LEVODOPA CARBIDOPA TEVA 250 mg/25 mg Scored tab, Bottle/50

Scored tablet.

The tablet can be divided into equal doses.

Levodopa................................................................................................................................................250,00 mg

Carbidopa monohydrate ....................................................................................................................... 27,00 mg

Quantity corresponding to anhydrous carbidopa ................................................................................... 25,00 mg

For a scored tablet.

Excipients:

Parkinson's disease and parkinsonian syndromes of neurodegenerative origin.

Dosage

Levodopa/carbidopa treatment must be started gradually; the maintenance dose will be reached in steps, seeking the minimum effective dose. The optimal daily dosage is individual. Depending on the severity of the disease, a period of up to 6 months may be necessary before an optimal result is obtained.

Initial treatment

It is advised to start treatment with the lowest possible dose.

At the onset of the disease, it is recommended to start treatment with ½ tablet of levodopa/carbidopa 250 mg/25 mg or even ½ tablet of levodopa/carbidopa 100 mg/10 mg. As soon as it is established that the patient tolerates this initial dose well, it may be increased slowly and very gradually, in steps (½ tablet every day or every two days) until the optimal dosage has been reached.

The absence of clinical response or an insufficient clinical response (less than 30 % improvement in the UPDRS motor score) should call the diagnosis into question and suspect an etiology other than idiopathic Parkinson's disease.

Maintenance treatment

The optimal dose is strictly individual. In most patients, the maintenance dosage may vary from 3 to 6 tablets of levodopa/carbidopa 250 mg/25 mg per day, without exceeding 8 tablets per day. The daily dose should not be increased if abnormal movements appear (overdose); it must even be slightly decreased if they persist. When these effects have disappeared or lessened, doses may be increased again if parkinsonian signs become troublesome again, even if following a slower progression.

In patients presenting with end-of-dose type efficacy fluctuations, or abnormal movements, it is justified to divide levodopa/carbidopa intakes throughout the day, to use the different galenic forms, or to add another antiparkinsonian agent. The number of intakes and their distribution over the day must be adjusted individually to obtain an optimal effect.

Particular observations

• In elderly subjects, treatment must be adapted with care.

• Patients treated with other antiparkinsonian agents may receive levodopa/carbidopa. In this case, during the initiation of levodopa/carbidopa treatment and the onset of its therapeutic effects, it may be necessary to reduce the dosage of the other medicines or to withdraw them gradually. Conversely, the introduction of another antiparkinsonian agent (MAO-B inhibitor, COMT inhibitor, dopaminergic agonist), by increasing the effect of levodopa/carbidopa, may lead to a reduction in the levodopa dose.

• When substituting levodopa/carbidopa for a combination of levodopa and another decarboxylase inhibitor, treatment must be interrupted at least 12 hours before administering levodopa/carbidopa. Start with a levodopa/carbidopa dosage that provides the same amount of the levodopa-decarboxylase inhibitor combination.

After surgery under general anesthesia, treatment will be resumed at the previous dose, unless the patient has been unable to swallow the tablets for more than 4-5 days, in which case treatment will be resumed by slowly increasing the dosage up to the previously prescribed dose.

Paediatric population

Safety of use has not been established in patients under 18 years of age.

Method of administration

The patient must swallow the tablets whole, without chewing or crushing them.

The absorption of levodopa/carbidopa may be altered by food intake. It is recommended, as far as possible, to take levodopa/carbidopa at the end of a meal, or in any case, with a little food.

• Hypersensitivity to the active substances or to any of the excipients listed in section Composition ;

• Severe psychoses, mental confusion;

• Cardiac accidents with angina and recent rhythm disorders;

• Angle-closure glaucoma;

• In combination with reserpine (see section Interactions) ;

• In combination with antiemetic neuroleptics (see section Interactions) ;

• As levodopa may activate the growth of a malignant melanoma, LEVODOPA CARBIDOPA TEVA is contraindicated in patients with suspicious and unidentified skin lesions or in patients with a history of melanoma.

