Levocom retard Asino prolonged-release tablets 100 mg/25 mg No. 100

Instructions for Levocom retard Asino prolonged-release tablets 100 mg/25 mg No. 100

Composition

active ingredient: levodopa, carbidopa (as carbidopa monohydrate);

1 prolonged-release tablet of Levocom retard Asino 100/25 contains:
levodopa 100 mg, carbidopa monohydrate, which corresponds to carbidopa – 25 mg;

excipients: hypromellose, colloidal anhydrous silica, fumaric acid, sodium stearyl fumarate, quinoline yellow (E 104), macrogol 6000, yellow iron oxide (E 172), red iron oxide (E 172), titanium dioxide (E 171).

Dosage form

Extended-release tablets.

Main physicochemical properties: round, biconvex tablet of orange-brown color with rounded edges.

Pharmacotherapeutic group

Antiparkinsonian drugs. DOPA and its derivatives.

ATX code N04B A02.

Pharmacodynamics

Mechanism of action

Levocom retard Asino is a combination drug for the treatment of Parkinson's disease and Parkinson's syndrome. It contains carbidopa, a peripherally acting decarboxylase inhibitor, and levodopa, a metabolic precursor of dopamine. Levocom retard Asino is available as a polymer-based drug with prolonged absorption.

The effect of levodopa on the symptoms of Parkinson's disease is due to the action of dopamine formed in the brain. Levodopa reduces the symptoms of Parkinson's disease after decarboxylation to form dopamine in the brain.

Carbidopa does not cross the blood-brain barrier. Carbidopa only inhibits the extracerebral decarboxylation of levodopa, which results in more levodopa being transported to the brain for conversion to dopamine. Thus, there is no need to use high doses of levodopa at short intervals. In particular, a lower dose causes fewer peripheral side effects. Carbidopa prevents the acceleration of the peripheral conversion of levodopa to dopamine, which is known to occur under the influence of pyridoxine (vitamin B6).

Pharmacodynamics.

Extended-release levodopa/carbidopa is particularly useful in reducing the “off period” in patients with dyskinesias and involuntary movement disorders on prior levodopa/decarboxylase inhibitor combination therapy at peak plasma levels.
Patients with Parkinson's disease treated with levodopa may experience movement disorders characterized by lack of effect before the next dose of the drug, dyskinesia at peak plasma levels, and akinesia. This "on-off phenomenon" is characterized by unpredictable alternations of motor activity and immobility. Although the mechanism of action is not fully understood, it has been determined that such fluctuating mobility may be attenuated by stable levodopa plasma levels.

Clinical efficacy.

Patients with fluctuating movement disorders had fewer off-periods with levodopa/carbidopa extended-release. Overall improvement in on-off and daily activities among patients with on-off, as assessed by patients and physicians, was also better with levodopa/carbidopa extended-release than with non-extended-release levodopa/carbidopa.

Pharmacokinetics

Absorption.

The release of active substances occurs over 4–6 hours. This form of the drug is characterized by smaller fluctuations in blood plasma levels; the maximum level of levodopa in blood plasma is 60% lower compared to forms of the drug without extended release.

After taking Levocom retard Asino, the average time to reach maximum levodopa levels in the blood plasma is approximately 2 hours, compared to 0.75 hours with levodopa/carbidopa in a non-extended-release form.

The effect of food on the pharmacokinetics of levodopa/carbidopa extended-release was studied in 12 healthy subjects. The maximum plasma levodopa level (Cmax) was slightly higher after food (approximately 25%) and the exposure (AUC) was approximately 40% higher compared to the fasted state.

Distribution.

Data is missing.

Metabolism

Carbidopa metabolism: After oral administration of radiolabeled carbidopa, peak plasma concentrations were reached after 2–4 hours in healthy subjects and after 1.5–5 hours in patients with Parkinson's disease.

Levodopa metabolism: Levodopa is rapidly absorbed from the gastrointestinal tract and undergoes extensive metabolism. After a single dose of the radiolabeled levodopa in patients with Parkinson's disease on an empty stomach, peak plasma concentrations are observed within 0.5–2 hours and persist for 4–6 hours. At peak concentrations, approximately 30% of the radioisotope is incorporated into catecholamines, 15% into dopamine, and 10% into dopa. Radioactivity is rapidly excreted in the urine; 1/3 of the dose is excreted within 2 hours. 80–90% of the metabolites present in the urine are phenylcarboxylic acids, including homovanillic acid. After 24 hours, 1–2% of the radioactive isotopes are excreted as dopamine and less than 1% as adrenaline, noradrenaline, and unchanged levodopa.

