Levocom retard asino

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOCOM RETARD ACINO (LEVOCOM RETARD ACINO)

Composition:

Active substances: levodopa, carbidopa (as carbidopa monohydrate);

One prolonged-release tablet of Levocom Retard Acino 100/25 contains: levodopa 100 mg, carbidopa monohydrate equivalent to carbidopa – 25 mg;

One prolonged-release tablet of Levocom Retard Acino 200/50 contains: levodopa 200 mg, carbidopa monohydrate equivalent to carbidopa – 50 mg;

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

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties:

Levocom Retard Acino 100/25: round, biconvex tablet of orange-brown color with rounded edges.

Levocom Retard Acino 200/50: round tablet of orange-brown color.

Pharmacotherapeutic group. Antiparkinson agents. L-DOPA and its derivatives.

ATC code N04B A02.

Pharmacological Properties

Pharmacodynamics

Levocom Retard Asino is a combination of carbidopa, a decarboxylase inhibitor, and levodopa, a metabolic precursor of dopamine.

Levodopa alleviates the symptoms of Parkinson's disease by being decarboxylated to dopamine in the brain, where dopamine levels are reduced in these patients (replacement therapy). Since at least 95% of orally administered levodopa is decarboxylated in peripheral tissues, only a small fraction reaches the brain.

Dopamine formed in peripheral tissues, and the adrenergic substances derived from it, cause numerous adverse effects on the gastrointestinal and cardiovascular systems when levodopa is used as monotherapy.

Concomitant administration of the decarboxylase inhibitor carbidopa substantially prevents the peripheral decarboxylation of levodopa. As a result, the dose of levodopa required to achieve a similar clinical effect can be reduced to 20% of that needed for monotherapy. This allows avoidance of adverse effects on the gastrointestinal and cardiovascular systems.

Pharmacokinetics

Extended-release levodopa/carbidopa 100 mg/25 mg

The pharmacokinetics of the extended-release combination of levodopa/carbidopa 100 mg/25 mg has been studied in patients with Parkinson's disease. Administration of extended-release levodopa/carbidopa 100 mg/25 mg twice daily at total daily doses of 50–150 mg carbidopa and 200–600 mg levodopa over 3 months (open, uncontrolled studies) did not result in accumulation of levodopa in plasma.

Extended-release levodopa/carbidopa 200 mg/50 mg

The pharmacokinetics of the extended-release combination of levodopa/carbidopa 200 mg/50 mg has been studied in healthy young (23–45 years) and elderly (55–76 years) volunteers.

Comparison of pharmacokinetic parameters showed that bioavailability and plasma concentrations were on average higher in elderly patients after administration of the extended-release levodopa/carbidopa 200 mg/50 mg combination.

The mean time to reach maximum concentration was approximately 2 hours for extended-release levodopa/carbidopa 200 mg/50 mg tablets, and 0.75 hours for extended-release levodopa/carbidopa 100 mg/25 mg tablets.

On average, peak plasma concentration levels of the extended-release levodopa/carbidopa 200 mg/50 mg combination were 60% lower (depending on dose) than those of the 100 mg/25 mg formulation, and the in vivo absorption period of extended-release levodopa/carbidopa 200 mg/50 mg lasted from 4 to 6 hours.

Plasma levodopa levels fluctuated less with administration of extended-release levodopa/carbidopa 200 mg/50 mg compared to levodopa/carbidopa 100 mg/25 mg.

Since the bioavailability of levodopa in extended-release 200 mg/50 mg tablets is only about 70% compared to levodopa/carbidopa 100 mg/25 mg tablets, the daily dose of levodopa in extended-release formulations is usually higher than in immediate-release dosage forms.

There was no evidence of excessively rapid or uncontrolled release of the active substance. It is unknown whether high-protein food affects absorption, and to what extent.

Dopamine formation is inhibited in the presence of carbidopa. The formation of 3-O-methyldopa becomes the primary metabolic pathway. During further metabolism of dopamine, secondary metabolites such as 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) are formed. The urinary excretion of levodopa, dopamine, DOPAC, and HVA over 24 hours accounted for 0.53%, 4.24%, 32%, and 25.9% of the administered dose, respectively. Levodopa is 6% bound to plasma proteins.

On average, 50% of an oral 50 mg dose of carbidopa is excreted in urine and 34% in feces, indicating incomplete absorption. The recovery rate of unchanged carbidopa after oral administration averaged 10.2% of the administered dose. Three major metabolites were identified in urine.

