Levodopa/Carbidopa/Entacapone-Teva (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Teva Pharmaceutical Works, Private Limited Company (Hungary)

ATC Code

N04BA03 (Levodopa, decarboxylase inhibitor and catechol-O-methyltransferase inhibitor)

Active Substances

Levodopa (Rec.INN registered by WHO)

Carbidopa (Rec.INN registered by WHO)

Entacapone (Rec.INN registered by WHO)

Dosage Forms

	Levodopa/Carbidopa/Entacapone-Teva	Film-coated tablets 50 mg+12.5 mg+200 mg: 30 or 100 pcs.
		Film-coated tablets 100 mg+25 mg+200 mg: 30 or 100 pcs.
		Film-coated tablets 150 mg+37.5 mg+200 mg: 30 or 100 pcs.
		Film-coated tablets 200 mg+50 mg+200 mg: 30 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light brown in color with marking “50” on one side and smooth on the other side, round, biconvex.

Excipients: microcrystalline cellulose, anhydrous lactose (<5 g), low-substituted hydroxypropyl cellulose, povidone (K-30), colloidal silicon dioxide, magnesium stearate.

Coating composition Opadry 13M265001 – titanium dioxide (E171), hypromellose, glycerol, yellow iron oxide (E172), polysorbate 80, red iron oxide (E172), black iron oxide (E172), magnesium stearate.

30 pcs. – bottles (1) – cardboard packs.
100 pcs. – bottles (1) – cardboard packs.

Film-coated tablets pale red in color with marking “100” on one side and smooth on the other side, oblong, biconvex.

Excipients: microcrystalline cellulose, anhydrous lactose (<5 g), low-substituted hydroxypropyl cellulose, povidone (K-30), colloidal silicon dioxide, magnesium stearate.

Coating composition Opadry 13M250006 – titanium dioxide (E171), hypromellose, glycerol, polysorbate 80, allura red AC aluminum lake (E129), carmine (E120), magnesium stearate.

30 pcs. – bottles (1) – cardboard packs.
100 pcs. – bottles (1) – cardboard packs.

Film-coated tablets dark red in color with marking “150” on one side and smooth on the other side, oval, biconvex.

Excipients: microcrystalline cellulose, anhydrous lactose (<5 g), low-substituted hydroxypropyl cellulose, povidone (K-30), colloidal silicon dioxide, magnesium stearate.

Coating composition Opadry 13M265000 – titanium dioxide (E171), hypromellose, glycerol, polysorbate 80, red iron oxide (E172), azorubine aluminum lake (E122), magnesium stearate.

30 pcs. – bottles (1) – cardboard packs.
100 pcs. – bottles (1) – cardboard packs.

Film-coated tablets brown in color with marking “200” on one side and smooth on the other side, oblong, biconvex.

Excipients: microcrystalline cellulose, anhydrous lactose (<5 g), low-substituted hydroxypropyl cellulose, povidone (K-30), colloidal silicon dioxide, magnesium stearate.

Coating composition Opadry 13M265002 – titanium dioxide (E171), hypromellose, glycerol, yellow iron oxide (E172), polysorbate 80, red iron oxide (E172), black iron oxide (E172), magnesium stearate.

30 pcs. – bottles (1) – cardboard packs.
100 pcs. – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiparkinsonian drug (dopamine precursor + peripheral dopa decarboxylase inhibitor + COMT inhibitor)

Pharmacotherapeutic Group

Antiparkinsonian agent (dopamine precursor+peripheral decarboxylase inhibitor+COMT inhibitor)

Pharmacological Action

Combined antiparkinsonian agent. It is a combination of levodopa – a metabolic precursor of dopamine, carbidopa – an inhibitor of aromatic amino acid decarboxylase, and entacapone – a COMT inhibitor.

Levodopa increases dopamine content in the brain. Dopamine is formed directly from levodopa with the participation of aromatic amino acid decarboxylase. The antiparkinsonian effect of levodopa is due to its conversion to dopamine directly in the CNS. Levodopa is rapidly decarboxylated in peripheral tissues, turning into dopamine, which, however, does not cross the BBB.

Carbidopa inhibits the process of decarboxylation of levodopa and the formation of dopamine in peripheral tissues, which indirectly leads to an increase in the amount of levodopa entering the CNS.

As a result of inhibition of dopa decarboxylase, Levodopa is biotransformed with the participation of COMT into a potentially dangerous metabolite 3-O-methyldopa (3-OMD).

Entacapone is a reversible, specific inhibitor of COMT, mainly of peripheral action. Entacapone slows the clearance of levodopa from the bloodstream, which leads to increased bioavailability of levodopa, prolonging its therapeutic effect.