Since the bioavailability of levodopa with extended-release levodopa/carbidopa is approximately 70% compared to non-extended-release levodopa/carbidopa, the daily dose of levodopa with extended-release formulation is generally higher than with standard formulation.

In healthy younger volunteers, the absolute bioavailability of levodopa after a single dose of levodopa/carbidopa extended-release formulation is approximately 42%.

In healthy elderly individuals, rates ranging from 71% to 78% were determined both after a single dose of the drug and after its multiple use.

Breeding.

Data is missing.

Indication

Idiopathic Parkinson's disease and Parkinson's syndrome. Postencephalitic parkinsonism. To reduce the "off period" in patients previously treated with immediate-release combinations of levodopa and carbidopa and who experience motor fluctuations due to the end-of-dose effect (the phenomenon of "drug exhaustion"), peak-dose dyskinesia, akinesia or similar signs of transient motor disorders. The drug is not intended for the treatment of drug-induced parkinsonism.

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the drug. Suspected undiagnosed skin lesions (dermatoses) or melanoma in history. Angle-closure glaucoma. Concomitant use of Levocom retard Asino and non-selective monoamine oxidase inhibitors (MAOIs). Treatment with MAO inhibitors should be discontinued at least two weeks before prescribing the drug. The drug can be used with selective MAO-B inhibitors (e.g. selegiline) in recommended doses.
It is not recommended for the treatment of drug-induced extrapyramidal disorders.

Interaction with other medicinal products and other types of interactions

Caution should be exercised when Levocom retard Asino is used concomitantly with antihypertensive agents, as symptomatic orthostatic hypotension may occur. Therefore, at the beginning of therapy with Levocom retard Asino, it may be necessary to adjust the dosage of the antihypertensive agent. In rare isolated cases, adverse reactions, including hypertension and dyskinesia, have been reported with the concomitant use of tricyclic antidepressants and carbidopa/levodopa (for concomitant use of MAO inhibitors, see section "Contraindications").

In studies, a decrease in the bioavailability of carbidopa and/or levodopa was observed when used with ferrous sulfate or ferrous gluconate.

Dopamine D2 receptor antagonists (e.g. phenothiazines, butyrophenones and risperidone) and isoniazid may reduce the therapeutic effect of levodopa. Phenytoin and papaverine have also been reported to block the antiparkinsonian effect of levodopa. Patients taking these medicinal products together with Levok retard Asino should be monitored for therapeutic effect.

The simultaneous use of Levocom retard Asino and substances that lead to a decrease in dopamine reserves (for example, reserpine and tetrabenazine), or other drugs that reduce monoamine reserves, is not recommended.

Concomitant oral administration of selegiline and carbidopa/levodopa may be associated with the occurrence of serious orthostatic hypotension, but this is not solely due to the use of carbidopa/levodopa.

Postprandial administration of Levocom retard Asino may slightly prolong the time to reach its maximum concentration in the blood plasma, as well as the decay time.

A high-protein diet may reduce the effect of levodopa.

Application features

Levocom retard Asino should be used with caution in patients with severe cardiovascular or respiratory diseases, bronchial asthma, or diseases of the kidneys, liver, or endocrine system.

Patients receiving levodopa monotherapy should discontinue levodopa at least 8 hours before starting Levocom retard Asino therapy (at least 12 hours before changing therapy if levodopa is used in a prolonged-release form).

Patients receiving levodopa monotherapy may experience dyskinesia. Carbidopa helps to increase the amount of levodopa in the brain, which results in more dopamine being produced. If dyskinesia occurs, a dose reduction should be considered. Like levodopa, Levodopa retard Asino may also cause involuntary movements and psychological disorders. These reactions are associated with increased dopamine levels in the brain after levodopa administration. A dose reduction may be indicated to correct these reactions. All patients should be closely monitored for changes in mental status, depression with suicidal thoughts, or other serious behavioral disorders. Patients with a history of or current history of psychosis should be treated with caution.