Clinical characteristics.

Indications.

As an adjunctive therapy in Parkinson's disease in patients who have developed motor fluctuations during treatment with immediate-release levodopa/decarboxylase inhibitors.

Levocom Retard Asino should be used in combination with other medicinal products for the treatment of Parkinson's disease as an alternative to immediate-release levodopa/decarboxylase inhibitor preparations (standard).

There is insufficient clinical experience with the use of Levocom Retard Asino in patients who have not previously received levodopa or other antiparkinsonian agents, either when switching from treatment with Levocom Retard Asino 100/25 mg tablets to Levocom Retard Asino 200/50 mg tablets, or during long-term treatment.

Note

Levocom Retard Asino is not intended for the treatment of extrapyramidal and other movement disorders caused by medicinal products.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the drug. Suspicious undiagnosed skin lesions (dermatoses) or history of melanoma, since levodopa may activate malignant melanoma. Closed-angle glaucoma. Concomitant use of Levocom Retard Asino and non-selective monoamine oxidase inhibitors (MAO). Treatment with MAO inhibitors should be discontinued at least two weeks before starting the drug. The drug may be used with selective MAO-B inhibitors (e.g., selegiline) at recommended doses.

Interaction with other medicinal products and other forms of interaction.

Levocom Retard Asino should be used with caution when administered concomitantly with the following medicinal products:

Antihypertensive agents

Symptomatic orthostatic hypotension has been observed in patients receiving levodopa/decarboxylase inhibitor preparations together with antihypertensive agents (particularly those containing reserpine). Therefore, dosage adjustment of the antihypertensive agent may be required at the beginning of therapy with Levocom Retard Asino.

Antidepressants

Rare isolated cases of adverse reactions, including arterial hypertension and dyskinesia, have been reported with concomitant use of tricyclic antidepressants and carbidopa/levodopa combination (for concomitant use of MAO inhibitors, see section "Contraindications").

Concomitant oral administration of selegiline and carbidopa/levodopa may be associated with the development of severe orthostatic hypotension, although this is not solely attributable to carbidopa/levodopa administration.

Anticholinergic agents

Anticholinergic agents may impair absorption of the medicinal product in patients, thus reducing the efficacy of Levocom Retard Asino.

Concomitant use with other medicinal products during treatment of Parkinson's disease

Anticholinergic agents, dopamine agonists, and amantadine may be taken together with Levocom Retard Asino. Dose adjustment of Levocom Retard Asino tablets may be necessary when these medicinal products are administered concomitantly. Interactions with other antiparkinsonian agents have not been studied. For interaction with anticholinergic agents, see above.

Other medicinal products

Neuroleptic medicinal products such as phenothiazines, butyrophenones, risperidone, and isoniazid may reduce the therapeutic effect of levodopa. Reduced efficacy of levodopa has been reported during treatment of Parkinson's disease when administered concomitantly with phenytoin, papaverine, and opioids. Patients should be carefully monitored for lack of therapeutic effect. Concomitant use of Levocom Retard Asino with sympathomimetics may potentiate their effects, thus requiring dose reduction.

Concomitant use of Levocom Retard Asino and medicinal products that deplete dopamine stores (e.g., reserpine and tetrabenazine), or other medicinal products that reduce monoamine stores, is not recommended.

Since levodopa competes with certain amino acids, levodopa absorption may be impaired in some patients on a high-protein diet. Since carbidopa prevents the interference of pyridoxine with the action of levodopa, Levocom Retard Asino may be prescribed to patients taking pyridoxine (vitamin B6).

The effect of concomitant administration of antacids and prolonged-release levodopa/carbidopa combination on levodopa bioavailability has not been studied.

Concomitant intake of medicinal products containing ferrous sulfate or ferrous gluconate may lead to reduced bioavailability of Levocom Retard Asino.

Laboratory tests

Changes in various laboratory diagnostic parameters may occur:

• measurement of catecholamines, creatinine, uric acid, glucose, alkaline phosphatase, AST, ALT, LDH, bilirubin, and blood urea nitrogen;
• decreased hemoglobin and hematocrit, increased serum glucose and leukocyte levels, presence of bacteria and blood in urine;
• false-positive ketone test results when using test strips (this reaction is not altered by boiling urine samples);
• false-negative results may occur when using the glucose oxidase method for detecting glucosuria;
• false-positive Coombs test (hemolytic anemia has been diagnosed very rarely).