Pharmacokinetics

Levodopa is rapidly but incompletely (20-30% of the administered dose) absorbed from the gastrointestinal tract. Ingestion of food rich in large amounts of neutral amino acids may delay and reduce absorption. C_max after oral administration is reached in 2-3 hours. Individual bioavailability is 15-33%. Slightly binds to plasma proteins (10-30%). V_d – 1.6 L/kg. Actively metabolized in all tissues by dopa decarboxylase and COMT to dopamine, norepinephrine, epinephrine and 3-O-methyldopa. 75% of the administered dose is excreted in the urine as metabolites within 8 hours. Excreted unchanged in urine (35% over 7 hours) and in feces. Total clearance of levodopa is 0.55-1.38 L/kg/h. T_1/2 is 0.6-1.3 hours. The bioavailability of levodopa is significantly higher in women.

Carbidopa is absorbed and taken up somewhat more slowly compared to levodopa. Data on pharmacokinetics are limited. Binds to plasma proteins by approximately 36%. Individual bioavailability is 40-70%. Among the metabolites excreted in the urine, the main ones are: alpha-methyl-3-methoxy-4-hydroxyphenylpropionic acid and alpha-methyl-3,4-dihydroxyphenylpropionic acid. T_1/2 is 2-3 hours. It is biotransformed in the liver into two main metabolites, which are excreted in the urine as glucuronides and unconjugated structures. Unchanged Carbidopa is 30% excreted in the urine. Among the metabolites excreted in the urine, the main ones are alpha-methyl-3-methoxy-4-hydroxyphenylpropionic acid and alpha-methyl-3,4-dihydroxyphenylpropionic acid. T_1/2 is 0.6-1.3 hours.

Entacapone is rapidly absorbed from the gastrointestinal tract. C_max after a single oral dose is reached in 1 hour. Individual bioavailability is 35% (after a single oral dose of 200 mg). Binds to plasma proteins by 98%, mainly to albumin; at therapeutic concentrations, it does not displace other drugs with a high degree of complex formation (including warfarin, salicylic acid, phenylbutazone, diazepam) from protein binding. V_d – 0.27 L/kg. Almost completely metabolized. Undergoes a “first-pass” effect through the liver, a small amount of entacapone, which is an (E)-isomer, is converted into a (Z)-isomer (accounts for approximately 5% of the total amount of entacapone in plasma). The main pathway of metabolism of entacapone and its active metabolite is conjugation with glucuronic acid. Excreted in urine by 10-20% and in feces and bile – by 80-90%. Total clearance is about 0.7 L/kg/h. T_1/2 is 0.4-0.7 hours. Due to the short T_1/2, no true accumulation of levodopa or entacapone occurs upon repeated administration. The metabolism of entacapone is slowed in patients with mild to moderate hepatic impairment (Child-Pugh classes A and B), leading to an increase in plasma concentrations of entacapone in both the absorption and elimination phases.

Indications

Parkinson’s disease and parkinsonian syndrome (except drug-induced) in cases where the use of a combination of Levodopa and Carbidopa is ineffective.

ICD codes

Dosage Regimen

Determine the dosage individually based on clinical response and tolerability.

Select the tablet strength that provides the appropriate levodopa dose.

Administer each dose with or without food; however, a high-protein diet can interfere with absorption.

Take tablets one at a time; do not split or crush them.

The usual frequency of administration is three to four times per day.

The maximum recommended daily dose of entacapone is 1600 mg (eight tablets of any strength).

For patients not currently taking levodopa, initiate treatment with one tablet of Levodopa/Carbidopa/Entacapone-Teva 100 mg/25 mg/200 mg three times daily.

For patients switching from standard levodopa/carbidopa, the initial dose of this combination should provide an equivalent amount of levodopa.

When converting from levodopa/carbidopa plus entacapone, substitute the new combination tablet for the corresponding doses of the individual components.

A reduction of the total daily levodopa dose by 10-30% may be necessary to manage dopaminergic adverse reactions, such as dyskinesia.

Adjust subsequent doses slowly, at intervals not shorter than every second or third day.

Monitor for orthostatic hypotension, especially during the initial titration phase.

Observe patients for the emergence of excessive daytime sleepiness and sudden onset of sleep.

Discontinuation of treatment should be gradual to avoid the potential for neuroleptic malignant syndrome and a marked increase in parkinsonian symptoms.

Adverse Reactions

From the hematopoietic system common – anemia; uncommon – thrombocytopenia.

Mental disorders common – depression, hallucinations, confusion*, nightmares*, insomnia; uncommon – psychosis, agitation*; no data – suicidal behavior.

From the nervous system very common – dyskinesia*; common – exacerbation of parkinsonian symptoms (e.g., bradykinesia*), tremor, “on-off” phenomenon, dystonia, cognitive impairment (amnesia, dementia), drowsiness, dizziness*, headache; no data – NMS*.

From the organ of vision common – blurred vision.

