Index of drugs

Treatment of adult patients with Parkinson's disease who have motor end fluctuations that can not be stabilized with levodopa / dopa decarboxylase inhibitor (DDC).

1 tabl powl. contains 50 mg, 100 mg or 150 mg levodopa and 12.5 mg, 25 mg or 37.5 mg carbidopa, respectively, in combination with 200 mg entacapone. The product contains sucrose.

A combined preparation containing levodopa, a precursor to dopamine; carbidopa - peripheral DDC inhibitor and entacapone - COMT inhibitor. Carbidopa is a peripheral DDC inhibitor that reduces the peripheral metabolism of levodopa to Dopamine, allowing more levodopa to enter the brain. When decarboxylation of levodopa is reduced by administration together with a DDC inhibitor, a lower dose of levodopa may be used. The incidence of side effects, such as nausea, is also reduced. When inhibiting decarboxylase activity by a DDC inhibitor, COMT becomes the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-methyldopa (3-OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible, specific and mainly peripheral COMT inhibitor designed for simultaneous administration with levodopa. Entacapone delays the clearance of levodopa in the bloodstream, resulting in an increase in the area under the curve (AUC) in the pharmacokinetic profile of levodopa. As a consequence, the clinical response to each dose of levodopa is increased and prolonged. There are significant inter- and intra-individual differences regarding the absorption of levodopa, carbidopa and entacapone. Both levodopa and entacapone are rapidly absorbed and excreted. Carbidopa is absorbed and excreted slightly slower than levodopa. In the case of separate administration, without the other two active substances, the bioavailability of levodopa is 15-33%, carbidopa 40-70% and entacapone 35% after oral administration of a dose of 200 mg. Meals rich in a large amount of neutral amino acids may delay and reduce the absorption of levodopa. Food has no significant effect on the absorption of entacapone. Levodopa binds to plasma proteins only to a small extent (10-30%) and carbidopa is bound to about 36%, whereas entacapone is significantly bound to plasma proteins (around 98%). Levodopa is extensively metabolised to various metabolites. The most important metabolic pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by O-catechol methyltransferase (COMT). Carbidopa is metabolised to 2 major metabolites, excreted in the urine as glucuronides and unconjugated compounds. Carbidopa in unchanged form accounts for 30% of the total urinary excretion rate. Entacapone is almost completely metabolised before excretion in the urine (10-20%) and bile / faecal (80-90%). The main metabolic pathway is glucuronidation of entacapone and its active metabolite, cis-isomer, which accounts for about 5% of the total amount contained in the plasma. T_0,5 in the elimination phase, 0.6-1,3 h for levodopa, 2-3 h for carbidopa and 0.4-0.7 h for entacapone when administered separately.

Hypersensitivity to the active substances or to any of the excipients. Severe hepatic failure. Glaucoma with a narrow angle of perception. Phaeochromocytoma. Co-administration with non-selective MAO-A and MAO-B inhibitors (eg phenelzine, tranylcypromine). Simultaneous use with selective MAO-A inhibitors and selective MAO-B inhibitors. Malignant neuroleptic syndrome and / or non-traumatic rhabdomyolysis.

