Instructions Confundus Trio film-coated tablets bottle 200 mg/50 mg/200 mg No. 100
Composition
active ingredients: levodopa, carbidopa, entacapone;
1 film-coated tablet contains 50 mg levodopa, 12.5 mg carbidopa, 200 mg entacapone
or 100 mg levodopa, 25 mg carbidopa, 200 mg entacapone,
or 150 mg levodopa, 37.5 mg carbidopa, 200 mg entacapone,
or 200 mg levodopa, 50 mg carbidopa, 200 mg entacapone;
excipients: corn starch, mannitol (E 421), croscarmellose sodium, povidone, magnesium stearate, hypromellose, sucrose, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), polysorbate 80, glycerol 85%.
Dosage form
Film-coated tablets.
Main physicochemical properties:
film-coated tablets, 50/12.5/200 mg: brownish-red, grayish-red, round, biconvex, marked LCE 50 on one side;
film-coated tablets, 100/25/200 mg: brownish-red, grayish-red, oval, marked LCE 100 on one side;
film-coated tablets, 150/37.5/200 mg: brownish-red, grayish-red, oblong-elliptical in shape, marked LCE 150 on one side;
Film-coated tablets, 200/50/200 mg: dark brown-red, oval, marked LCE 200 on one side.
Pharmacotherapeutic group
Medicinal products for the treatment of diseases of the nervous system. Antiparkinsonian drugs. Dopaminergic drugs. DOPA and its derivatives. Levodopa, decarboxylase inhibitor and COMT inhibitor. ATC code N04B A03.
Pharmacological properties
Pharmacodynamics.
According to current understanding, the symptoms of Parkinson's disease are associated with a decrease in the amount of dopamine in the striatum. Dopamine does not cross the blood-brain barrier. Levodopa, a precursor of dopamine, crosses the blood-brain barrier and reduces the symptoms of the disease. If levodopa is taken without metabolic enzyme inhibitors, it is metabolized to a greater extent in the periphery and only a small part of the dose taken reaches the central nervous system.
Carbidopa and benserazide, DDC inhibitors, reduce the peripheral metabolism of levodopa to dopamine, so that more levodopa reaches the brain. When the inhibition of levodopa decarboxylation is reduced by concomitant use of DDC inhibitors, a lower dose of levodopa can be used, which reduces the development of adverse reactions such as nausea.
When decarboxylase is inhibited by a DDC inhibitor, catechol-O-methyltransferase (COMT) becomes the major peripheral metabolic pathway, accelerating the conversion of levodopa to 3-O-methyldopa (3-OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible, specific COMT inhibitor that acts primarily peripherally and was developed for concomitant administration with levodopa. Entacapone slows the clearance of levodopa from the circulation, leading to an increase in the area under the concentration-time curve (AUC) in the pharmacokinetic profile of levodopa. Consequently, the clinical response to each dose of levodopa is enhanced and prolonged.
The effect of the drug is confirmed by the results of clinical studies based on the double-blind method.
Pharmacokinetics.
General characteristics of active components.
Absorption/distribution. There are significant inter- and intra-group differences in the absorption of levodopa, carbidopa and entacapone. Levodopa and entacapone are rapidly absorbed and eliminated. Compared with levodopa, carbidopa is absorbed and eliminated somewhat more slowly. The bioavailability of levodopa was 15-33% when administered separately from the other two active ingredients, the bioavailability of carbidopa was 40-70% and that of entacapone was 35% after a 200 mg oral dose. Food rich in numerous neutral amino acids may delay and reduce the absorption of levodopa. The absorption of entacapone is not significantly affected by food. The volume of distribution of levodopa (0.36-1.6 l/kg) and entacapone (0.27 l/kg) is small, and data on the volume of distribution of carbidopa are not available.
Levodopa is only slightly bound to plasma proteins, approximately 10-30%, and carbidopa is approximately 36%, whereas entacapone is extensively bound to plasma proteins (approximately 98%), mainly to serum albumin. At therapeutic concentrations, entacapone does not displace other extensively bound drugs (e.g. warfarin, salicylic acid, butadione, or diazepam), and is not significantly displaceable by any of these drugs at therapeutic or higher concentrations.
