Pharmacological properties
Pharmacodynamics. According to modern ideas, the symptoms of Parkinson's disease are associated with the replacement of dopamine in the striatum. Dopamine does not penetrate the blood-brain barrier. Levodopa, a precursor of dopamine, crosses the blood-brain barrier and reduces the severity of the symptoms of the disease. When 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, inhibitors of DOPA decarboxylase (DDC), reduce the peripheral metabolism of levodopa to dopamine. Thus, more levodopa reaches the brain.
When inhibition of levodopa decarboxylation is reduced by concomitant use of DDC inhibitors, a reduced 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 main peripheral metabolic pathway that accelerates the conversion of levodopa to 3-O-methyldopa (3-OMD), a potentially harmful metabolite of levodopa.
Entacapone is a specific, reversible COMT inhibitor that acts primarily peripherally and is designed to be co-administered with levodopa. Entacapone slows the clearance of levodopa from the circulation, which leads to an increase in the AUC in the pharmacokinetic profile of levodopa. Thus, the clinical response to each dose of levodopa is enhanced and lasts longer. 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 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 many 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 plasma 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 elimination: Levodopa is extensively metabolized to various metabolites, the most important pathways being decarboxylation of DDA and O-methylation of COMT.
Carbidopa is metabolized to two major metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid), which are excreted in the urine as glucuronides and unbound compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.
Entacapone is almost completely metabolized before excretion in urine (10-20%) and bile/faeces (80-90%). The main metabolic pathway is glucuronidation of entacapone, and its active metabolite, the cis-isomer, accounts for about 5% of the total amount in plasma.
The total clearance of levodopa is in the range of 0.55-1.38 l/kg/h, and of entacapone - in the range of 0.70 l/kg/h. T ½ of levodopa is 0.6-1.3 h, of carbidopa - 2-3 h and of entacapone - 0.4-0.7 h for each ingredient separately.
Due to the short T½, no stable accumulation of levodopa or entacapone was observed upon repeated administration.
Pharmacokinetics in special patient groups
Elderly patients. 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 is influenced by age. The pharmacokinetics of entacapone are independent of age.
There is no significant difference in the AUC of levodopa, carbidopa, or entacapone between 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.
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 of Stalevo may be used in patients on dialysis.
Indication
Parkinson's disease. movement disorders (gait instability) caused by insufficient dosage, not stabilized by levodopa/DDK inhibitor treatment.
Application
The tablets should be taken orally, regardless of meals. One tablet contains one dose of the drug, so it is necessary to take the whole tablet.
The optimal daily dose of Stalevo for each patient should be carefully selected. The daily dose of Stalevo should be optimized by using one of the following concentrations of Stalevo - 50/12.5/200, 100/25/200 or 150/37.5/200 mg, or 200/50/200 mg levodopa/carbidopa/entacapone.
Patients should be advised to take only one tablet of Stalevo at the selected dose. Nausea and vomiting may occur in patients taking less than 70-100 mg of carbidopa per day. Since experience with a total daily dose of 200 mg of carbidopa is limited and the maximum recommended daily dose of entacapone is 2000 mg, the maximum daily dose of Stalevo is 10 tablets for the 50/12.5/200, 100/25/200 and 150/37.5/200 mg doses. For the 200/50/200 mg doses, the maximum daily dose is 7 tablets.
Stalevo is usually used in patients who are currently taking appropriate doses of levodopa or standard-release DDC inhibitors and entacapone.
The regimen for transferring patients taking levodopa/DDK inhibitor drugs (carbidopa or benserazide) and entacapone tablets to Stalevo:
a) Patients currently taking entacapone and levodopa/carbidopa standard release at doses equivalent to the Stalevo tablet strengths may be directly switched to the corresponding Stalevo tablets. For example, a patient taking 1 tablet of 50/12.5 mg levodopa/carbidopa and 1 tablet of 200 mg 4 times daily may take 1 tablet of 50/12.5/200 mg Stalevo 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 Stalevo 50/12.5/200 mg tablets (or 100/25/200, or 150/37.5/200, or 200/50/200 mg), the dose of Stalevo should be carefully titrated to obtain the optimal clinical response. Initially, the dose of Stalevo should be adjusted to match as closely as possible the total daily dose of levodopa taken; c) when initiating treatment in patients currently taking entacapone and levodopa/benserazide in standard-release formulations, levodopa/benserazide should be discontinued the evening before and Stalevo should be initiated the following morning. The dose of Stalevo should be started with the same amount of levodopa or slightly higher (5-10%).