In patients already treated with levodopa alone, dyskinesias may appear, as carbidopa favours the delivery of levodopa to the brain, so that a greater amount of dopamine is formed. The occurrence of dyskinesias may require a dose reduction (see section Adverse effects).

All patients must be closely monitored if depression with suicidal tendencies occurs. Caution is required in psychotic patients and in patients with a known history of psychoses. If an existing psychosis worsens, the dose of levodopa/carbidopa must be reduced or treatment discontinued.

Careful medical supervision, including possible hospitalisation at the start of treatment, in patients with a history or manifestations of:

• psychiatric disorders: risk of worsening. In case of significant intellectual deterioration, levodopa treatment should be maintained at the minimum effective dose;

• cardiac conditions (coronary insufficiency, rhythm disorders, heart failure);

• orthostatic arterial hypotension. The aetiology should be sought before starting treatment (it is often iatrogenic). Simple measures should be advised (for example: increased hydrosaline intake, wearing compression stockings). Drug treatment is indicated in cases of symptomatic orthostatic arterial hypotension;

• gastroduodenal ulcers (delay the start of treatment in case of an ongoing ulcer flare).

Somnolence and sudden onset sleep episodes have been reported during treatment with levodopa. Sudden falling asleep during daily activities, in some cases without prodromes, has been very rarely reported. Patients must be informed of the possibility of these effects and warned to be cautious when driving or using machines during levodopa treatment. Patients who have experienced somnolence or sudden onset sleep episodes must not drive vehicles or use machines. A dose reduction or discontinuation of treatment may be considered.

Levodopa/carbidopa must be used with caution in patients with:

• severe cardiovascular disease;

• severe pulmonary disease;

• bronchial asthma;

• severe renal or hepatic disease;

• endocrine disturbances;

• Cushing's syndrome;

• haematemesis;

• convulsions.

Levodopa/carbidopa must be used with caution in patients who have suffered a recent myocardial infarction and who have residual atrial, nodal or ventricular rhythm disorders. The cardiac function of these patients must be closely monitored at the start of treatment and during dose adjustments.

During long-term treatment, hepatic and renal function, haematopoietic function and the cardiovascular system must be monitored regularly.

Administer with caution in open-angle glaucoma. Regular monitoring of intraocular pressure is advised, as levodopa may theoretically cause an increase in intraocular pressure.

Treatment with levodopa/carbidopa may lead to a vitamin B6 deficiency, which may increase the risk of convulsions, particularly in patients receiving high doses and/or with poor nutritional status. Monitoring of pyridoxine (vitamin B6) concentrations and vitamin B6 supplementation should be considered in patients receiving high doses of levodopa/carbidopa and in those presenting clinical signs suggestive of a vitamin B6 deficiency.

At the start of treatment, avoid abrupt discontinuation of the usual anticholinergic antiparkinsonian medicines the patient may be receiving.

Levodopa/carbidopa treatment must not be interrupted abruptly. Such interruption of treatment may result in the equivalent of a "neuroleptic malignant syndrome" (hyperthermia, muscle rigidity, psychiatric disorders, increased serum creatine phosphokinase) which may threaten the vital prognosis. After evaluation, levodopa/carbidopa treatment may possibly be resumed. Patients whose levodopa/carbidopa dose is abruptly reduced or whose medicine is stopped should therefore be closely monitored, especially in case of concomitant administration of antipsychotic agents.

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2 to approximately 6 times greater) of developing melanoma than the rest of the population. There is no clear cause-and-effect relationship between Parkinson's disease or other factors, such as the medicines used to treat this disease, and the observed increase in risk.

Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in misuse of the product, observed in some patients treated with carbidopa/levodopa. Before treatment is initiated, patients and caregivers must be warned of the potential risk of developing DDS (see also section Adverse effects).

Impulse control disorders

The occurrence of impulse control disorders should be regularly monitored in patients.