Note

Prior to anesthesia with halothane, cyclopropane, and other agents that increase cardiac sensitivity to sympathomimetic amines, the drug should be discontinued at least 8 hours before anesthesia, unless opioids are administered concomitantly.

If treatment has been temporarily discontinued, it may be resumed by prescribing the usual dosage as soon as the patient is able to take the drug.

Special precautions for use.

Levocom Retard Asino should not be administered to patients with severe cardiovascular or respiratory disorders, bronchial asthma, or kidney, liver, or endocrine organ diseases (e.g., hyperthyroidism, pheochromocytoma), as well as in cases of peptic ulcer or history of seizures, tachycardia, severe hematological disorders, or in the presence of contraindications to sympathomimetics, endogenous or exogenous psychoses.

Note

Like levodopa, Levocom Retard Asino should be used with caution in patients who have had myocardial infarction or who have supraventricular, nodal, or ventricular arrhythmias. During initial dose titration in such patients, cardiac monitoring with particularly careful observation is required.

Excretion of the active components of Levocom Retard Asino tablets in urine, saliva, and sweat may cause stains on clothing that cannot be removed after drying; therefore, stains should be washed off immediately when fresh.

Warning

After many years of treatment with levodopa-containing medications, sudden discontinuation or rapid dose reduction of Levocom Retard Asino may lead to withdrawal syndrome (malignant neuroleptic syndrome with muscle rigidity, elevated body temperature, mental status changes, and increased serum creatine phosphokinase levels) or akinetic crisis. Both conditions are life-threatening. Therefore, treatment interruptions with levodopa, if clinically indicated, should only be carried out in a hospital setting, especially if the patient is receiving neuroleptics.

Dopamine dysregulation syndrome (DDS) has been observed in some patients treated with carbidopa/levodopa. This is an addiction disorder leading to excessive drug consumption. Patients and caregivers should be informed about the potential risk of developing DDS before initiating treatment (see also section "Adverse reactions").

Impulse control disorders

Patients should be monitored for the development of impulse control disorders. Patients and caregivers should be aware that in some patients receiving dopamine agonists and/or other dopaminergic drugs for Parkinson’s disease, symptoms of impulsive behavioral disorders (such as pathological gambling, increased libido, hypersexuality, compulsive shopping/spending, compulsive overeating) have been observed. If such symptoms occur, the treatment regimen should be reevaluated.

Treatment monitoring

During dose adjustment, periodic blood tests and assessments of liver and kidney function should be performed (at least once a year).

In patients with a history of myocardial infarction, cardiac arrhythmias, or coronary circulation disorders, regular monitoring of circulation and ECG is recommended, especially at the beginning of treatment. Special medical supervision is also required for patients with a history of seizures or peptic ulcer disease of the stomach or duodenum.

In cases of chronic open-angle glaucoma, Levocom Retard Asino may be used provided intraocular pressure is adequately controlled and careful monitoring for possible changes during treatment is performed.

All patients should be closely observed for psychiatric changes and signs of depression, with or without suicidal thoughts. The drug should be used with caution in patients with a current or past history of psychosis.

Malignant melanoma

Epidemiological data suggest that patients with Parkinson’s disease have a 2–6 times higher risk of developing melanoma compared to the general population. It is not yet known whether this increased risk is due to Parkinson’s disease itself or to other factors, such as medications used in the treatment of Parkinson’s disease.

Given the above factors, patients and caregivers should be informed about the necessity of frequent and regular melanoma screening. Periodic skin examinations should be performed by qualified specialists (dermatologists).

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

There is insufficient data on the use of the levodopa/carbidopa combination during pregnancy. In preclinical studies, the drug caused pathological changes in internal organs and the skeleton in rabbits.

Levocom Retard Asino tablets should not be used during pregnancy. However, in each individual case, it should be determined whether discontinuation of Levocom Retard Asino in a pregnant woman may be justified, as the severity of untreated disease may pose a serious risk to the patient.

Breastfeeding period

It is unknown whether carbidopa is excreted in breast milk. It is known that in studies involving women with Parkinson’s disease, levodopa was excreted in breast milk.

Levodopa/carbidopa suppresses prolactin release and thus lactation. Women should avoid breastfeeding during treatment with the levodopa/carbidopa combination.

