Drug Class Description
Anti-parkinsonian dopaminergic

Generic Name
Llevodopa/Carbidopa/Entacapone

Drug Description
Each tablet contains 50 mg of levodopa, 12.5 mg of carbidopa and 200 mg of entacapone.Excipient: Each tablet contains 1.2 mg of sucrose.

Presentation
Film-coated tablet Brownish or greyish red, round, convex, unscored film-coated tablets marked with 'LCE 50' on one side.

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.

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 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 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 200 mg/50 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.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.

Child Dosage
Stalevo is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

Elderly Dosage
No dose adjustment of Stalevo is required for elderly patients.

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 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.- 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
The following section describes the undesirable effects reported for levodopa/carbidopa and for entacapone used in combination with levodopa/DDC inhibitor.Levodopa /carbidopaAdverse reactions that occur frequently with levodopa/carbidopa are those due to central neuropharmacological activity of dopamine. These reactions can usually be diminished by levodopa dose reduction. The most common adverse reactions are dyskinesias including choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be taken as early signs to consider levodopa dose reduction. Nausea, also related to enhanced central dopaminergic activity, is a common adverse reaction of levodopa/carbidopa.Other adverse reactions associated with levodopa/carbidopa therapy are mental changes, including paranoid ideation and psychotic episodes; depression with or without development of suicidal tendencies; and cognitive dysfunction. Adding of entacapone to levodopa/DDC inhibitor therapy (carbidopa or benserazide), i.e. initiation of Stalevo treatment in an entacapone naive patient, may aggravate some of these mental changes.Less frequent adverse reactions of levodopa/carbidopa therapy are irregular heart rhythm and/or palpitations, orthostatic hypotensive episodes, bradykinetic episodes (the 'on-off' phenomenon), anorexia, vomiting, dizziness, and somnolence.Gastrointestinal bleeding, development of duodenal ulcer, hypertension, phlebitis, leucopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia, agranulocytosis, chest pain, dyspnoea and paraesthesia have occurred rarely with levodopa/carbidopa.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 and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation.Other adverse reactions that have been reported with levodopa and may, therefore, be potential adverse reactions of Stalevo as well, include:Nervous system disorders: Ataxia, numbness, increased hand tremor, muscle twitching, muscle cramp, trismus, activation of latent Horner's syndrome. Also falling and gait abnormalities are potential undesirable effects.Eye disorders: Diplopia, blurred vision, dilated pupils, oculogyric crises.Gastrointestinal disorders: Dry mouth, bitter taste, sialorrhoea, dysphagia, bruxism, hiccups, abdominal pain and distress, constipation, diarrhoea, flatulence, burning sensation of the tongue.Renal and urinary disorders: Urinary retention, urinary incontinence, dark urine, priapism.Skin and subcutaneous tissue disorders:Flushing, increased sweating, dark sweat, rash, hair loss.Metabolism and nutrition disorders: Weight gain or loss, oedema.Psychiatric disorders: Confusion, insomnia, nightmares, hallucinations, delusions, agitation, anxiety, euphoria.Miscellaneous: Weakness, faintness, fatigue, headache, hoarseness, malaise, hot flushes, sense of stimulation, bizarre breathing patterns, neuroleptic malignant syndrome, malignant melanoma.EntacaponeThe most frequent adverse reactions caused by entacapone relate to the increased dopaminergic activity and occur most commonly at the beginning of the treatment. Reduction of levodopa dose decreases the severity and frequency of the reactions. The other major class of adverse reactions are gastrointestinal symptoms, including nausea, vomiting, abdominal pain, constipations and diarrhoea. Urine may be discoloured reddish-brown by entacapone, but this is a harmless phenomenon.The following adverse reactions, listed in Table 1, have been accumulated both from clinical studies with entacapone and since the introduction of entacapone into the market for the combination use of entacapone with levodopa/DDC inhibitor.Table 1. Adverse reactionsNervous system disordersVery common: Dyskinesia, Parkinsonism aggravated.Common: Dizziness, dystonia, hyperkinesia.Gastrointestinal disordersVery common: Nausea.Common: Diarrhoea, abdominal pain, dry mouth, constipation, vomiting.Very rare: Anorexia.Not known: Colitis.Renal and urinary disordersVery common: Urine discolouration.Skin and subcutaneous tissue disordersRare: Erythematous or maculopapular rash.Very rare: Urticaria.Not known: Skin, hair, beard and nail discolorations.General disorders and administration site conditionsCommon: Fatigue, sweating increased, fall.Uncommon: Weight decrease.Hepatobiliary disordersRare: Hepatic function tests abnormal.Not known: Hepatitis with mainly cholestatic features.Psychiatric disordersCommon: Insomnia, hallucinations, confusion, nightmares, agitation.*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).Entacapone in association with levodopa has been associated with isolated cases of excessive daytime somnolence and sudden sleep onset episodes.Isolated cases of NMS have been reported following the abrupt reduction or discontinuation of entacapone and other dopaminergic treatments.Isolated cases of rhabdomyolysis have been reported.Isolated cases of angioedema have been reported after the initiation of Stalevo.Laboratory tests :The following laboratory abnormalities have been reported with levodopa/carbidopa treatment and should, therefore, be acknowledged when treating patients with Stalevo:Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of levodopa/carbidopa than with levodopa alone. Transient abnormalities include elevated values of blood urea, AST (SGOT), ALT (SGPT), LDH, bilirubin, and alkaline phosphatase.Decreased haemoglobin, haematocrit, elevated serum glucose and white blood cells, bacteria and blood in the urine have been reported.Positive Coombs' tests have been reported, both for levodopa/carbidopa and for levodopa alone, but haemolytic anaemia is extremely rare.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.

Manufacturer
Orion Pharma

Drug Availability
(POM)

Updated
12 August 2009