Metabolism and excretion: Levodopa is extensively metabolized to various metabolites, the most important pathways being decarboxylation by DOPA decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT).
Carbidopa is metabolized to two major metabolites, which are excreted in the urine as glucuronides and unbound compounds. Unchanged carbidopa accounts for 30% of total urinary excretion.
The total clearance of levodopa is in the range of 0.55-1.38 l/kg/h and of entacapone is in the range of 0.70 l/kg/h. The elimination half-life (t1/2el) of levodopa is 0.6-1.3 hours, of carbidopa 2 to 3 hours and of entacapone 0.4 to 0.7 hours for each ingredient separately.
Due to the short half-life, there is no stable accumulation of levodopa or entacapone upon repeated administration.
In vitro data using human liver microsomal preparations show that entacapone inhibits cytochrome P450 2C9 (IC504 µM). Entacapone has little or no inhibition of other cytochrome P450 isoenzyme types (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19).
Pharmacokinetics in special patient groups.
Elderly: When levodopa is taken without carbidopa and entacapone, its absorption in elderly patients is more intense and its elimination is slower than in young subjects. However, when carbidopa is combined with levodopa, the absorption of levodopa in young and elderly subjects is similar, although the AUC in elderly subjects is 1.5 times higher due to reduced DKA inhibitor activity and lower clearance, which are influenced by age. The pharmacokinetics of entacapone are independent of age.
There is no significant difference between the AUC of levodopa, carbidopa or entacapone in younger patients (45-60 years) and elderly subjects (60-75 years).
Gender: The bioavailability of levodopa is significantly higher in women than in men due to differences in body weight. The bioavailability of carbidopa and entacapone is not affected by gender.
Hepatic impairment: The metabolism of entacapone is slower in patients with mild to moderate hepatic impairment (Child-Pugh class A and B), resulting in increased plasma concentrations of entacapone during the absorption and elimination phases. No specific pharmacokinetic studies of carbidopa and levodopa in patients with hepatic impairment have been reported, but caution is advised in patients with biliary obstruction or severe hepatic disease.
Renal impairment: Renal impairment does not affect the pharmacokinetics of entacapone. No specific studies of the pharmacokinetics of levodopa and carbidopa in patients with renal impairment have been reported. However, longer dosing intervals for Confundus® Trio may be required in patients on dialysis.
Indication
Parkinson's disease. Movement disorders (instability) caused by dosage inefficiency in treatment with levodopa/dopa decarboxylase inhibitors.
Contraindication
Hypersensitivity to levodopa, carbidopa, entacapone or any other component of the drug.
Severe liver failure.
Narrow-angle glaucoma.
Pheochromocytoma.
Concomitant use of Confundus® Trio with non-selective monoamine oxidase inhibitors (MAO-A and MAO-B) (e.g. phenelzine, tranylcypromine).
Concomitant use of selective MAO-A and MAO-B inhibitors with Confundus® Trio.
History of neuroleptic malignant syndrome (NMS) and/or non-traumatic rhabdomyolysis.
Undiagnosed skin diseases or history of melanoma.
Severe heart failure. Severe cardiac arrhythmia.
Severe psychoses.
Interaction with other medicinal products and other types of interactions
Other antiparkinsonian drugs
There is no information on the interaction of other antiparkinsonian drugs and the drug Confundus® Trio. High doses of entacapone may affect the absorption of carbidopa. However, no interaction with carbidopa was observed at the recommended dosage (200 mg entacapone up to 10 times a day). No interaction between entacapone and selegiline was observed in patients with Parkinson's disease who were taking levodopa/DDC inhibitor. When using the drug Confundus® Trio, the daily dose of selegiline should not exceed 10 mg.
Caution should be exercised when using Confundus® Trio and the following medicines simultaneously.
Antihypertensive drugs: Symptomatic orthostatic hypotension may develop when levodopa is used concomitantly with antihypertensive drugs and dose adjustment of the antihypertensive drug may be required.
