SINEMET - PACKAGE LEAFLET - LEAFLETS

Home / leaflets / 2021

Sinemet - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Levodopa, Carbidopa

SINEMET 250 mg + 25 mg tablets
SINEMET 100 mg + 25 mg tablets

Sinemet package inserts are available for pack sizes:

SINEMET 250 mg + 25 mg tablets, SINEMET 100 mg + 25 mg tablets
SINEMET 200 mg + 50 mg modified release tablets, SINEMET 100 mg + 25 mg modified release tablets

Why is Sinemet used? What is it for?

Sinemet tablets contain the active ingredients carbidopa and levodopa and are used for the treatment of Parkinson's disease and parkinsonian syndrome.

Sinemet is useful in relieving many symptoms of Parkinson's disease, especially muscle stiffness and slowing down in the speed of movement (bradykinesia); it is useful in the treatment of tremor, difficulty in swallowing (dysphagia), excessive production of saliva (drooling) and difficulty in maintaining balance (postural instability).

Compared to levodopa alone, therapy with Sinemet favors the control of the symptoms of the disease, the variations in the therapeutic response and the reduction of unwanted effects. These benefits allow more patients to get adequate relief from the symptoms of Parkinson's disease.

Sinemet is also indicated for patients with Parkinson's disease and syndrome who are taking vitamin preparations containing pyridoxine.

What is Parkinson's disease?

It is a pathology of the nervous system that causes tremors, stiffness, slowness of movement and difficulty in walking; it is caused by low levels of dopamine, a substance that is normally produced by the brain and that plays an essential role in controlling muscle movements.

Contraindications When Sinemet should not be used

Do not take Sinemet

if you are allergic to the active substances levodopa and carbidopa or to any of the other ingredients of this medicine (listed in section 6);
if you suffer from increased pressure in the eye (narrow-angle glaucoma);
if you have recently suffered from heart problems (acute phase of myocardial infarction);
if you have undiagnosed suspicious skin lesions;
if you have or have suffered from skin cancer (melanoma);
if you are taking or have taken within the previous two weeks medicines for the treatment of depression and Parkinson's syndrome (monoamine oxidase inhibitors), except low doses of selective monoamine oxidase type B inhibitors (see section "Warnings and precautions" and "Others medicines and Sinemet ");
if you are under the age of 18;
if you are pregnant or breast-feeding (see "Pregnancy and breast-feeding" section).

Precautions for use What you need to know before taking Sinemet

Talk to your doctor or pharmacist before taking Sinemet. If you experience any unusual signs or symptoms while taking Sinemet, contact your doctor or pharmacist immediately.

Tell your doctor before using this medicine:

if you are currently taking levodopa-only medicines. In this case you must wait at least 12 hours before starting therapy with Sinemet. Sinemet should be given at a dose that provides approximately 20% of the previous levodopa dose (see section 3 "How to take Sinemet"). You should definitely avoid taking additional doses of levodopa, unless prescribed by your doctor;
if you are currently taking a recommended dose of a selective monoamine oxidase type B inhibitor used for the treatment of Parkinson's disease (eg selegiline hydrochloride) (see section 2 "Other medicines and Sinemet"). Since selegiline potentiates the effects of levodopa, adverse reactions to levodopa may be amplified, especially if you are on high dose levodopa therapy. He will be kept under observation by the doctor. Adding selegiline to levodopa therapy may lead to involuntary movements and / or agitation. These undesirable effects disappear following a reduction in the levodopa dose;
if there are adverse reactions caused by causes external to the nervous system (extrapyramidal) induced by medicines, such as involuntary movements of the muscles (tardive dyskinesia) and the inability to sit still (acatasia), because in this case, treatment with Sinemet is not recommended ;
if you suffer from or have suffered in the past from thought disturbances, delusions, hallucinations (psychosis);
if you have suffered in the past from severe involuntary movements or psychotic episodes following treatment with levodopa alone. These reactions are thought to be due to an increase in brain dopamine (a substance produced by the body that acts as a messenger in the cells of the nervous system) after the administration of levodopa, and consequently the use of Sinemet can cause a relapse. All patients should be carefully monitored for the development of mental alterations, suicidal depression or other severe antisocial behaviors;
if you have a rapid rise in dopamine levels after taking Sinemet, compared with levodopa alone, as this may result in premature impairment of muscle movement (dyskinesias). These disorders require a reduction in the dose of Sinemet;
if you suffer from a severe cardiovascular disease;
if you have severe lung disease or bronchial asthma;
if you suffer from kidney or liver problems, or if you have endocrine system disorders (a system that includes a set of glands that release hormones into the bloodstream);
if you have recently had a heart attack (myocardial infarction) and still have heart rhythm disturbances (atrial, nodal or ventricular arrhythmias). In this case, your doctor will need to monitor your heart function very carefully during the initial dose adjustment period;
if you have suffered from injury to the wall of your stomach or intestines in the past (peptic ulcer). Taking Sinemet, like levodopa, may increase the risk of upper gastrointestinal bleeding (haemorrhage);
if you abruptly stop taking medicines to treat Parkinson's disease; this can cause symptoms similar to neuroleptic malignant syndrome, manifested by muscle stiffness and increased body temperature, mental changes and increased serum creatine phosphokinase ( an enzyme present in the blood) Your doctor will monitor you closely if your dose of Sinemet is abruptly reduced or stopped, especially if you are taking antipsychotic medicines;
if you are in a state of excessive sleepiness or if you tend to fall asleep suddenly. In this case, you should not drive, use machines and contact your doctor;
if you have suffered from convulsions in the past;
if you suffer from eye diseases caused by the alteration of the internal pressure of the eye (chronic open-angle glaucoma). You can still take Sinemet, as long as the internal pressure of the eye is well compensated and the doctor carefully checks the variations in the pressure. during therapy.

As for levodopa, in case of prolonged treatments, it is advisable to undergo periodic blood tests and liver, kidney and cardiocirculatory function.

Patients and healthcare professionals are recommended to have frequent and regular monitoring for the prevention of skin cancer (melanoma) when using Sinemet for any indication. Some studies have shown that Parkinson's disease patients are at a higher risk of developing melanoma (2 to about 6 times greater) than the general population. It is not clear whether the increased risk observed is due to Parkinson's disease or other factors, such as the use of medicines to treat the disease itself. For these reasons, it is recommended that periodic skin examinations be carried out by qualified personnel (eg dermatologists. ).

Tell your doctor if you or someone in your family / caregiver notices that urges or desires are developing to behave in ways that are unusual for you and you cannot resist the urge or temptation to perform certain activities that could harm yourself or others. These behaviors are called impulse control disorders and can include addiction to gambling, excessive eating or spending, an abnormal, exaggerated sexual desire, or an increase in sexual thoughts or feelings. The physician may find it necessary to reassess, modify or discontinue treatment.

It is possible that during treatment with Sinemet there is an alteration in the results of some laboratory tests:

increase in certain substances in the blood (liver transaminases, LDH, bilirubin, alkaline phosphatase, nitrogen, creatinine and uric acid);
positive Coombs test (a test used to detect the presence of certain types of antibodies in the blood);
decrease in hemoglobin and hematocrit (which can lead to anemia), increase in blood sugar (hyperglycaemia) and white blood cells, and presence of blood and bacteria in the urine. Hemolytic anemia (breakdown of red blood cells) is extremely rare.

If you experience any unusual signs or symptoms while taking SINEMET, consult your doctor or pharmacist immediately.

Children and adolescents

Sinemet is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy in infants and children.

Interactions Which drugs or foods can modify the effect of Sinemet

Other medicines and Sinemet

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

You should be especially careful when taking Sinemet together with the following medicines:

antihypertensive medicines, used to treat high blood pressure: concomitant administration with Sinemet may lead to a fall in blood pressure following a sudden transition from sitting or lying to standing (symptomatic postural hypotension). Before starting treatment with Sinemet, consult your doctor for a "possible dose modification;
medicines used to treat depression: side effects, including high blood pressure and involuntary movements of the muscles (dyskinesia), have rarely been observed during concomitant treatment with Sinemet and some medicines used to treat depression (tricyclic antidepressants); If you are taking monoamine oxidase inhibitors see the section "Do not take Sinemet";
Medicinal products containing iron (eg ferrous sulphate or ferrous gluconate): induce a reduction in the absorption and effectiveness of carbidopa and / or levodopa (the active ingredients of Sinemet);
antipsychotic medicines such as phenothiazines and butyrophenones, used for the treatment of psychosis: the therapeutic effects of levodopa can be reduced by these medicines;
medicines such as phenytoin, used to treat epilepsy and papaverine, used to relax muscles: the therapeutic effects of levodopa can be undone by these medicines. If you are taking antipsychotics, phenytoin or papaverine concomitantly with Sinemet, your doctor will have to closely monitor you in relation to any "loss of therapeutic response;
medicines containing agents that reduce dopamine stores in the body, such as reserpine, used to treat hypertension and tetrabenazine, used to treat spasms and uncontrollable muscle movements, or with other medicines known to empty the stores of monoamine, such as adrenaline and noradrenaline: the use of Sinemet is not recommended with these medicines;
medicines containing selegiline, used to treat Parkinson's disease, depression and senile dementia: concomitant therapy with selegiline and carbidopa-levodopa can cause severe drop in blood pressure not attributable to carbidopalevodopa alone (see section 2 "Warnings and precautions" ); - monoamine oxidase inhibitor medicines, used for the treatment of depression and Parkinson's disease (except low doses of selective monoamine oxidase type B inhibitors): you must not take these medicines at the same time as Sinemet and you must stop taking these inhibitors for at least two weeks before the start of therapy with Sinemet.

Sinemet with food and drink

The absorption of Sinemet may be reduced in some patients who consume high amounts of protein in their diet. Consult your doctor if your diet contains high amounts of protein.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Do not use Sinemet if you are pregnant, if you think you are pregnant or if you are breast-feeding.

Driving and using machines

Treatment with Sinemet can cause sleepiness (excessive numbness) and episodes of sudden sleep attack. For this reason, he must refrain from driving or from engaging in any activity in which impaired attention could expose himself or others to the risk of serious harm or death (eg the use of machinery) until such recurring episodes and the drowsiness have not resolved.

Dosage and method of use How to use Sinemet: Dosage

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

The optimal dose must be established according to your needs and the doctor's instructions; this may require adjustment of both the dose and the frequency of administration. The fully effective dose is usually reached within 7 days.

The tablets in the two formulations (Sinemet 100 mg +25 mg and 250 mg +25 mg) can be administered separately or jointly as needed, to achieve the optimal dose. The tablet can be divided into equal parts according to its therapeutic needs.

If you have never been treated with levodopa

Sinemet 100 mg + 25 mg tablets: the recommended dose is one tablet three times a day.

If the doctor deems it appropriate, the dose can be increased by one tablet per day, or every other day, up to a maximum of eight tablets of Sinemet 100 mg + 25 mg tablets.

Sinemet 250 mg + 25 mg tablets: the recommended starting dose is half a tablet once or twice a day. If the doctor deems it necessary, the dose can be increased by half a tablet a day or every other day until an optimal response is achieved.

If you are currently being treated with levodopa alone

You must stop treatment with levodopa at least 12 hours before starting Sinemet therapy (24 hours for levodopa in slow-release formulations). A daily dose of Sinemet that provides 20% of the previous daily dose of levodopa should be considered.

If you took less than 1,500 mg of levodopa per day:

Sinemet 100 mg + 25 mg tablets: the recommended starting dose is one tablet three or four times a day.

If you have taken more than 1,500 mg of levodopa per day:

Sinemet 250 mg + 25 mg tablets: the recommended starting dose is one tablet three or four times a day.

Maintenance therapy

The recommended dose for maintenance therapy, in most cases, can range from 3 to 6 tablets per day; you should not take more than 8 tablets a day, in fact there is no benefit by increasing the dose of carbidopa beyond that provided by 8 tablets. To obtain the adequate amount of levodopa available for transport to the brain for its subsequent transformation into dopamine, the dose of carbidopa to be taken should be 70 to 100 mg per day. Some patients may require a higher dose of carbidopa; not Sufficient data are available to support a carbidopa daily dose greater than 200 mg.

During carbidopa therapy you can also take other medicines used to treat Parkinson's disease, except levodopa; your doctor will be able to adjust the dose of these medicines.