Patients and caregivers must be informed of behavioural symptoms of impulse control disorders such as: pathological gambling (compulsion to gamble), increased libido, hypersexuality, compulsive spending or buying, excessive food consumption and eating disorders, which may occur in patients treated with dopamine agonists and/or levodopa-containing dopaminergic treatments including LEVODOPA CARBIDOPA TEVA. A change in treatment should be considered if such symptoms occur.

Laboratory tests

The following biological abnormalities have been reported with levodopa/carbidopa treatment: increased values in liver function tests, such as alkaline phosphatase, AST, ALT, lactate dehydrogenase, bilirubin, urea, creatinine, uric acid and positive Coombs test.

Decreases in haematocrit and haemoglobin values, increases in blood glucose, and the presence of leukocytes, bacteria and blood in the urine have been observed.

The levodopa/carbidopa combination may cause a false positive result when urinary ketones are tested using a urine dipstick; this reaction is not altered by boiling the urine sample. The use of glucose oxidase-based methods may give false negative results for glycosuria.

Paediatric population

To date, the safety and efficacy of levodopa/carbidopa have not been established in neonates and children. Use in children under 18 years of age is not recommended.

Contraindicated combinations (see section Contraindications)

+ Antiemetic neuroleptics

Reciprocal antagonism of levodopa and neuroleptics.

Use an antiemetic free of extrapyramidal effects.

+ Reserpine

Inhibition of the effects of levodopa.

Combinations not recommended (see section Warnings and precautions)

+ Antipsychotic neuroleptics (except clozapine)

Reciprocal antagonism of levodopa and neuroleptics.

In parkinsonian patients, use the minimum effective doses of each of the two medicines.

+ Tetrabenazine

Reciprocal antagonism between levodopa and tetrabenazine.

Associations requiring precautions for use

+ Iron

Decreased digestive absorption of levodopa.

Take iron salts apart from levodopa (more than 2 hours if possible).

+ Methyldopa

Increased effects of levodopa but also of its adverse effects; enhancement of the antihypertensive effect of methyldopa.

Clinical monitoring and possibly reduction of levodopa doses.

+ Antihypertensives

During the titration phase, an adjustment of the antihypertensive dosage may be necessary.

+ Anticholinergics

Anticholinergic drugs may act synergistically with levodopa to improve tremor. However, their concomitant use may lead to worsening of abnormal movements. Anticholinergic drugs may alter the action of levodopa by delaying absorption. An adjustment of the levodopa dose may prove necessary.

Associations to be taken into account

+ selective MAO-B inhibitors (selegiline)

Increased risk of orthostatic hypotension.

+ non-selective MAOs

Potentiation of pharmacological effects, particularly blood pressure effects, through inhibition of the metabolism of catecholamines formed in the extracerebral compartment.

The combination of L-dopa with dopa-decarboxylase inhibitors (DDCIs) makes this interaction unlikely.

+ Spiramycin

Inhibition of carbidopa absorption with decreased plasma concentrations of levodopa.

Clinical monitoring and possible adjustment of the levodopa dosage.

+ Baclofen

Risk of worsening of parkinsonian syndrome or central adverse effects (visual hallucinations, confusional state, headaches).

+ Dapoxetine

Risk of increased adverse effects, notably dizziness or syncope.

Other medicinal products

Benzodiazepines and isoniazid may reduce the therapeutic effects of levodopa. The positive effect of levodopa on Parkinson's disease is impaired by antiepileptics (phenytoin) and papaverine.

Sympathomimetics may increase the cardiovascular adverse effects associated with levodopa.

Insofar as levodopa competes with certain amino acids, the absorption of levodopa may be disrupted in patients receiving a high-protein diet.

Women of childbearing potential / Contraception in men and women

Women of childbearing potential must use reliable contraceptive methods.

Pregnancy

Studies carried out in animals have demonstrated a teratogenic effect.

Clinically, there are currently no sufficiently relevant data to assess a possible teratogenic or fetotoxic effect of the levodopa/carbidopa combination when administered during pregnancy.