Ability to influence reaction speed when driving or operating machinery

Since Levocom Retard Asino may cause fatigue even when used as directed, and in very rare cases excessive daytime sleepiness and sudden sleep attacks (possibly even without prior warning signs), patients should be advised to exercise particular caution when driving or operating machinery. Patients who experience excessive daytime sleepiness or sudden sleep attacks should not drive or operate machinery that could expose themselves or others to the risk of serious injury. In such cases, dose reduction or discontinuation of therapy should also be considered.

Method of Administration and Dosage

Levocom Retard Asino contains carbidopa and levodopa in a 1:4 ratio.

The daily dose of the drug should be individually adjusted for each patient through careful stepwise titration. An increase in the daily dose of levodopa by up to 30% may be required. During the titration phase, patients must be closely monitored for worsening nausea and pathological involuntary movements, including dyskinesia, chorea, and dystonia. In cases of more severe gastrointestinal complaints, particularly if they occur at the beginning of treatment, antiemetic agents such as domperidone (medications not containing metoclopramide) may occasionally be used.

The dosage level and intervals must be individually determined by a physician following thorough evaluation.

Initial Dose

Patients previously treated with other standard combination preparations containing levodopa and decarboxylase inhibitors

The daily dose of Levocom Retard Asino should contain approximately 10% more levodopa. Depending on the response to treatment, an increase in the daily levodopa dose of up to 30% may be required.

The interval between doses should be from 4 to 12 hours.

Titration

After initiation of treatment, the dose of the drug may be increased or decreased, and the interval between doses may be extended or shortened, depending on the response to therapy. For most patients, administration of 2 to 8 tablets of Levocom Retard Asino with prolonged release per day, divided into individual doses and taken at intervals of 4 to 12 hours throughout the day, may be acceptable.

If different doses are required, it is recommended to use the lower dose in the evening.

Dosage adjustments should be made at intervals of at least 3 days.

Maintenance Dose

Levocom Retard Asino tablets are usually taken over a prolonged period (replacement therapy). Duration of treatment is not limited, provided it is well tolerated.

Combination with other medicinal products for the treatment of Parkinson's disease

Experience with concomitant use of anticholinergics, dopamine agonists, and amantadine is limited. If such combination therapy is used, dosage reduction of either the concomitant agents or Levocom Retard Asino may be necessary.

Discontinuation of treatment with the drug

Careful monitoring of the patient is required when the dose is abruptly reduced or treatment with Levocom Retard Asino is discontinued, especially if the patient is taking antipsychotic medications.

Levocom Retard Asino tablets with prolonged release must not be chewed or crushed; they should be taken whole only.

Method and Duration of Administration

The duration of treatment is determined by the physician. Clinical experience with long-term therapy is limited. It is preferable to take the tablets 30 minutes before or 90 minutes after a meal, with a small amount of liquid and biscuits. High-protein meals should be avoided before administration.

Children

The safety and efficacy of Levocom Retard Asino have not been established in patients under 18 years of age. Use in patients under 18 years of age is not recommended.

Overdose.

Symptoms of overdose

Symptoms of overdose correspond to those described in the section "Adverse Reactions."

Treatment measures in case of overdose

Therapeutic measures in acute overdose with Levocom Retard Asino are primarily the same as those for levodopa overdose. However, in cases of overdose with Levocom Retard Asino, administration of pyridoxine is ineffective.

In case of overdose, gastric lavage should be performed immediately, along with clinical monitoring and general supportive measures, with special attention to cardiovascular function. Cardiac arrhythmias may be prevented by using beta-adrenergic blockers. There is no specific antidote. Experience with dialysis is lacking.

Adverse reactions.

It is known that the use of the prolonged-release formulation of levodopa/carbidopa in patients with moderate or severe motor disorders did not lead to adverse reactions related to the pharmaceutical form of the drug.

The most commonly observed adverse reaction was dyskinesia (abnormal, involuntary movements).

Dyskinesia occurred somewhat more frequently in patients treated with the prolonged-release formulation of levodopa/carbidopa compared to those treated with the immediate-release formulation, because the reduced "off" time with the prolonged-release formulation of levodopa/carbidopa results in a longer "on" time (with more frequent occurrence of dyskinesia).