If you take lower doses of carbidopa you may experience nausea and vomiting. Since the therapeutic effects of the treatment and side effects occur more quickly with Sinemet tablets than with levodopa alone, your doctor will monitor you for the period of dose adjustment.

When taking Sinemet tablets you may experience involuntary movements which may require a lowering of the dosage. Forced and involuntary closing of the eyelids (blepharospasm) can instead be a sign of overdose.

If you are going to have surgery that requires general anesthesia, take Sinemet tablets as long as you are able to take fluids and medicines by mouth, then resume your usual daily therapy when you are able to take the tablets again.

Overdose What to do if you have taken too much Sinemet

If you take more Sinemet than you should

In case of accidental ingestion / intake of an overdose of Sinemet, notify your doctor or pharmacist immediately or contact the nearest hospital.

Method of treatment in case of overdose of Sinemet

The rescue procedures foresee the need to carry out, together with an "immediate gastric lavage, also an" appropriate supportive therapy.

Intravenous administration of fluids should be done with caution and the airways should be kept clear. An electrocardiographic examination should be performed and the patient should be carefully monitored for the possible development of abnormal heart beat (arrhythmias) and, if necessary, appropriate "antiarrhythmic therapy should be given. In addition, consideration should be given to the possibility that the patient may have taken other medicines together with Sinemet To date, no experience has been reported on the efficacy of dialysis in overdose. Pyridoxine has no effect in "canceling" the action of Sinemet.

If you forget to take Sinemet

Do not take a double dose to make up for a forgotten tablet.

If you have forgotten to take a tablet, take it as soon as you remember. If it is almost time for the next tablet, do not take the forgotten tablet, but continue at the usual dosage schedule.

If you stop taking Sinemet

If your dose of Sinemet is abruptly reduced or stopped, your doctor will monitor you regularly, especially if you are taking antipsychotic medicines. Abrupt discontinuation of medicinal products for the treatment of Parkinson's disease may result in symptoms similar to neuroleptic malignant syndrome manifested by muscle stiffness, fever, delirium and increased serum creatine phosphokinase.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Sinemet

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Side effects that may frequently be seen in patients taking Sinemet are due to dopamine activity in the brain. These effects can usually be reduced by reducing the dose.

The most common side effects are:

random and continuous movements (choreiforms), abnormal muscle contractions (dystonia) and other involuntary movements (dyskinesia);
feeling sick (nausea);
changes in muscle contraction (muscle spasms) and forced and involuntary closing of the eyelids (blepharospasm). The presence of these symptoms suggests a reduction in dose.

Other undesirable effects reported in clinical trials or during the actual marketing of Sinemet are:

loss of consciousness (syncope), chest pain, anorexia;
changes in heart rate and / or palpitations, posture-related episodes of low blood pressure (orthostatic hypotension), hypertension, venous inflammation (phlebitis);
vomiting, bleeding from the stomach and / or intestines (gastrointestinal bleeding), duodenal ulcer, dark saliva, diarrhea;
decrease in some types of white blood cells (leukopenia, agranulocytosis), platelets (thrombocytopenia), and red blood cells (haemolytic and non-haemolytic anemia);
allergic phenomena such as inflammatory reactions and swelling of the skin (angioedema), hives, itching, Henoch-Schonlein purpura which occurs with joint injuries and pain;
neuroleptic malignant syndrome manifested by muscle stiffness, high body temperature and mental disorders (see section "Warnings and precautions"), difficulty in movement (bradykinesia and the on-off phenomenon), dizziness, somnolence (excessive numbness), including very rarely excessive daytime sleepiness and episodes of sudden sleep attacks;
changes in feeling in the limbs or other parts of the body (paraesthesia);
mental disorders, such as thought forms that deviate from reality (paranoid ideation) and psychotic episodes including delirium, hallucinations and thought forms that deviate from reality (paranoid ideation), depression with and without suicidal tendencies, dementia, activity disturbances dream (alteration of dreams), agitation and confusion;
breathing problems (dyspnoea);
hair loss (alopecia), rash, dark sweat;
dark urine;
inability to resist the urge or temptation to take actions that could be harmful to oneself or others, which may include: - strong urge to gamble excessively, despite serious personal or family consequences; - altered or increased sexual desire that is of significant concern to you or others; - uncontrollable shopping or overspending; - compulsive eating (eating large amounts of food in a short time) or bulimia (eating more food than normal and more than is necessary to satisfy your hunger).

