Stalevo

/ Novartis

The optimum daily dosage must be determined by careful titration of levodopa in each patient. The daily dose should preferably be optimised using one of the six available tablet strengths (50/12.5/200 mg, 75/18.75/200 mg, 100/25/200 mg, 125/31.25/200 mg, 150/37.5/200 mg or 200/50/200 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 dosage greater than 200 mg carbidopa is limited, the maximum recommended daily dose of entacapone is 2000 mg and therefore the maximum Stalevo dose, for the Stalevo strengths of 50/12.5/200 mg, 75/18.75/200 mg, 100/25/200 mg, 125/31.25/200 mg, and 150/37.5/200 mg, is 10 tablets per day. Ten (10) tablets of Stalevo 150/37.5/200 mg equal 375 mg of carbidopa a day. Therefore, using a maximum recommended daily dose of 375 mg of carbidopa, the maximum daily dose of Stalevo 200/50/200 mg is 7 tablets per day.
The maximum total daily levodopa dose administered in the form of Stalevo should not exceed 1500 mg.
Starting Stalevo therapy
Patients with Parkinson’s disease with end-of-dose motor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment
Switching from levodopa/ DDC inhibitor (carbidopa or benserazide) preparations and entacapone to Stalevo: Usually Stalevo is intended for use in patients already receiving treatment with corresponding doses of standard-release levodopa/DDC inhibitor and entacapone. As with levodopa/carbidopa, non-selective monoamine oxidase (MAO) inhibitors are contraindicated for use with Stalevo. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Stalevo. Stalevo may be administered concomitantly with the manufacturer’s recommended dose of MAO inhibitors with selectivity for MAO type B (e.g., selegiline HCl).
Patients who are currently receiving treatment with entacapone and standard-release levodopa/carbidopa in doses equal to Stalevo tablet strengths can be directly switched to the corresponding Stalevo tablets. When initiating Stalevo therapy in patients currently receiving treatment with entacapone and levodopa/carbidopa in doses not equal to the available Stalevo tablet strengths (50/12.5/200 mg, 75/18.75/200 mg, 100/25/200 mg, 125/31.25/200 mg, 150/37.5/200 mg, or 200/50/200 mg), Stalevo dosing should be carefully titrated for optimal clinical response. At the start of therapy, Stalevo should be adjusted to correspond as closely as possible to the total daily dose of levodopa currently used. When initiating Stalevo in patients currently treated with entacapone and levodopa/benserazide in a standard-release formulation, treatment should be stopped for one night and Stalevo therapy started the next morning. The therapy should begin with a dosage of Stalevo that will provide either the same amount of levodopa or slightly (5-10 %) more.
Switching in patients not currently treated with entacapone to Stalevo: As with levodopa/carbidopa, non-selective monoamine oxidase (MAO) inhibitors are contraindicated for use with Stalevo. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Stalevo. Stalevo may be administered concomitantly with the manufacturer’s recommended dose of MAO inhibitors with selectivity for MAO type B (e.g., selegiline HCl). Initiation of Stalevo at a dosage corresponding to current treatment may be considered 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 medication (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 dosage 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.
Dosage 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 dosage recommendations. When less levodopa is required, the total daily dosage 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 dosage recommendations should be followed.
Discontinuation of Stalevo therapy: If Stalevo treatment (levodopa/carbidopa/entacapone) is discontinued and the patient is switched 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: The safety and efficacy of Stalevo in children aged below 18 years have not been established. No data are available.
Elderly: No adjustment of Stalevo dosage is necessary in elderly patients.
Hepatic impairment: Caution is recommended when administering Stalevo to patients with mild to moderate hepatic impairment. Dose reduction may be necessary.
Renal impairment: Renal impairment does not affect the pharmacokinetics of entacapone. No specific studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment, and Stalevo should therefore be administered with caution in patients with severe renal impairment including those receiving dialysis therapy.
Method of administration: 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.

Treatment of patients with Parkinson’s disease and end-of-dose motor fluctuations not stabilized on levodopa/dopa decarboxylase (DDC) inhibitor treatment.

Known hypersensitivity to the active substances or to any of the excipients. Severe hepatic impairment. Narrow-angle glaucoma. Pheochromocytoma. Concomitant use 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, These inhibitors must be discontinued at least two weeks prior to initiating therapy with Stalevo. A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic rhabdomyolysis. Lactation.

Stalevo is not recommended for the treatment of drug-induced extrapyramidal reactions. Stalevo therapy should be administered with caution to patients with ischemic heart disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease, or history of peptic ulcer disease or 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 dosage adjustments. All patients treated with Stalevo should be monitored carefully for the development of mental changes (e.g. hallucinoses and psychoses), depression with suicidal tendencies, and 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 caution is necessary when giving Stalevo to patients who are taking other medicinal products which may cause orthostatic hypotension. Entacapone in combination 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, undesirable dopaminergic effects, 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 is introduced in a patient not previously 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.
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.
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. Early diagnosis is important for the appropriate management of NMS. A syndrome resembling NMS including muscular rigidity, elevated body temperature, mental changes and increased serum creatine phosphokinase has been reported with the abrupt withdrawal of antiparkinsonian agents. Isolated cases of NMS have been reported, especially following abrupt reduction or discontinuation of entacapone. When considered necessary, withdrawal of Stalevo and other dopaminergic treatment should proceed slowly, and if signs and/or symptoms occur despite a slow withdrawal of Stalevo, an increase in levodopa dosage may be necessary. Prescribers should exercise caution when switching patients from Stalevo to levodopa/DDC inhibitor therapy without entacapone. When considered necessary, the replacement of Stalevo with levodopa and DDC inhibitor without entacapone should proceed slowly and an increase in levodopa dosage 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 medication by mouth. If therapy has to be stopped temporarily, Stalevo may be restarted as soon as oral medication can be taken at the same daily dosage as before. Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during extended therapy with Stalevo. For patients experiencing diarrhea, a follow-up of weight is recommended in order to avoid potential excessive weight decrease. Prolonged or persistent diarrhoea suspected to be related to Stalevo 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. 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. Patients should be regularly monitored for the development of impulse control disorders. Patients and caregivers 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. 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.
Patients with rare hereditary problems: of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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.
For full details see prescribing information.

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. Because Stalevo contains entacapone, it should not be used concurrently with Comtan (entacapone). Caution should be exercised when the following active substances are administered concomitantly with levodopa therapy.
Antihypertensives: Symptomatic postural hypotension may occur when levodopa is initiated in patients already receiving antihypertensives. Dosage 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: rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, alphamethyldopa, apomorphine, and 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, 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 Rwarfarin 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 in 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 a 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. Stalevo may be given to patients with Parkinson’s disease who are taking vitamin preparations that contain pyridoxine hydrochloride (Vitamin B6).
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.

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. The potential risk for humans is unknown. Stalevo should not be used during pregnancy.
Breast-feeding: Levodopa is excreted in human breast milk. There is evidence that lactation is suppressed during treatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but it 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.

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 is similar to acute overdose with levodopa. 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 gastrointestinal 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 antiarrhythmic 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.

Shelf-life: 3 years.
Storage: Store below 25°C. After first opening of the bottle, use within 6 months. Store in the original package.