Antidepressants: Rarely, adverse reactions such as hypertension and dyskinesia have occurred with concomitant use of tricyclic antidepressants and levodopa/carbidopa. No interactions have been observed between entacapone and imipramine and between entacapone and moclobemide. No pharmacodynamic interactions have been observed when levodopa, carbidopa and entacapone are administered with tricyclic antidepressants, norepinephrine reuptake inhibitors such as desipramine, maprotiline and venlafaxine, and medicinal products metabolised by COMT (e.g. catechol-structured compounds, paroxetine), but caution should be exercised when co-administered with Confundus® Trio.
Confundus® Trio may potentially affect drugs whose metabolism depends on the cytochrome P450 2C9 isoenzyme, such as S-warfarin. Therefore, monitoring of blood clotting time is recommended when Confundus® Trio is used concomitantly with warfarin.
Concomitant use of anesthetics may cause arrhythmia.
The simultaneous use of the drug and products containing pyridoxine hydrochloride is possible.
Concomitant therapy with selegiline may lead to severe orthostatic hypotension.
Anticholinergics may act synergistically with levodopa to reduce tremor, and this feature is often used to enhance the therapeutic effect; however, they may exacerbate involuntary movements. In high doses, they may also reduce the beneficial effects of levodopa by slowing its absorption, thereby increasing the gastric metabolism of the drug.
Sympathomimetics may potentiate the cardiovascular side effects of levodopa.
Other forms of interaction: Since levodopa has the ability to compete with some amino acids, patients on a high-protein diet may experience impaired absorption of Confundus® Trio.
Levodopa and entacapone can form chelates with iron in the gastrointestinal tract. The interval between taking Confundus® Trio and iron preparations should be at least 2-3 hours.
In vitro: Entacapone binds to human albumin at position II, which is also the binding site for several other drugs, including diazepam and ibuprofen. Based on in vitro studies, no significant displacement is expected at therapeutic drug concentrations. No evidence of such interactions has been found.
Application features
Confundus® Trio is not recommended for the treatment of drug-induced extrapyramidal reactions, as well as for the treatment of Huntington's chorea.
Therapy with the drug should be prescribed with caution to patients with ischemic heart disease, severe diseases of the cardiovascular or respiratory systems, bronchial asthma, kidney or endocrine diseases, gastric ulcer or a history of seizures.
Patients with myocardial infarction with damaged atrial node or patients with a history of ventricular arrhythmia require cardiac monitoring, especially at the beginning of therapy or when the dose is increased.
All patients receiving Confundus® Trio should be monitored for the development of psychiatric changes, depression with suicidal tendencies, and other forms of antisocial behavior. Patients with a history of or current psychosis should be treated with caution.
Precautions should be taken when concomitantly using antipsychotics with dopamine receptor blocking properties, in particular, special attention should be paid to D2 receptor antagonists and the patient should be monitored for loss of antiparkinsonian effect or worsening of parkinsonian symptoms.
If psychotic symptoms worsen, the drug should be discontinued.
Confundus® Trio should be used with caution in patients with chronic wide-angle glaucoma, intraocular pressure should be well controlled, and the patient should be monitored for changes in intraocular pressure.
Confundus® Trio may cause orthostatic hypotension. Therefore, caution should be exercised when prescribing Confundus® Trio to patients taking other medications that may cause orthostatic hypotension.
The drug should be prescribed with caution to patients with Cushing's syndrome and patients with a history of orthostatic hypotension.
Entacapone together with levodopa may cause drowsiness and episodes of sudden sleep onset in patients with Parkinson's disease, so caution should be exercised when driving or performing work that requires quick reactions.
In clinical trials, it was noted that undesirable dopaminergic effects, such as dyskinesia, occurred more frequently in patients receiving entacapone and dopamine agonists (such as bromocriptine), selegiline or amantadine, compared to patients receiving placebo concomitantly with entacapone. Dose adjustments of other antiparkinsonian drugs may be necessary when prescribing Confundus® Trio to patients not currently taking entacapone.