The preparation is not recommended for the treatment of drug-induced extrapyramidal reactions. It should be administered with caution to patients with ischemic heart disease, severe cardiovascular or pulmonary disease, bronchial asthma, kidney disease or endocrine disease, a history of peptic ulcer disease, or a history of seizures. Patients with a history of myocardial infarction who have atrial node arrhythmia or ventricular arrhythmia, cardiac function should be monitored particularly closely during initial titration.All patients treated with the product should be carefully monitored for psychiatric disorders, depression with suicidal tendencies and other serious antisocial behavior. Patients with psychosis in the interview or with current psychosis should be treated with caution. Caution should be exercised with the use of antipsychotic drugs with Dopamine receptor blocking properties, particularly D-receptor antagonists₂ - patients should be closely monitored for loss of anti-parkinsonian effects or worsening of Parkinson's symptoms. Patients with chronic wide-angle glaucoma may be treated with care with caution provided that intraocular pressure is well controlled and the patient's intraocular pressure changes are carefully monitored. The preparation may induce orthostatic hypotension, therefore caution should be used when it is given to patients taking other medicines that may cause orthostatic hypotension. Due to the risk of secondary rhabdomyolysis, severe dyskinesias or neuroleptic malignant syndrome (NMS) in patients with Parkinson's disease, a sudden dose reduction or discontinuation of levodopa should be closely monitored, particularly in patients taking neuroleptics. A syndrome resembling neuroleptic malignant syndrome has been observed, including muscle stiffness, elevated body temperature, psychological changes and increased serum creatine phosphokinase following a sudden discontinuation of anti-Parkinson's drugs. Since administration of entacapone, single cases of NMS have been reported, particularly after sudden dose reduction or discontinuation of entacapone and other dopaminergic agents given concomitantly. If it proves necessary to replace the preparation with levodopa and a DDC inhibitor without entacapone or with other dopaminergic medications, it should be done slowly and if necessary, increase the dose of levodopa. If general anesthesia is necessary, the therapy can be continued for as long as the patient is allowed to take fluids and oral medications. If treatment is interrupted for some time, the treatment can be resumed as soon as oral medications are allowed, at the same daily dose as before. Weight control is recommended to prevent excessive reduction in patients with diarrhea. Prolonged or persistent diarrhea during treatment with entacapone may be a sign of colitis. In the event of prolonged or persistent diarrhea, discontinue use and consider appropriate treatment and testing. Patients should be monitored systematically if they develop impulse control disorders. Patients and their carers should be advised that during treatment with the preparation, behavioral symptoms of impulse control disorders may occur, including pathological propensity to gambling, increased sex drive (libido), increased sexual activity, compulsive spending or buying, paroxysmal overeating, and compulsive food. In the event of the above symptoms, it is recommended to evaluate the treatment. In patients with progressive anorexia, asthenia and weight loss in a relatively short time, an overall medical assessment should be considered, including the assessment of liver function. Caution should be exercised in patients with mild to moderate hepatic impairment and in patients with severe renal insufficiency, including those undergoing dialysis. The safety and efficacy of the preparation in children below 18 years have not been established. The product contains sucrose - should not be used in patients with rare hereditary disorders such as fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency.

There are no adequate data on the use of the levodopa / carbidopa / entacapone combination in pregnant women. Studies conducted on animals have shown reproductive toxicity of individual components. The potential risk for humans is unknown. The preparation should not be used during pregnancy unless the benefits for the mother outweigh the possible risks to the fetus. Levodopa is excreted in human milk. Treatment with levodopa inhibits lactation. Carbidopa and entacapone were secreted with milk in animals, but it is not known whether they are excreted in human milk.Women should not breast-feed during treatment with the preparation.

Very common: dyskinesia, diarrhea, nausea, muscle pain, musculoskeletal pain, connective tissue pain, and chromaturia. Common: anemia, weight loss, decreased appetite, depression, hallucinations, nightmares, anxiety, insomnia, Parkinsonism (eg bradykinesia), tremors, on / off fluctuations, dystonia, mental retardation (eg memory impairment, dementia), drowsiness, pain and dizziness, blurred vision, cases of ischemic heart disease other than myocardial infarction (eg angina pectoris), irregular heart rhythm, orthostatic hypotension, hypertension, dyspnea, constipation, vomiting, indigestion, abdominal pain and discomfort, dry mouth, rash, excessive sweating, muscle cramps, joint pain, urinary tract infection, chest pain, peripheral edema, falls, gait disturbances, weakness, fatigue. Uncommon: thrombocytopenia, psychosis, agitation, myocardial infarction, gastrointestinal bleeding, colitis, dysphagia, abnormal liver function tests, discoloration other than urine (eg skin, nails, hair, sweat), urinary retention, malaise . Rare: angioneurotic edema. Frequency unknown: suicidal behavior, neuroleptic malignant syndrome, hepatitis mainly with cholestasis features, urticaria, rhabdomyolysis. Convulsions occur rarely after administration of levodopa / carbidopa; their causal relationship with levodopa / carbidopa has not been established. Patients treated with dopamine agonists and / or other dopaminergic levodopa-containing medications may experience impulse control disorders: pathological propensity to gamble, increased sex drive (libido), increased sexual activity, compulsive spending or buying, paroxysmal overeating and eating compulsive. The use of entacapone in combination with levodopa has been associated with isolated cases of excessive daytime sleepiness and episodes of sudden drowsiness.