Stalevo switching regimen for patients not currently treated with entacapone. Stalevo therapy can be initiated at doses appropriate to the current treatment in patients with Parkinson's disease and end-of-dose movement disorders who are not stabilised on their current levodopa/DDC inhibitor/standard-release treatment, particularly in patients without a history of dyskinesia and with levodopa doses of 800 mg/day. It is recommended that these patients start entacapone separately and, if necessary, increase the levodopa dose before switching to Stalevo.
Entacapone potentiates the effects of levodopa. Patients with dyskinesia may require a 10-30% reduction in levodopa dose when initiating Stalevo. The daily dose of levodopa may be reduced by extending the dosing intervals and/or reducing the levodopa dose, depending on the clinical condition of the patient.
Dose adjustment during treatment: If a higher dose of levodopa is required, increasing the frequency of dosing and/or using an alternative strength of Stalevo should be considered within the dosing recommendations.
If a lower dose of levodopa is required, the total daily dose of Stalevo should be reduced by decreasing the frequency of dosing, increasing the time between doses, or by reducing the concentration of Stalevo.
If other levodopa preparations are taken with Stalevo tablets, the maximum dosage recommendations should be followed.
Discontinuation of Stalevo therapy: If Stalevo (levodopa/carbidopa/entacapone) treatment must 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 achieve adequate control of parkinsonian symptoms.
Use in children. The safety and efficacy of Stalevo in patients under 18 years of age have not been established. Therefore, the use of this medicinal product in patients under 18 years of age is not recommended.
Use in elderly patients. Elderly patients do not require special dosage adjustment of Stalevo.
Use in patients with renal impairment. Mild to moderate renal impairment does not affect the pharmacokinetics of entacapone. Stalevo should be used with caution in patients with severe renal impairment.
Contraindication
Hypersensitivity to levodopa, carbidopa, entacapone or any other component of the drug. Severe hepatic impairment. Narrow-angle glaucoma. Pheochromocytoma. Concomitant use of Stalevo with non-selective MAO-A and MAO-B inhibitors (e.g. phenelzine, tranylcypromine). Concomitant use of selective MAO-A and MAO-B inhibitors with Stalevo. History of neuroleptic malignant syndrome (NMS) and/or non-traumatic rhabdomyolysis. Severe psychosis.
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); muscle pain, musculoskeletal and connective tissue disorders (12%); urine discoloration to red-brown (10%). In clinical trials of Stalevo or entacapone in combination with levodopa/DDC inhibitor, cases of gastrointestinal bleeding and angioedema have been reported. Cases of hepatitis with signs of cholestasis, rhabdomyolysis and neuroleptic malignant syndrome may occur with Stalevo, although no cases were reported in clinical trials.
Summary of adverse reactions
From the blood and lymphatic system: often - anemia; infrequently - thrombocytopenia; leukopenia, hemolytic and non-hemolytic anemia, agranulocytosis.
Metabolism: often - weight loss *, decreased appetite *.
On the part of the psyche: often - depression, hallucinations, confusion *, nightmares *, anxiety, insomnia; infrequently - psychosis, agitation *; frequency unknown - suicidal behavior; mania, exhaustion, euphoria, dementia, change in mental status (including paranoid thoughts and transient psychosis), delusions, anxiety, agitation, fear, thinking disorders, disorientation, numbness, sudden attacks of drowsiness.
From the nervous system: very often - dyskinesia *; often - exacerbation of parkinsonism (for example, bradykinesia) *, tremor, the phenomenon of "on-off" (on-off), dizziness, dystonia, mental disorders, including dementia and memory impairment, drowsiness, dizziness *, headache; frequency unknown - neuroleptic malignant syndrome; 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 syndrome.
From the organ of vision: often - blurred vision; diplopia, mydriasis, oculomotor crisis, gaze spasm.
From the cardiovascular system: often - coronary artery disease, except myocardial infarction (e.g. angina pectoris) **, cardiac arrhythmias, orthostatic hypotension, hypertension; infrequently - myocardial infarction **, gastrointestinal bleeding, palpitations.
On the part of the respiratory system: often - dyspnea; respiratory failure, hoarseness.
From the digestive system: very often - diarrhea *, nausea *; often - constipation *, vomiting *, dyspepsia, abdominal pain *, dry mouth *; infrequently - colic *, 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.
On the part of the liver: infrequently - changes in liver function tests *; frequency unknown - hepatitis with signs of cholestasis *.
Skin and subcutaneous tissue disorders: common: rash*, increased sweating; uncommon: discolouration of skin, nails, hair and sweat*; rare: angioedema; frequency unknown: urticaria*.