Rarely, rhabdomyolysis may occur secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS). Therefore, careful monitoring is necessary when levodopa is abruptly withdrawn or reduced, especially in patients receiving neuroleptics. NMS, including rhabdomyolysis and hyperthermia, is characterized by motor symptoms (rigidity, myoclonus, tremor), mental status changes (e.g., agitation, confusion, coma), hyperthermia, autonomic dysfunction (tachycardia, unstable blood pressure) and elevated serum creatine phosphokinase. In isolated cases, only some of these symptoms are present. Early diagnosis is important for appropriate treatment of NMS. A syndrome similar to NMS has been reported following abrupt withdrawal of antiparkinsonian agents, including muscle rigidity, fever, mental changes and elevated serum creatine phosphokinase.
Rhabdomyolysis secondary to severe dyskinesia or ALS has occasionally been observed in patients with Parkinson's disease. Therefore, any abrupt dose reduction or discontinuation of levodopa should be monitored, especially in patients also taking neuroleptics.
It has been reported that patients with Parkinson's disease have an increased risk of developing melanoma. It is not known whether this risk is related to Parkinson's disease or to other factors, such as the use of medications to treat Parkinson's disease. Therefore, it is recommended to constantly monitor the skin for possible melanoma and to have periodic skin examinations by a qualified specialist.
If necessary, replacing Confundus® Trio with levodopa and a DDC inhibitor should be done slowly; an increase in the dose of levodopa may be required.
If general anesthesia is required, treatment with Confundus® Trio can be continued as long as the patient is allowed to take oral fluids and medications. If treatment needs to be temporarily interrupted, Confundus® Trio can be resumed at the same daily dose as soon as the patient is able to take oral medications.
During the use of the drug Confundus® Trio, it is recommended to periodically assess the state of liver function, hematopoietic, cardiovascular and urinary systems.
Patients with a history of diarrhea should have their weight monitored to avoid excessive weight loss. Prolonged or persistent diarrhea occurring with entacapone may be a sign of colitis. In such cases, the drug should be discontinued and appropriate medical therapy should be initiated.
Pathological gambling, increased libido and hypersexuality may occur during treatment with dopamine agonists or other dopaminergic drugs, such as Confundus® Trio.
Patients and their caregivers should be warned about possible changes in behavior that indicate impaired impulse control, including impulsive buying, overeating, and impulsive eating. In this case, the dose of the drug should be reduced or the drug should be discontinued.
Dopamine dysregulation syndrome is an addictive disorder that has led to excessive use of the drug in some patients treated with carbidopa/levodopa. Before starting treatment, patients and their caregivers should be warned about the potential risk of developing dopamine dysregulation syndrome (see section "Adverse reactions").
Patients with anorexia, asthenia, and weight loss in a short period of time require medical examination and monitoring of liver function.
Levodopa/carbidopa may cause a false-positive result in the rapid urine ketone test, which is not altered by boiling the urine sample. The use of the glucose oxidase method may give false-negative results for glycosuria.
Confundus® Trio contains sucrose, therefore patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency are not recommended to use this medicine.
There is a decrease in hemoglobin, hematocrit, an increase in serum glucose and an increase in white blood cells, an increase in the number of bacteria and blood in the urine. Positive tests for red blood cell antibodies are noted, but hemolytic anemia is practically not observed.
Laboratory tests: transient changes include increases in blood urea, creatinine, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, bilirubin, alkaline phosphatase, and protein-bound iodine.
Confundus® Trio contains mannitol as an excipient, which may have a laxative effect.
The drug contains glycerin, which may cause headache, irritation of the gastric mucosa and diarrhea.
This medicinal product contains croscarmellose sodium as an excipient. Caution should be exercised when used in patients on a controlled sodium diet.
Use during pregnancy or breastfeeding
The drug is contraindicated during pregnancy and breastfeeding. All women of reproductive age receiving the drug should use effective methods of contraception.
There is insufficient information on the effectiveness and safety of the drug in pregnant women, so the drug should not be used during pregnancy.
The drug can be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. Levodopa is excreted in breast milk. It is likely that during levodopa therapy, the ability to breastfeed may be inhibited. There is no data on the excretion of carbidopa and entacapone in breast milk. There is no information on the safety of levodopa, carbidopa and entacapone for the child, therefore, women should not breastfeed while using Confundus® Trio.