From the cardiovascular system common – manifestations of coronary artery disease, except myocardial infarction (Heberden’s disease**), cardiac arrhythmia, orthostatic hypotension, hypertension; uncommon – myocardial infarction**.

From the respiratory system common – dyspnea.

From the gastrointestinal tract very common – diarrhea*, nausea: common – decreased appetite, constipation, vomiting, dyspepsia, abdominal discomfort and pain, dry mouth; uncommon – colitis, dysphagia, gastrointestinal bleeding.

From the liver and biliary tract uncommon – deviations in liver function test parameters, no data – hepatitis (common – cholestatic*).

From the skin and subcutaneous tissues common – rash, hyperhidrosis; uncommon – staining of skin, nails, hair, sweat; rare – angioedema; no data – urticaria.

From the musculoskeletal system very common – pain in muscles, bones and joints; common – muscle spasms, joint pain; no data – rhabdomyolysis.

From the urinary system very common – chromaturia; common – urinary tract infections; uncommon – urinary retention.

Other common – chest pain, peripheral edema, gait disturbance, possibly accompanied by falls, asthenia, fatigue, weight loss; uncommon – malaise.

Some of the adverse reactions are associated with increased dopaminergic activity (dyskinesia, nausea, vomiting) and are usually observed at the beginning of treatment. Reducing the dose of levodopa reduces the severity and frequency of these dopaminergic reactions. Some adverse reactions (including diarrhea and reddish-brown discoloration of urine) occur directly due to the properties of entacapone; in some cases, Entacapone may also cause staining of skin, nails, hair and sweat. Seizures have sometimes been observed during treatment with carbidopa/levodopa. However, a causal relationship between seizures and the use of these substances has not been established.

Impulse control disorders such as pathological gambling, increased libido, hypersexuality, compulsive spending, binge eating and compulsive eating may occur during treatment with dopamine agonists and/or other dopaminergic drugs, including this combination drug.

There are isolated cases where Entacapone in combination with levodopa caused excessive daytime sleepiness and episodes of sudden falling asleep.

Contraindications

Severe hepatic impairment; angle-closure glaucoma; pheochromocytoma; concomitant use with non-selective MAO inhibitors of types A and B (e.g., phenelzine, tranylcypromine); concomitant use with selective MAO inhibitors of types A and B; NMS and/or atraumatic acute rhabdomyolysis (including history); children and adolescents under 18 years of age; pregnancy; lactation period (breastfeeding); hypersensitivity to this combination.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated for use in severe hepatic impairment.

Should be used with caution in liver diseases.

Use in Renal Impairment

The drug should be used with caution in kidney diseases.

Pediatric Use

Contraindication: children and adolescents under 18 years of age.

Geriatric Use

Pharmacokinetic parameters are the same in younger (45-64 years) and older (65-75 years) patients.

Special Precautions

This combination should be used with caution in severe cardiovascular and pulmonary insufficiency, bronchial asthma, liver diseases, kidney diseases; diabetes mellitus and other decompensated endocrine diseases, erosive and ulcerative lesions of the gastrointestinal tract; history of seizures, history of myocardial infarction (with persistent cardiac arrhythmias), history of psychosis and/or during treatment, depression with suicidal tendencies, antisocial behavior; open-angle glaucoma. Caution should be exercised when using this combination concomitantly with drugs that can cause orthostatic hypotension; with neuroleptics that block dopamine (especially dopamine D₂ receptor antagonists); with tricyclic antidepressants, desipramine, maprotiline, venlafaxine; with warfarin and drugs metabolized by COMT (paroxetine).

Not recommended for the treatment of drug-induced extrapyramidal reactions.

In patients who have had a myocardial infarction and have lesions of the sinoatrial node or ventricular arrhythmias, cardiac function should be monitored, especially during the initial dose titration period.

All patients taking this combination should be carefully checked for mental changes, depression with suicidal tendencies and other significant antisocial reactions.

Should be prescribed with caution to patients with psychoses (including history).

When used concomitantly with neuroleptics (dopamine receptor blockers, especially D₂ receptor antagonists), careful monitoring of the patient is necessary for a decrease in the antiparkinsonian effect of the drug or worsening of Parkinson’s disease symptoms.

During treatment, careful monitoring of the patient’s intraocular pressure and recording of all pressure changes is necessary.

Taking this combination may cause orthostatic hypotension. Should be prescribed with caution to patients taking other medications that may also cause orthostatic hypotension.

In combination with levodopa, Entacapone may cause drowsiness and episodic sudden sleep attacks in patients with Parkinson’s disease.

Clinical studies have confirmed a higher incidence of dopaminergic adverse reactions (e.g., dyskinesia) in patients receiving treatment with entacapone and dopamine agonists (bromocriptine), selegiline and amantadine, compared with patients receiving placebo with this combination of drugs. Dose adjustment of other antiparkinsonian drugs taken may be required when prescribing this combination to patients not previously treated with Entacapone.