Musculoskeletal and connective tissue disorders: very common - muscle pain, musculoskeletal and connective tissue disorders *; common - muscle spasm, joint pain; frequency unknown - rhabdomyolysis *.
Renal and urinary disorders: very common - chromaturia *; common - urinary tract infections; uncommon - urinary retention, urinary incontinence.
On the part of the immune system: hypersensitivity reactions, Schönlein-Henoch purpura.
Laboratory indicators: increased ALT, AST, LDH, bilirubin, blood urea nitrogen, creatinine, uric acid, positive Coombs test, decreased hemoglobin and hemocrit, increased plasma glucose levels, 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 disorders: often - chest pain, peripheral edema, falls, gait disturbance, asthenia, fatigue; infrequently - malaise.
* Adverse reactions more commonly associated with entacapone than with levodopa/DDC inhibitor (in clinical trials, the difference in frequency was at least 1%).
Description of selected adverse reactions. The most frequent adverse reactions caused by entacapone are associated with 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 reactions.
Several adverse reactions, such as diarrhea and urine discoloration to a reddish-brown color, are directly related to the active ingredient entacapone. Entacapone can also change the color of the skin, nails, hair, and sweat.
Convulsions rarely occur 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 Stalevo, especially at high doses, which are usually reversible upon dose reduction or discontinuation of the drug.
Entacapone, associated with levodopa, may lead to increased daytime sleepiness and episodes of sudden sleep onset.
Special instructions
Stalevo is not recommended for the treatment of drug-induced extrapyramidal reactions, nor for the treatment of Huntington's chorea.
Therapy with the drug should be prescribed with caution to patients with coronary artery disease, severe diseases of the cardiovascular or respiratory system, bronchial asthma, diseases of the kidneys or endocrine glands, stomach ulcer or a history of seizures.
Patients with myocardial infarction with a damaged atrial node or with a history of ventricular arrhythmia require monitoring of cardiac activity, especially at the beginning of therapy or when the dose is increased.
All patients receiving Stalevo should be monitored for the development of psychiatric changes, depression with suicidal tendencies, and other forms of antisocial behavior. Caution should be exercised in treating patients with a current or history of psychosis.
Precautions should be taken when concomitantly taking antipsychotics with dopamine receptor blocking properties, in particular, attention should be paid to D2 receptor antagonists and patients should be monitored for loss of antiparkinsonian effect.
If psychotic symptoms worsen, the drug must be discontinued.
Stalevo 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.
Stalevo may cause orthostatic hypotension. Therefore, caution should be exercised when prescribing Stalevo to patients taking other medicinal products 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 studies, it was noted that undesirable dopaminergic effects, such as dyskinesia, were observed more often in patients receiving entacapone and dopamine agonists (bromocriptine), selegiline or amantadine, compared with patients receiving placebo simultaneously with entacapone.
Dose adjustments of other antiparkinsonian medications may be necessary when prescribing Stalevo to patients not currently taking entacapone.
In patients previously treated with levodopa alone, dyskinesia may occur because carbidopa allows more levodopa to reach the brain and thus more dopamine to be formed. If dyskinesia occurs, a dose reduction is required.
Rarely, secondary rhabdomyolysis may occur in 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 plasma creatine phosphokinase. In some cases, only some of these symptoms develop. Early diagnosis is important for appropriate treatment of NMS. A syndrome similar to NMS has been reported after abrupt discontinuation of antiparkinsonian agents, including muscle rigidity, elevated body temperature, mental changes and elevated plasma creatine phosphokinase.
Rhabdomyolysis secondary to severe dyskinesia or tardive dyskinesia has occasionally been reported in patients with Parkinson's disease. Therefore, any abrupt dose reduction or discontinuation of levodopa should be monitored, particularly in patients also taking neuroleptics.
If necessary, switching from Stalevo to levodopa and a DDC inhibitor should be done slowly and an increase in the levodopa dose may be necessary.
If general anesthesia is required, treatment with Stalevo can be continued as long as the patient is allowed to take oral fluids and medications. If treatment needs to be temporarily interrupted, Stalevo can be resumed at the same daily dose as soon as the patient is able to take oral medications.
During the period of use of Stalevo, periodic assessment of the function of the liver, hematopoietic, cardiovascular and urinary systems is recommended.
Patients with a history of diarrhea should be monitored for weight loss to avoid excessive weight loss. Prolonged or persistent diarrhea occurring with entacapone may be a sign of colitis. In this case, 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 Stalevo.
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 should be reduced or the drug should be discontinued.
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 affected by boiling the urine sample. The glucose oxidase method may give false-negative results for glycosuria.
