pathological gambling, increased libido, 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 Stalevo (see section 4.4).

Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated with carbidopa/levodopa. Affected patients show a compulsive pattern of dopaminergic drug misuse above doses adequate to control motor symptoms, which may in some cases result in severe dyskinesias (see also section 4.4).

Entacapone in association with levodopa has been associated with isolated cases of excessive daytime somnolence and sudden sleep onset episodes.

Reporting of suspected adverse reactions

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

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The post-marketing data includes isolated cases of overdose in which the reported highest daily doses of levodopa and entacapone have been at least 10 000 mg and 40 000 mg, respectively. The acute symptoms and signs in these cases of overdose included agitation, confusional state, coma, bradycardia, ventricular tachycardia, Cheyne-Stokes respiration, discolourations of skin, tongue and conjunctiva, and chromaturia. Management of acute overdose with Stalevo therapy is similar to acute overdose with levodopa. Pyridoxine, however, is not effective in reversing the actions of Stalevo. Hospitalisation is advised and general supportive measures should be employed with immediate gastric lavage and repeated doses of charcoal over time. This may hasten the elimination of entacapone in particular by decreasing its absorption/reabsorption from the GI tract. The adequacy of the respiratory, circulatory and renal systems should be carefully monitored and appropriate supportive measures employed. ECG monitoring should be started and the patient carefully monitored for the possible development of arrhythmias. If required, appropriate anti-arrhythmic therapy should be given. The possibility that the patient has taken other active substances in addition to Stalevo should be taken into consideration. The value of dialysis in the treatment of overdose is not known.