Rarely, rhabdomyolysis is observed in patients with Parkinson’s disease against the background of dyskinesias or NMS. A sharp reduction in dose or sudden withdrawal of levodopa should be controlled, especially in patients receiving treatment with neuroleptics. NMS, rhabdomyolysis and hyperthermia are characterized by motor symptoms (muscle rigidity, myoclonus, tremor), mental state changes (agitation, confusion, coma), increased body temperature, autonomic dysfunctions (tachycardia, blood pressure fluctuations), as well as increased serum CPK levels. In some cases, only isolated symptoms and signs from the above are observed. Early detection of symptoms is extremely important for the effective treatment of NMS. There are reports of a syndrome similar to NMS, characterized by muscle rigidity, elevated body temperature, mental state changes and increased serum CPK levels, also associated with the sudden withdrawal of antiparkinsonian drugs. There are isolated reports of the development of NMS against the background of entacapone use, especially with sudden withdrawal or reduction of the dose of entacapone and concomitant dopaminergic drugs. From studies in which Entacapone was abruptly discontinued, no cases of NMS or rhabdomyolysis associated with withdrawal were identified. If it is necessary to transfer a patient from therapy with this combination to levodopa and dopa decarboxylase inhibitors, the transition should occur gradually; an increase in the dose of levodopa will probably be required.

If anesthesia is necessary, this combination can be taken as long as the patient is allowed to take fluids and oral medications.

During long-term treatment, it is recommended to periodically monitor hepatic and hematological parameters, renal function, and the cardiovascular system.

It is recommended to monitor the patient’s body weight in case of diarrhea to prevent excessive weight loss.

Persistent prolonged diarrhea that occurs while taking entacapone may be a sign of colitis. In case of persistent prolonged diarrhea, the drug should be discontinued, appropriate treatment prescribed and the cause of the diarrhea determined.

Patients require careful monitoring for the development of impulse control disorders. Patients and individuals involved in their care should be informed about the potential emergence of behavioral symptoms of impulse control disorders, such as pathological gambling, increased libido, hypersexuality, compulsive spending, binge eating, or compulsive eating. These symptoms may occur during treatment with dopamine agonists and/or other dopaminergic drugs, including this combination. If such symptoms appear, a review of the treatment regimen is recommended.

Patients with progressive anorexia, asthenia, and weight loss, especially over a relatively short period, require a general medical examination and assessment of liver function.

Levodopa and Carbidopa may cause a false-positive reaction with urine test strips for ketones. Boiling the urine does not alter this reaction. The glucose oxidase method may yield a false-negative result for glycosuria.

Influence on the Ability to Drive and Operate Machinery

The use of this combination affects the ability to drive a car and operate machinery. The combination of Levodopa, Carbidopa, and Entacapone can cause dizziness and symptomatic orthostatic hypotension. Patients taking the drug should exercise caution when driving a car or operating machinery.

Patients taking this combination who experience drowsiness and/or episodic sudden sleep onset should be informed to refrain (until the symptoms resolve) from driving a car or engaging in work requiring increased attention, as they may pose a risk of serious injury or even death to themselves and others (for example, when operating machinery).

Drug Interactions

According to studies on the effects of multiple doses in Parkinson’s disease patients receiving treatment with levodopa/dopa-decarboxylase inhibitors, Entacapone and selegiline do not interact with each other. When used concomitantly with this combination, the dose of selegiline should not exceed 10 mg.

When levodopa is prescribed to patients taking antihypertensive agents, symptomatic orthostatic hypotension may occur. In such cases, dose adjustment of the antihypertensive agent is necessary.

Rarely, adverse reactions such as hypertension and dyskinesia may occur with the concomitant use of levodopa/carbidopa and tricyclic antidepressants.

Use with caution concomitantly with MAO-A inhibitors, tricyclic antidepressants, norepinephrine reuptake inhibitors (desipramine, maprotiline, venlafaxine), as well as agents metabolized by COMT (catechol structural compounds, paroxetine).

Dopamine receptor antagonists (including some antipsychotics and antiemetics), phenytoin, and papaverine may reduce the therapeutic effect of levodopa.

Due to the affinity of entacapone for the CYP2C9 isoenzyme in vitro, this combination has the potential to interact with active substances whose metabolism depends on this isoenzyme, for example, S-warfarin.

It is recommended to monitor the INR in patients who start receiving this combination while on warfarin therapy.

Since Levodopa competes with certain amino acids, the absorption of the drug containing this combination may be impaired in patients on a high-protein diet.

Levodopa and Entacapone can form chelates with iron in the gastrointestinal tract; therefore, this combination and iron preparations should be taken with an interval of 2-3 hours.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.