Stalevo 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 may be a decrease in hemoglobin, hematocrit, an increase in serum glucose, and an increase in white blood cells, bacteria, and blood in the urine. Positive tests for red blood cell antibodies are noted, but hemolytic anemia is practically not detected.
Laboratory tests: transient changes include increases in blood urea, creatinine, ALT, AST, LDH, bilirubin, alkaline phosphatase, and protein-bound iodine.
Stalevo contains mannitol as an excipient, which may have a laxative effect.
The drug contains glycerin, which can cause headache, irritation of the stomach lining, and diarrhea.
Use during pregnancy and breastfeeding. Levodopa and its combinations with carbidopa have caused malformations of internal organs and the skeleton in animal experiments.
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 efficacy and safety of the drug in pregnant women, therefore the drug is not recommended for use during pregnancy. The drug can be prescribed during pregnancy only if the expected benefit to the mother is higher than the potential risks to the fetus. Levodopa is excreted in breast milk. It is likely that during levodopa therapy, the ability to breastfeed may be suppressed. Data on the excretion of carbidopa and entacapone in breast milk are not available. There is no information on the safety of levodopa, carbidopa and entacapone for the child, therefore, breastfeeding should be avoided during the use of Stalevo. In preclinical studies of entacapone, carbidopa or levodopa, no adverse effects on fertility were observed.
Children: The use of the drug in this category of patients is not indicated.
Ability to influence the reaction rate when driving or operating other mechanisms. Taking entacapone together with levodopa and carbidopa may lead to dizziness and symptomatic orthostatic hypotension. Taking the drug is associated with drowsiness and cases of sudden sleep onset, so caution should be exercised when driving or operating other mechanisms.
Interactions
Other antiparkinsonian drugs. There is no information on the interaction of antiparkinsonian drugs and Stalevo. 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). In a study of the interaction between entacapone and selegiline in patients with Parkinson's disease receiving levodopa/DDC inhibitor, no interaction was observed. When using Stalevo, the daily dose of selegiline should not exceed 10 mg.
Caution should be exercised when using Stalevo and the following medicinal products concomitantly.
Antidepressants: Rarely, adverse reactions such as hypertension and dyskinesia have been observed with concomitant use of tricyclic antidepressants and levodopa/carbidopa. No interactions have been observed between entacapone and imipramine and between entacapone and moclobemide. No pharmacological interactions have been observed when levodopa, carbidopa and entacapone are combined with tricyclic antidepressants, norepinephrine reuptake inhibitors such as desipramine, maprotiline and venlafaxine and medicinal products metabolised by COMT (e.g. catechol-reductase inhibitors, paroxetine), but caution should be exercised when co-administered with Stalevo.
Other drugs: dopamine receptor antagonists (some antipsychotics and antiemetics), phenytoin and papaverine may reduce the therapeutic effect of levodopa, therefore, it is necessary to ensure that patients taking these drugs together with Stalevo do not experience a decrease in the therapeutic effect.
Stalevo has the potential to affect drugs whose metabolism depends on the cytochrome P450 2C9 isoenzyme, such as S-warfarin. Therefore, monitoring of blood clotting time is recommended when Stalevo is used concomitantly with warfarin.
Concomitant use of anesthetics may cause arrhythmia.
It is possible to use the drug simultaneously with products containing pyridoxine hydrochloride.
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. At 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 Stalevo.
Levodopa and entacapone may form chelates with iron in the gastrointestinal tract. The time interval between taking Stalevo 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 data, no significant displacement is expected at therapeutic drug concentrations. No evidence of such interactions has been found.
Overdose
Symptoms: early signs - muscle twitching, blepharospasm, ag, increased heart rate, decreased appetite, confusion, anxiety, insomnia, restlessness.
There are reports of daily doses of levodopa and entacapone of 10,000 and 40,000 mg, respectively. Acute symptoms in such cases include agitation, psychosis, coma, bradycardia, ventricular tachyarrhythmia, Cheyne-Stokes breathing, discoloration of the skin, tongue, conjunctiva, and chromaturia.
Treatment of acute overdose with Stalevo is similar to that of acute overdose with levodopa. However, pyridoxine is ineffective in reversing the effects of Stalevo. Hospitalization is recommended, general supportive measures should be taken with immediate gastric lavage and activated charcoal. This may accelerate the elimination of entacapone, in particular by reducing its absorption/reabsorption in 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 development of arrhythmias should be closely monitored. 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 Stalevo. The value of dialysis in the treatment of overdose is unknown.
Storage conditions
At a temperature not exceeding 25 °C.