Consequently, if possible, postpone initiation of the levodopa/carbidopa combination beyond the first trimester. If this is not possible, or if treatment was started before pregnancy, careful prenatal monitoring is necessary.

Breast-feeding

Due to the passage of levodopa into milk, breastfeeding is not recommended during treatment with LEVODOPA CARBIDOPA TEVA.

The attention of drivers of vehicles and users of machinery should be drawn to the possibility of drowsiness and dizziness associated with the use of this medicine. Patients treated with levodopa who experience drowsiness and/or episodes of sudden onset sleep must be informed that they must not drive vehicles or engage in activities where impaired alertness could expose themselves or others to a risk of serious accident or death (for example, operating machinery) until these effects have resolved (see section Warnings and precautions).

Adverse effects are classified by frequency, using the following classification: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1 000, < 1/100); rare (> 1/10 000, < 1/1 000) and very rare (< 1/10 000), frequency not known (cannot be estimated from the available data).

Infections and infestations 

Very common: urinary tract infection.

Blood and lymphatic system disorders

Rare: leukopenia, hemolytic and non-hemolytic anemia, thrombocytopenia.

Very rare: agranulocytosis.

Metabolism and nutrition disorders

Frequent: anorexia, vitamin B6 deficiency.

Uncommon: weight loss or weight gain.

Psychiatric disorders

Frequent: confusion, hallucinations, insomnia, somnolence, nightmares, depression, with or without suicidal tendency, euphoria, dementia, psychotic episodes.

Rare: agitation, thought disorders, disorientation, increased libido, anxiety, bruxism.

Frequency not known: dream abnormalities, delirium, paranoid manifestations, dopamine dysregulation syndrome.

Nervous system disorders

Frequent: syncope, dyskinesias (or abnormal movements), essentially of the choreoathetoid type, from the start of treatment. Dyskinesias and dystonias occurring over the long term indicate a variation in the sensitivity of dopaminergic receptors. The resurgence of symptoms, including end-of-dose akinesia, reflects the progression of the disease.

Bradykinesia (on-off episodes) may occur a few months or years after starting treatment with levodopa and is probably associated with disease progression. Adjustment of the dose and dosing interval may be necessary.

Uncommon: ataxia, increased tremor of the hands.

Rare: neuroleptic malignant syndrome, paresthesia, falls, gait disorders, trismus, headache, activation of a latent Claude Bernard-Horner syndrome, convulsions.

Frequency not determined: dizziness.

Somnolence has been reported during treatment with levodopa. In very rare cases, excessive daytime sleepiness and episodes of sudden onset sleep have been reported.

Eye disorders

Rare: blurred vision, blepharospasm, diplopia, mydriasis, eye spasms.

Cardiac disorders

Common: palpitations, irregular heart rhythm.

Vascular disorders

Common: orthostatic arterial hypotension, tendency to faint.

Uncommon: hypertension, arterial.

Rare: phlebitis.

Respiratory, thoracic and mediastinal disorders

Uncommon: hoarseness.

Rare: dyspnea, abnormal breathing, hiccups.

Gastrointestinal disorders

Frequent: nausea, vomiting, dry mouth.

Uncommon: constipation, diarrhea, hypersalivation, dysphagia, flatulence.

Rare: dyspepsia, gastrointestinal pain, dark discoloration of saliva, gastrointestinal hemorrhage, burning sensation of the tongue, duodenal ulcer.

Skin and subcutaneous tissue disorders

Rare: angioedema, urticaria, pruritus, rash, alopecia, hyperhidrosis, black discoloration of sweat, rheumatoid purpura (Henoch-Schönlein purpura).

Musculoskeletal and connective tissue disorders Uncommon: muscle spasm.

Frequency not known: muscle cramps, muscle dystonia.

Renal and urinary disorders

Uncommon: dark-coloured urine.

Rare: urinary retention, urinary incontinence, priapism.

General disorders and administration site conditions

Uncommon: feeling of weakness, malaise, disease exacerbation.

Rare: hot flushes.