No adverse effects on fertility were observed in preclinical studies with entacapone, carbidopa or levodopa. Animal reproductive studies have not been conducted with the combination of these drugs.
The ability to influence the reaction speed when driving or working with other mechanisms
Entacapone may cause dizziness and symptomatic orthostatic hypotension when taken with levodopa and carbidopa. Entacapone has been associated with drowsiness and sudden sleep onset, so caution should be exercised when driving or operating machinery.
Method of administration and doses
Tablets should be taken orally, regardless of meals.
One tablet contains one therapeutic dose, so it is necessary to take the whole tablet.
The optimal daily dose of Confundus® Trio for each patient should be carefully selected. The daily dose of this medicinal product should be optimized by using one of the following dosages: 50/12.5/200 mg, 100/25/200 mg, 150/37.5/200 mg or 200/50/200 mg levodopa/carbidopa/entacapone.
Patients should be advised to take only one tablet of Confundus® Trio at the selected dosage. Nausea and vomiting may occur in patients receiving less than 70-100 mg of carbidopa per day. Since experience with total daily doses of carbidopa above 200 mg is limited and the maximum recommended daily dose of entacapone is 2000 mg, the maximum daily dose of Confundus® Trio is 10 tablets for the dosages 50/12.5/200 mg, 100/25/200 mg, 150/37.5/200 mg and 7 tablets for the dosage 200/50/200 mg.
Confundus® Trio is usually used in patients who are currently taking appropriate doses of levodopa or standard-release dopa decarboxylase inhibitors and entacapone.
The regimen for transferring patients taking levodopa/DDC inhibitor drugs (carbidopa or benserazide) and entacapone tablets to Confundus® Trio.
a. Patients currently taking entacapone and levodopa/carbidopa standard release at doses equivalent to those in Confundus® Trio tablets may be directly switched to the corresponding tablets of this medicinal product. For example, a patient taking one 50/12.5 mg levodopa/carbidopa tablet and one 200 mg entacapone tablet 4 times daily may take one 50/12.5/200 mg Confundus® Trio tablet 4 times daily in place of their usual doses of levodopa/carbidopa and entacapone.
b. When initiating treatment in patients currently taking doses of entacapone and levodopa/carbidopa that are not equivalent to those in Confundus® Trio 50/12.5/200 mg tablets (or 100/25/200 mg, or 150/37.5/200 mg, or 200/50/200 mg), the dose of the medicinal product should be carefully titrated to obtain the optimal clinical response. The dose of Confundus® Trio should initially be adjusted to match the total daily dose of levodopa being taken as closely as possible.
c. When initiating treatment in patients currently taking entacapone and levodopa/benserazide in standard release dosage forms, levodopa/benserazide should be discontinued the evening before and Confundus® Trio should be started the following morning. The dose of Confundus® Trio should be started with the same or slightly higher (5-10%) levodopa content.
Switching regimen to Confundus® Trio for patients not currently treated with entacapone.
Treatment with Confundus® Trio at appropriate doses may be considered in some patients with Parkinson's disease and end-of-dose movement disorders who are not stabilized on their current standard-release levodopa/DDC inhibitor therapy. However, direct transfer from a levodopa/DDC inhibitor to Confundus® Trio is not recommended in patients with dyskinesia or those receiving levodopa doses above 800 mg/day. In such patients, it is recommended that entacapone be initiated separately and, if necessary, the levodopa dose be adjusted before switching to Confundus® Trio.
Entacapone potentiates the effect of levodopa. Patients with dyskinesia may require a 10-30% reduction in levodopa dose when starting Confundus® Trio. The daily dose of levodopa may be reduced by extending the dosing interval and/or reducing the levodopa dose, depending on the clinical condition of the patient.
If a higher dose of levodopa is required, consideration should be given to increasing the frequency of dosing and/or using an alternative dosage of Confundus® Trio within the dosing recommendations.