Orally. Adults. The optimal daily dose must be determined by carefully adjusting the dose of levodopa for each patient. The daily dose should be adjusted using one of the tablet strengths available (50 mg / 12.5 mg / 200 mg, 100 mg / 25 mg / 200 mg, 150 mg / 37.5 mg / 200 mg levodopa / carbidopa / entacapone). Nausea and vomiting are more likely to occur in patients receiving carbidopa at a dose of less than 70-100 mg per day. The experience with the use of carbidopa in a total daily dose of more than 200 mg is limited, while the maximum recommended daily dose of entacapone is 2,000 mg and therefore the maximum dose is 10 tablets. per day. Typically, the preparation is used in patients who are currently being treated with appropriate doses of levodopa with a standard-release DDC inhibitor and entacapone.Change in treatment in patients taking levodopa / DDC inhibitor (carbidopa or benserazide) and entacapone tablets for Stalevo. 1. Patients who are currently treated with entacapone and levodopa / carbidopa with standard release in doses identical to those found in Stalevo tablets can be switched directly to the appropriate tablets of the preparation. 2. When starting Stalevo therapy for patients currently treated with entacapone and levodopa / carbidopa at unequal doses in Stalevo tablets, the dosage should be carefully adjusted to achieve an optimal clinical response. At the time of initiation of therapy, the dose should be adjusted so that it corresponds as closely as possible to the currently used total daily dose of levodopa. 3. When initiating therapy with Stalevo for patients currently treated with entacapone and levodopa plus standard release benzodiazepine, levodopa / benserazide should be discontinued on the previous evening and Stalevo should be initiated the Next morning. The initial dose of the preparation should provide the same or slightly higher (by 5-10%) amount of levodopa.Change in treatment in patients currently not treated with entacapone for Stalevo. The initiation of treatment with the preparation may be considered in the doses corresponding to the current treatment in some patients with Parkinson's disease and end-of-dose motor fluctuations that are not stabilized by the current treatment with levodopa / standard-release DDC inhibitor.However, it is not recommended to switch directly from levodopa / DDC inhibitor to Stalevo in patients with dyskinesias or whose daily dose of levodopa is above 800 mg. In these patients, the use of entacapone as a separate medicine is recommended and the dose of levodopa should be adjusted before switching to Stalevo. Entacapone increases the effect of levodopa. Therefore, it may be necessary, especially in patients with dyskinesias, to reduce the dose of levodopa by 10-30% in the first days or weeks after starting treatment with Stalevo. The daily dose of levodopa can be reduced by prolonging the intervals and / or by reducing the amount of levodopa per dose according to the clinical condition of the patient.Dose adjustment during treatment. If a higher dose of levodopa is required, an increase in frequency of doses and / or use of an alternative strength formulation should be considered within the recommended dosage range. If a lower dose of levodopa is required, the total daily dose of Stalevo should be reduced by reducing the frequency of administration - increasing the interval between doses or by reducing the strength of the preparation. If other medicines containing levodopa are used concurrently with Stalevo tablets, the maximum dose recommendations should be followed.Discontinuation of therapy with the preparation. If treatment with the preparation is discontinued and the patient is switched to levodopa with a DDC inhibitor without entacapone, dosage adjustment of other anti-Parkinsonian medicinal products, particularly levodopa, is necessary to achieve an adequate level of control of parkinsonian symptoms. No dosage adjustment is necessary for elderly patients. A dose reduction may be necessary in patients with mild to moderate hepatic impairment. The tablets should be used with or without food. One tablet contains one therapeutic dose and can only be used as a whole.