Drug Description
Stalevo 200 mg/50 mg/200 mg film-coated tablets

Presentation
Each tablet contains 200 mg of levodopa, 50 mg of carbidopa and 200 mg of entacapone.Excipient: Each tablet contains 2.3 mg of sucrose

Indications
Film-coated tabletDark brownish red, oval, unscored film-coated tablets marked with 'LCE 200' on one side.

Adult Dosage
Each tablet is to be taken orally either with or without food. One tablet contains one treatment dose and the tablet may only be administered as whole tablets.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 six 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 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 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 200 mg/50 mg of levodopa/carbidopa with one tablet of entacapone 200 mg four times daily can take one 200 mg/50 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 200 mg/50 mg/200 mg, (or 50 mg/12.5 mg/200 mg or 75 mg/18.75 mg/200 mg or 100 mg/25 mg200 mg 125 mg/31.25 mg/200 mg or 150 mg/37.5 mg/200 mg) tablets, 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, discontinue dosing of levodopa/benserazide the previous night, and start Stalevo the next morning. Begin with a dose of Stalevo that will provide either the same amount of levodopa or slightly (5-10%) more.How to transfer patients not currently treated with entacapone to StalevoInitiation 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 treatmentWhen 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.Children and adolescents : Stalevo is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.Elderly : No dose adjustment of Stalevo is required for elderly patients.Hepatic impairment : It is advised that Stalevo should be administered cautiously to patients with mild to moderate hepatic impairment. Dose reduction may be needed.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.

Contra Indications
- Hypersensitivity to the active substances or to any of the excipients.- Severe hepatic impairment.- Narrow-angle glaucoma.- Pheochromocytoma.- Concomitant use of Stalevo with non-selective monoamine oxidase (MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine).- Concomitant use of a selective MAO-A inhibitor and a selective MAO-B inhibitor.- A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic rhabdomyolysis.

Special Precautions
- 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.- 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 eva luation 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.- Pathological gambling, increased libido and hypersexuality have been reported in Parkinson's disease patients treated with dopamine agonists and other dopaminergic treatments such as Stalevo.- For patients who experience progressive anorexia, asthenia and weight decrease within a relatively short period of time, a general medical eva luation including liver function should be considered.- 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.

Interactions
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.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.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.

Adverse Reactions
a. Summary of the safety profileThe 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 reactionsThe following adverse reactions, listed in Table 1, have been accumulated both from a pooled data of eleven double-blind clinical trials consisting of 3230 patients (1810 treated with Stalevo or entacapone combined with levodopa/DDC inhibitor, and 1420 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 (1100 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 reactionsBlood and lymphatic system disordersCommon:AnaemiaUncommon:ThrombocytopeniaMetabolism and nutrition disordersCommon:Weight decreased*, decreased appetite*Psychiatric disordersCommon:Depression, hallucination, confusional state*, abnormal dreams*, anxiety, insomniaUncommon :Psychosis, agitation*Not known:Suicidal behaviourNervous system disordersVery common:Dyskinesia*Common:Parkinsonism aggravated (e.g. bradykinesia)*,tremor, on and off phenomenon, dystonia, mental impairment (e.g. memory impairment, dementia), somnolence, dizziness*, headacheNot known:Neuroleptic malignant syndrome*Eye disordersCommon:Blurred visionCardiac disordersCommon:Ischemic heart disease events other than myocardial infarction (e.g. angina pectoris)**, irregular heart rhythmUncommon:Myocardial infarction**Vascular disorders:Common:Orthostatic hypotension, hypertensionUncommon:Gastrointestinal haemorrhageRespiratory, thoracic and mediastinal disordersCommon:DyspnoeaGastrointestinal disordersVery common:Diarrhoea*, nausea*Common:Constipation*, vomiting*, dyspepsia, abdominal pain and discomfort*, dry mouth*Uncommon:Colitis*, dysphagiaHepatobiliary disordersUncommon:Hepatic function test abnormal*Not known:Hepatitis with mainly cholestatic features (see section 4.4)*Skin and subcutaneous tissue disordersCommon:Rash*, hyperhidrosisUncommon:Discolourations other than urine (e.g. skin, nail, hair, sweat)*Rare:AngioedemaNot known:Urticaria*Musculoskeletal and connective tissue disordersVery common:Muscle, musculoskeletal and connective tissue pain*Common:Muscle spasms, arthralgiaNot known:Rhabdomyolysis*Renal and urinary disordersVery common:Chromaturia*Common:Urinary tract infectionUncommon:Urinary retentionGeneral disorders and administration site conditionsCommon:Chest pain, peripheral oedema, fall, gait disturbance, asthenia, fatigueUncommon: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 2082 patients with end-of-dose motor fluctuations receiving entacapone.Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship to levodopa/carbidopa therapy has not been established.Parkinson's disease patients treated with dopamine agonists and other dopaminergic treatments such as Stalevo, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido,hypersexuality and other urges,generally reversible upon reduction of the dose or treatment discontinuation.Entacapone in association with levodopa has been associated with isolated cases of excessive daytime somnolence and sudden sleep onset episodes.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.c. Description of selected adverse reactionsAdverse 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.

Manufacturer
Orion Pharma (UK) Limited

Drug Availability
POM – Prescription Only Medicine

Updated
13 September 2010