With the abrupt withdrawal of antiparkinsonian drugs, symptom complexes similar to neuroleptic malignant syndrome have been observed, with muscle rigidity, fever, mental changes and increased serum creatine phosphokinase levels. Therefore, careful monitoring of patients is required in the event of a sudden dose reduction or discontinuation of carbidopa/levodopa, especially in patients taking neuroleptics.

It is necessary to periodically perform blood tests and liver function tests, as well as assess heart and kidney function, especially during long-term therapy with the drug.

Concomitant use of psychoactive drugs with Levok retard Asino should be carried out with caution (see section "Interaction with other medicinal products and other types of interactions"). The drug should be used with caution in patients with a history of seizures.

In case of chronic open-angle glaucoma, the use of Levocom retard Asino is permitted subject to adequate control of intraocular pressure and careful monitoring for possible changes during drug therapy.
Levodopa is associated with the onset of somnolence and episodes of sudden sleep onset. Sudden onset of somnolence during normal daytime activities, sometimes without prodromal signs, has been reported very rarely. During treatment with levodopa, patients should exercise caution when driving or operating machinery. Patients who experience somnolence and/or episodes of sudden sleep onset should not drive or operate machinery.

As with levodopa monotherapy, gastrointestinal bleeding may occur in patients with a history of gastric or duodenal ulcers.

During anesthesia, Levocetirizine retard therapy may be continued as long as the patient can swallow liquids and oral medications.

After temporary discontinuation of drug therapy, the patient should resume taking the drug at the usual daily dose as soon as he is able to take oral forms of the drug again.

Epidemiological studies suggest that patients with Parkinson's disease have an approximately 2- to 6-fold increased risk of developing melanoma compared with the general population. It is currently unclear whether this increased risk is due to Parkinson's disease itself or to other factors, such as medications used to treat Parkinson's disease.
Considering the above factors, patients and prescribers should be aware of the need for frequent and regular screening for melanoma while using the drug.

Levocom retard Asino for any indications.

Periodic skin examinations should be performed by qualified specialists (dermatologists). The patient should be monitored for the development of impulsive disorders. Patients and caregivers should be aware that some patients treated with dopamine agonists and/or other dopaminergic drugs for Parkinson's disease have experienced symptoms of impulsive behavioral disorders (such as pathological gambling, hypersexuality, increased libido, shopping/spending, compulsive eating). If these symptoms occur, treatment with the drug should be reconsidered.

Ability to influence reaction speed when driving vehicles or other mechanisms

Individual responses to medication may vary. Certain adverse reactions observed with the use of levodopa/carbidopa may affect the ability to drive and use machines. Levocom retard Asino may cause drowsiness and episodes of sudden sleep onset. Therefore, patients with such symptoms should not drive or engage in activities that could put themselves or others at risk (e.g., operating machinery).

Use during pregnancy or breastfeeding

Animal studies have shown mixed results, depending on the species of laboratory animals. In animal studies using levodopa without carbidopa, developmental abnormalities of internal organs and the skeleton were observed. In other studies, no teratogenic effects were observed in animals.

The decision to discontinue Levocetirizine Retard Asino therapy in a pregnant woman should be made on a case-by-case basis, as the patient may be at serious risk due to the severity of the untreated illness.

If treatment with Levocetirizine retard is necessary during lactation, breastfeeding should be discontinued.

Method of administration and doses

Levocom retard Asino in the form of extended-release tablets should be taken with liquid; the tablet should not be divided, chewed, or crushed so as not to disrupt the extended-release effect.

The optimal daily dose of the drug should be selected for each patient individually by careful titration. During the dosage titration phase, the patient should be closely monitored for increased nausea and pathological involuntary movements, including dyskinesia, chorea and dystonia.

During treatment with Levok retard Asino, other antiparkinsonian agents, except levodopa, can be continued, although their dosage may need to be adjusted.

Initial dose.

Patients who have not previously received levodopa therapy.

Levocom retard Asino 100/25 was developed for use in patients with early-stage disease who have not previously received levodopa treatment, or for up-titration of patients who are prescribed Levocom retard Asino 200/50. The recommended starting dose is 1 prolonged-release tablet of Levocom retard Asino 100/25 twice daily. A dose of 1 to 4 prolonged-release tablets of Levocom retard Asino 100/25 twice daily is usually well tolerated in patients who require a higher dose of levodopa.