Other common adverse reactions (> 1%) included: nausea, hallucinations, confusion, dizziness, chorea, dry mouth, night terrors, dystonia, somnolence (including very rarely excessive daytime sleepiness and sudden sleep attacks), insomnia, depression, asthenia, vomiting, loss of appetite.

The following adverse reactions were also observed in clinical studies and during the post-marketing period.

Adverse reactions reported during the use of the medicinal product are listed below by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Metabolism and nutrition disorders: uncommon – weight loss.

Psychiatric disorders: uncommon – agitation, anxiety, disorientation; rare – psychiatric disorders, including paranoid ideation and psychotic episodes, depression with possible suicidal ideation; frequency not known – dopamine dysregulation syndrome (DDS).

DDS is a dependency disorder observed in some patients receiving treatment with carbidopa/levodopa. Patients exhibiting signs of DDS may demonstrate compulsive dopamine use, taking doses higher than required for adequate control of motor symptoms in Parkinson’s disease. In some cases, this may lead to severe dyskinesia (see section "Special warnings and precautions for use").

Impulse control disorders

Patients treated with dopamine agonists and/or other dopaminergic therapies containing levodopa, including prolonged-release levodopa/carbidopa combination, may develop pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating (see section "Special warnings and precautions for use").

Nervous system disorders: common – "on-off" phenomenon (fluctuations between mobility and immobility), headache, paraesthesia (e.g., tingling and numbness of limbs); uncommon – decreased mental acuity, extrapyramidal and other movement disorders, loss of consciousness; rare – neuroleptic malignant syndrome.

Eye disorders: rare – blurred vision.

Cardiac disorders: uncommon – palpitations.

Vascular disorders: common – orthostatic hypotension (orthostatic effects upon change in position); rare – flushing.

Respiratory, thoracic and mediastinal disorders: common – dyspnoea.

Gastrointestinal disorders: common – constipation, diarrhoea, dyspepsia; uncommon – abdominal pain; rare – dark saliva.

Skin and subcutaneous tissue disorders: uncommon – urticaria; rare – angioneurotic oedema, pruritus, alopecia, exanthema, darkening of sweat.

Musculoskeletal and connective tissue disorders: common – muscle cramps.

Renal and urinary disorders: rare – darkening of urine.

General disorders and administration site conditions: common – chest pain; uncommon – gait disturbance; rare – depression.

Injury, poisoning and procedural complications: uncommon – tendency to fall.

Infections and infestations: very common – urinary tract infections.

Other adverse reactions reported during the use of levodopa/carbidopa:

Benign and malignant neoplasms (including cysts and polyps): malignant melanoma (see section "Contraindications").

Blood and lymphatic system disorders: agranulocytosis, leukopenia, hemolytic and non-hemolytic anemia, thrombocytopenia.

Metabolism and nutrition disorders: weight gain.

Psychiatric disorders: bruxism, dementia, euphoria.

Nervous system disorders: activation of Horner’s syndrome, ataxia, bitter taste in mouth, convulsions, syncope, worsening of hand tremor, numbness of limbs, agitation.

Eye disorders: blepharospasm, oculogyric crisis, mydriasis, diplopia.

Cardiac disorders: cardiac arrhythmia.

Vascular disorders: hyperemia, arterial hypotension, phlebitis.

Respiratory, thoracic and mediastinal disorders: respiratory disorders, hoarseness.

Gastrointestinal disorders: burning sensation of the tongue, development of duodenal ulcer, dysphagia, flatulence, gastrointestinal hemorrhage, hiccup, increased salivation.

Skin and subcutaneous tissue disorders: Schönlein-Henoch purpura, increased sweating.

Musculoskeletal and connective tissue disorders: muscle twitching, trismus.

Renal and urinary disorders: urinary incontinence, urinary retention.

Reproductive system and breast disorders: priapism.

General disorders and administration site conditions: oedema, increased fatigue, weakness.

Investigations: see section "Interaction with other medicinal products and other forms of interaction".

Shelf life.

4 years.

Storage conditions.

No special storage conditions required. Store in the original packaging.

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 3 or 10 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Asino Pharma AG / Acino Pharma AG.

Manufacturer's address and place of business.

Birsweg 2, 4253 Liesberg, Switzerland / Birsweg 2, 4253 Liesberg, Switzerland.

Date of last revision.

In case of adverse effects or questions regarding the safety of the medicinal product, please contact the pharmacovigilance department of LLC "Asino Ukraine" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, tel/fax: +38 044 281 2333.