If a lower dose of levodopa is required, the total daily dose of Confundus® Trio should be reduced by reducing the frequency of administration, increasing the time between doses, or by using Confundus® Trio at a lower dosage.
If other levodopa preparations are taken together with Confundus® Trio tablets, the recommendations regarding maximum dosage should be followed.
Discontinuation of therapy with Confundus® Trio.
If treatment with Confundus® Trio (levodopa/carbidopa/entacapone) needs to be discontinued and the patient switched to levodopa/DDC inhibitor therapy without entacapone, the dose of other antiparkinsonian drugs, especially levodopa, should be increased to adequately control parkinsonian symptoms.
Application for the treatment of children.
The safety and efficacy of Confundus® Trio in patients under 18 years of age have not been established. Therefore, this medicinal product is not recommended for use in children.
Application for the treatment of elderly patients.
Elderly patients do not require special dosage adjustment of Confundus® Trio.
Use for the treatment of patients with impaired liver function.
Patients with mild to moderate hepatic impairment should be treated with caution. A dose reduction may be necessary.
Use for the treatment of patients with impaired renal function.
Renal impairment does not affect the pharmacokinetics of entacapone. Confundus® Trio should be administered with caution to patients with severe renal impairment and those on dialysis.
Children
The use of the drug is not indicated for this category of patients.
Overdose
Symptoms: early signs - muscle twitching, blepharospasm, hypertension, increased heart rate, decreased appetite, confusion, anxiety, insomnia, restlessness.
There are reports of daily doses of levodopa and entacapone of 10,000 mg and 40,000 mg, respectively. Acute symptoms in such cases include agitation, psychosis, coma, bradycardia, ventricular tachyarrhythmia, Cheyne-Stokes respiration, discoloration of the skin, tongue, conjunctiva, and chromaturia.
Treatment of acute overdose with Confundus® Trio is similar to that of acute overdose with levodopa. However, pyridoxine is ineffective in reversing the effects of Confundus® Trio. Hospitalization is recommended; general supportive measures should be taken with immediate gastric lavage and administration of activated charcoal. This may accelerate the elimination of entacapone, in particular by reducing its absorption/reabsorption from the gastrointestinal tract.
Close monitoring of the respiratory, cardiovascular and urinary systems is necessary, and appropriate supportive measures should be taken. ECG monitoring should be initiated and the possibility of arrhythmias observed. Appropriate antiarrhythmic therapy should be administered as necessary. It should be taken into account that the patient may have been taking other medications in addition to Confundus® Trio. The value of dialysis in the treatment of overdose is unknown.
Side effects
Conclusions on the safety profile of the drug.
The most common adverse reactions are dyskinesia (19% of patients); gastrointestinal disorders, including nausea and diarrhea (15% and 12%, respectively); musculoskeletal pain and pain in muscles and connective tissue (12%); urine discoloration to red-brown (10%). In clinical trials of Confundus® Trio or entacapone in combination with levodopa/DDC inhibitor, cases of gastrointestinal bleeding and Quincke's edema were identified. Hepatitis with signs of cholestasis, rhabdomyolysis and neuroleptic malignant syndrome may occur with Confundus® Trio, although no such cases were identified during clinical trials.
Summary of adverse reactions.
From the blood and lymphatic system.
Common: anemia.
Uncommon: thrombocytopenia.
Leukopenia, hemolytic and non-hemolytic anemia, agranulocytosis.
On the part of metabolism.
Common: weight loss*, loss of appetite*.
From the psychological side.
Common: depression, hallucinations, confusion*, nightmares*, anxiety, insomnia.
Uncommon: psychosis, agitation*.
Frequency unknown: suicidal behavior, dopamine dysregulation syndrome.
Mania, exhaustion, euphoria, dementia, mental status changes (including paranoid thoughts and transient psychosis), delusions, anxiety, agitation, fear, thinking disorders, disorientation, numbness, sudden attacks of drowsiness.
From the nervous system.
Very common: dyskinesia*
Common: Exacerbation of parkinsonism (e.g. bradykinesia)*, tremor, on-off phenomenon, dizziness, dystonia, mental disorders including dementia and memory impairment, somnolence, dizziness*, headache.