If necessary, levodopa therapy can also be started with Levocom retard Asino 200/50. The recommended initial dose is 1 prolonged-release tablet of Levocom retard Asino 200/50 two or three times a day. The initial dose of the drug should not exceed 600 mg of levodopa per day, and the interval between doses should be at least 6 hours.

Patients receiving treatment with other standard combination drugs containing levodopa and decarboxylase inhibitors.

The daily dose of Levocom retard Asino should contain approximately 10% more levodopa. Depending on the response to treatment, it may be necessary to increase the daily dose of levodopa by up to 30%.

The interval between doses of Levocom retard Asino should be from 4 to 8 hours during the time when the patient is awake, on any given day.

Application of the initial conversion dose of Levocom retard Asino 200/50:

Titration with an increase in dose by 100 mg, if necessary, can be carried out using the drug Levocom retard Asino 100/25.

Patients receiving levodopa as monotherapy.
Levodopa should be stopped at least 8 hours before starting Levocom retard Asino. In late-stage mild to moderate disease, the recommended starting dose of Levocom retard Asino is 1 prolonged-release tablet two or three times a day.

Titration.
Once treatment is initiated, the dose may be increased or decreased, and the interval between doses may be lengthened or shortened, depending on the response to therapy. For most patients, 2 to 8 extended-release tablets per day may be acceptable.

Treatment with higher doses of the drug (up to 12 extended-release tablets) with shorter intervals between doses may be used, but is generally not recommended.

If the interval between doses of the drug is less than 4 hours or different doses of the drug are used per dose, it is recommended to use a lower dose of the drug in the evening.

In some patients, the onset of action of the drug, the first dose of which was taken in the morning, may be observed with a delay of up to one hour compared to the non-extended-release formulation of levodopa/carbidopa.

It is recommended to adjust the dosage of the drug at intervals of at least 3 days.

Maintenance dose.
Since Parkinson's disease is characterized by a progressive course, it is recommended to conduct regular examinations and, if necessary, adjust the dosage of Levocom retard Asino.

If the patient's response to Levocom retard therapy is insufficient after dose titration, consideration should be given to switching to a non-extended-release formulation.

Levocom retard Asino can be used concomitantly with anticholinergics, dopamine agonists and amantadine. Dosage adjustment may be required when these drugs are used adjunctively with Levocom retard Asino.

For some patients with severe pathological symptoms who require more frequent use of levodopa, levodopa/carbidopa 100/25 in a non-extended-release form can be used in addition to Levocom retard Asino.

Discontinuation of drug therapy.

If the dose is suddenly reduced or treatment with Levocetirizine retard is discontinued, the patient should be closely monitored, especially if he is receiving neuroleptics (see section "Special warnings and precautions for use").

If general anesthesia is required, the use of Levocom retard Asino may continue as long as oral forms of the drug are permitted.

Children

The safety and efficacy of Levocom retard Asino have not been demonstrated in patients under the age of 18. Use in patients under the age of 18 is not recommended.

Overdose

Treatment of acute overdose of Levocom retard Asino is basically the same as for overdose of levodopa. However, if symptoms of overdose of Levocom retard Asino are present, the use of pyridoxine is ineffective.

In case of overdose, general supportive measures should be taken, including immediate gastric lavage if the drug was taken recently. Intravenous fluids should be administered with great caution, ensuring adequate oxygenation. The patient's electrocardiogram should be carefully monitored for possible arrhythmias. Appropriate antiarrhythmic agents should be used if necessary. It should be taken into account that the patient may have taken other medications. There is currently no experience with dialysis. Therefore, its value in the treatment of overdose is unknown.

Adverse reactions

Common adverse reactions in patients taking levodopa/carbidopa are related to the central effects of dopamine.

Typically, they can be reduced by reducing the dose of the drug.

The most common are dyskinesias, including choreiform, dystonic and other involuntary movement disorders, as well as nausea. Muscle cramps and blepharospasm may be early signs of relative overdose of the drug.

It is known that the use of the combination of levodopa/carbidopa in a prolonged-release form in patients with moderate to severe movement disorders did not lead to the occurrence of adverse reactions related to the dosage form of the drug. Dyskinesias were observed somewhat more often in patients receiving levodopa/carbidopa in a prolonged-release form compared with patients receiving the drug in a non-prolonged-release form, since the reduction of the "off period" with levodopa/carbidopa in a prolonged-release form is replaced by a longer "on period" (with a more frequent occurrence of dyskinesias).