Frequency not known: fluctuation of effects, fatigue, chest pain.

Impulse control disorders

Pathological gambling (compulsion to gamble), increased libido, hypersexuality, compulsive spending or buying, excessive food consumption and eating disorders may occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa, including LEVODOPA CARBIDOPA TEVA (see section Warnings and precautions).

Dopamine dysregulation syndrome (DDS) is an addictive disorder observed in some patients treated with levodopa/carbidopa. Patients with such a syndrome show compulsive misuse of the dopaminergic medicinal product beyond the doses needed to control motor symptoms, which may in some cases lead to severe dyskinesias in particular (see also section Warnings and precautions).

It is possible to considerably limit the disorders occurring at the start of treatment by starting gradually.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/.

Known accidents of overdose with levodopa are extremely rare.

It nevertheless appears that the following clinical picture may be observed:

• complete disappearance of parkinsonian signs;

• initial arterial hypertension, rapidly followed by hypotension lasting a few hours and prolonged by orthostatic hypotension;

• sinus tachycardia;

• mental confusion;

• insomnia;

• anorexia;

• nausea, vomiting.

The effects of this overdose last about one week. Treatment has been symptomatic.

Treatment of acute levodopa/carbidopa overdose is generally the same as that of acute levodopa-alone overdose, although pyridoxine does not allow the effect of levodopa/carbidopa to be attenuated.

The patient must be placed under ECG monitoring in order to detect the possible occurrence of cardiac rhythm disorders. If necessary, an appropriate anti-arrhythmic treatment must be administered.

To date, no experience of dialysis is available; its usefulness in the treatment of overdose is therefore not established.

Pharmacotherapeutic class: Dopaminergic antiparkinsonian agent, ATC code: N04BA02.

The dopamine deficit in the basal ganglia is the main biochemical abnormality of Parkinson's disease. Levodopa, administered orally and then via the blood, passes into brain tissue and, through its conversion to dopamine, compensates for this deficit. Replacement therapy is effective on akinesia as well as rigidity. Tremor is less favourably influenced and in a later manner.

Carbidopa, a peripheral decarboxylase inhibitor, allows a reduction in the amount of levodopa ingested for an equivalent or greater therapeutic effect. Peripheral decarboxylation being inhibited, this efficacy is obtained more rapidly and is accompanied by a decrease in peripheral side effects (nausea, orthostatic hypotension).

Levodopa is an amino acid, the physiological precursor of dopamine.

Rapidly absorbed in the digestive tract, levodopa is transformed mainly into dopamine under the action of peripheral dopa decarboxylase. Gastric acidity, simultaneous intake of food, and meals rich in protein or in certain amino acids delay the absorption of the product and decrease its plasma peak.

Only a small amount of intact ingested levodopa crosses the blood-brain barrier to be transformed into dopamine under the action of cerebral dopa decarboxylase.

The half-life varies from 1 to 3 hours.

80 % of the levodopa dose is excreted by the kidney within 24 hours in the form of dopamine metabolites. These may colour the urine brown-black without pathological significance.

After absorption, carbidopa shows a plasma peak within one and a half to five hours in parkinsonian patients.

Carbidopa is rapidly metabolized into at least two metabolites. The presence of carbidopa modifies the metabolism of levodopa by preventing its peripheral decarboxylation into dopamine, thus allowing a greater quantity of dopa to pass into the cerebral compartment.

At therapeutic doses, carbidopa does not cross the blood-meningeal barrier.

After independent oral administration, the half-life of carbidopa is approximately 3 hours and that of levodopa is 45 minutes. When carbidopa and levodopa are administered together, the half-life of levodopa is prolonged to approximately 3 hours.

For the vial packaging: 4 years.

For the blister packaging: 3 years.

Blister packs

Store at a temperature not exceeding 25°C.

Store in the original package.

Vial

This medicine does not require any particular storage precautions.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400934368219 (Fl/50).

Price:

7,92 euros (Fl/50).

Social Security reimbursement at 65%.
Collection.