Ataxia, bradykinesia, chorea, increased hand tremor, muscle twitching, muscle spasms, trismus, paresthesias, convulsions, tendency to faint, loss of consciousness, activation of latent Bernard-Horner syndrome.
Blepharospasm, activation of latent Horner's syndrome.
From the organs of vision.
Common: blurred vision.
Diplopia, mydriasis, oculomotor crisis, gaze spasm.
From the cardiovascular system.
Common: ischemic heart disease other than myocardial infarction (e.g. angina pectoris)**, cardiac arrhythmias, orthostatic hypotension, hypertension.
Uncommon: myocardial infarction**, gastrointestinal bleeding.
Palpitation.
On the part of the respiratory system.
Common: dyspnoea.
Breathing problems, hoarseness of voice.
From the gastrointestinal tract.
Very common: diarrhea*, nausea*.
Common: constipation*, vomiting*, dyspepsia, abdominal pain*, dry mouth*.
Uncommon: colitis*, dysphagia.
Bitter taste in the mouth, hypersalivation, bruxism, hiccups, flatulence, glossalgia, dark saliva, burning sensation on the tongue, duodenal ulcer, weight gain, edema. Abdominal discomfort.
From the liver.
Uncommon: changes in liver function tests*.
Frequency unknown: hepatitis with signs of cholestasis*.
On the skin and subcutaneous tissue.
Common: rash*, increased sweating.
Uncommon: changes in skin, nail, hair and sweat colour*.
Rare: angioedema.
Frequency unknown: urticaria*.
Hair loss.
On the part of the musculoskeletal system and connective tissue.
Very common: musculoskeletal pain and muscle and connective tissue pain*.
Common: muscle spasm, joint pain.
Frequency not known: rhabdomyolysis*.
From the kidneys and urinary tract.
Very common: chromaturia*.
Common: urinary tract infections.
Uncommon: urinary retention.
Enuresis.
From the immune system.
Hypersensitivity reactions, Henoch-Schonlein purpura.
Laboratory indicators.
Increased ALT, AST, lactate dehydrogenase, bilirubin, blood urea nitrogen, creatinine, uric acid, positive Coombs test. Decreased hemoglobin and hemocrit, increased serum glucose, leukocytosis, bacteriuria, hematuria.
Other adverse reactions.
General weakness, sudden exacerbation of concomitant diseases, flushing, malignant melanoma. Impulsive desire to make a purchase, craving for spending, overeating, impulsive eating. Priapism.
General violations.
Common: chest pain, peripheral edema, fall, gait disturbance, asthenia, fatigue.
Uncommon: general malaise.
*Adverse reactions more commonly associated with entacapone than with levodopa/DDC inhibitor (difference in frequency of at least 1% in clinical trials).
**The rates of myocardial infarction and other ischemic heart disease (0.43% and 1.54%, respectively) were derived from analyses of 13 double-blind studies involving 2082 patients with end-of-dose motor fluctuations treated with entacapone.
Description of selected adverse reactions.
The most frequent adverse reactions caused by entacapone are related to increased dopaminergic activity and in most cases occur at the beginning of treatment. Reducing the dose of levodopa leads to a decrease in the severity and frequency of the reactions.
Several adverse reactions, including diarrhea and a change in urine color to a reddish-brown color, are directly related to the active substance entacapone. Entacapone can also change the color of the skin, nails, hair, and sweat.
Convulsions occur rarely during treatment with levodopa/carbidopa, but a causal relationship has not been established.
Pathological gambling, increased libido and hypersexuality have been reported in patients taking dopamine agonists or other dopaminergic agents, such as Confundus® Trio, especially at high doses, which are usually reversible upon dose reduction or discontinuation of the drug.
Dopamine dysregulation syndrome is an addictive disorder observed in some patients treated with carbidopa/levodopa. Patients with this syndrome exhibit a compulsive pattern of dopaminergic drug abuse at doses higher than those required for adequate control of motor symptoms, which may in some cases lead to the development of severe dyskinesia (see section 4.4).
Entacapone, when combined with levodopa, may cause increased daytime sleepiness and sudden