The most common adverse reactions reported were dyskinesias (a form of abnormal involuntary movements).

Adverse reactions observed in 1% or more of patients in clinical trials

Other serious adverse effects include psychiatric disorders, including paranoid thoughts and psychotic episodes, depression with possible suicidal thoughts, and dementia.
Adverse effects observed in clinical trials or post-marketing use:

Infectious and parasitic diseases: urinary tract infections, upper respiratory tract infections.
Benign and malignant neoplasms (including cysts and polyps): malignant melanoma (see section "Contraindications").

From the blood and lymphatic system: agranulocytosis, leukopenia, hemolytic and non-hemolytic anemia, thrombocytopenia.

Metabolic and nutritional disorders: anorexia.

Psychiatric: increased excitability, anxiety, bruxism, confusion, dementia, depression with or without suicidal tendencies, disorientation, unusual dreams, euphoria, hallucinations, insomnia, psychotic episodes, including delusions and paranoid thoughts.
In the post-marketing setting, there have been reports of pathological gambling, increased libido, hypersexuality, shopping/spending urges and binge eating following the use of dopamine agonists and/or other dopaminergic drugs, including, in rare cases, in patients receiving levodopa, including Levocom retard Asino (see section "Special warnings and precautions for use").

Nervous system: activation of Horner's syndrome, ataxia, bradykinetic episodes ("on-off" phenomenon), chorea, convulsions, decreased reaction, dizziness, dyskinesia, dystonia, extrapyramidal and movement disorders, weakness, falls and gait disturbances, headache, hand tremor, numbness of the extremities, pathological movement/position of the eyes according to the acute dystonic type (oculogram crisis), paresthesia, agitation, drowsiness, including very rare cases of severe daytime drowsiness and episodes of sudden sleep onset, syncope, spasm of the masticatory muscles.

On the part of the organs of vision: blepharospasm, blurred vision, mydriasis, diplopia.

Cardiac disorders: cardiac arrhythmia, palpitations.

Vascular disorders: hyperemia, increased sweating, hypertension, orthostatic effects, including orthostatic hypotension, phlebitis.

From the respiratory system, chest organs and mediastinum: respiratory distress, shortness of breath, hoarseness of voice.

On the part of the digestive system: bitterness in the mouth, burning of the tongue, constipation, darkening of saliva, development of duodenal ulcers, diarrhea, dry mouth, dyspepsia, dysphagia, flatulence, gastrointestinal bleeding, abdominal pain of gastrointestinal etiology, hiccups, nausea, increased salivation, vomiting.

Skin and subcutaneous tissue disorders: hair loss, angioedema, darkening of sweat, Henoch-Schonlein purpura, increased sweating, itching, rash, urticaria.

Musculoskeletal and connective tissue disorders: muscle spasms, muscle twitching.

From the kidneys and urinary system: dark urine, urinary incontinence, urinary retention.

Reproductive system and breast disorders: priapism.

General disorders: asthenia, chest pain, edema, fatigue, malaise, neuroleptic malignant syndrome (see section "Special warnings and precautions for use"), weakness.

Research results: weight gain, weight loss.
Laboratory tests showed abnormalities in creatinine, uric acid, alkaline phosphatase, serum glutamate oxaloacetate transaminase (aspartate aminotransferase), serum glutamatepyruvate transaminase (alanine aminotransferase), lactate dehydrogenase, bilirubin, blood urea nitrogen, and Coombs' test.

There have been reports of decreased hemoglobin and hematocrit levels, increased serum glucose levels, and the presence of leukocytes, bacteria, and blood in the urine.

Carbidopa/levodopa preparations may cause false-positive results in urine ketone tests when using dipsticks to detect ketonuria. The result is not affected by boiling urine samples.

False-negative results can be obtained when determining glycosuria using the glucose oxidase method.

Expiration date

4 years.

Storage conditions

Does not require any special storage conditions. Store in original packaging.

Keep out of reach of children.

Packaging

10 tablets in a blister; 10 blisters in a cardboard pack.

Vacation category

According to the recipe.

Producer

Acino Pharma AG/Acino Pharma AG.

Location of the manufacturer and its business address

Birsweg 2, 4253 Liesberg, Switzerland.