Seizures have rarely been observed, however it has not been proven with certainty that the seizures are caused by Sinemet.

Tell your doctor if any of these behaviors occur so they can decide what to do to manage or reduce symptoms.

Therapy with Sinemet (and similar drugs) can cause alterations in some laboratory tests:

increase in certain substances in the blood (liver transaminases, LDH, bilirubin, alkaline phosphatase, nitrogen, creatinine and uric acid);
positive Coombs test (a test used to detect the presence of certain types of antibodies in the blood);
decreased hemoglobin and hematocrit (which can lead to anemia), increased blood sugar (hyperglycemia) and white blood cells, and presence of blood and bacteria in the urine;
false positive for the presence in the urine of certain substances (ketone bodies) if a strip test for the determination of ketonuria is used. This reaction is not altered by boiling the urine sample. False negativity tests can occur when glucose-oxidase methods are used to detect glucose in the urine.

Other side effects have been seen during the use of levodopa-containing medicines or with levodopa / carbidopa combination medicines and there may be potential side effects of Sinemet:

difficulty digesting (dyspepsia), dry mouth, changes in taste, excessive production of saliva (drooling), difficulty swallowing (dysphagia), involuntary contraction of the chewing muscles leading to excessive brushing of the teeth (bruxism), hiccups, discomfort and abdominal pain, constipation, flatulence, burning sensation in the tongue;
weight loss or gain, edema;
muscle weakness (asthenia), decreased mental acuity, disorientation, loss of muscle coordination (ataxia), numbness, increased hand tremor, muscle cramps, abnormal jaw muscle contractions (trismus), activation of a pre-existing Horner syndrome (a eye disorder) which manifests itself with the onset of injuries and difficulty in moving the eyes, insomnia, agitation and anxiety, euphoria, ease of falling, impaired walking;
flushing, increased sweating;
double vision (diplopia), blurred vision, dilated pupils, fixed eye position (oculogyric crisis);
urinary retention, incontinence, persistent, abnormal and painful erections (priapism);
weakness, fainting, tiredness, headache, change in the normal tone of voice (hoarseness), malaise, flushing, feeling of excitement, irregular breathing rhythm, skin tumors (malignant melanoma) (see section 2 "Do not take Sinemet" ).

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Keep the medicine protected from light.

Do not use this medicine after the expiry date which is stated on the package after "EXP". The expiry date refers to the last day of that month.

The expiry date indicated refers to the medicine in intact packaging, correctly stored.

Do not throw away any medicines via wastewater or household waste.

Ask your pharmacist how to throw away medicines you no longer use.

This will help protect the environment.

Composition and pharmaceutical form

What Sinemet contains

The active ingredients of Sinemet tablets are: levodopa and carbidopa.

Each Sinemet 100 mg + 25 mg tablet contains: 100 mg of levodopa and 27 mg of hydrated carbidopa, equivalent to 25 mg of anhydrous carbidopa.

The other ingredients are: microcrystalline cellulose, pregelatinised starch, maize starch, magnesium stearate, quinoline yellow (E104).

Each tablet of Sinemet 250 mg + 25 mg contains: 250 mg of Levodopa and 27 mg of Carbidopa hydrate, equivalent to 25 mg of anhydrous carbidopa.

The other ingredients are: microcrystalline cellulose, pregelatinised starch, maize starch, magnesium stearate, (E132) indigo carmine.

Description of what Sinemet looks like and contents of the pack

Sinemet comes in tablet form. The tablets are packed in opaque blisters.

Each blister of Sinemet 250 mg + 25 mg contains 50 tablets.

Each blister of Sinemet 100 mg + 25 mg contains 50 tablets.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Sinemet can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

SINEMET TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

SINEMET 250 mg + 25 mg tablets

One tablet contains 250 mg of levodopa and 27 mg of hydrated carbidopa (equivalent to 25 mg of anhydrous carbidopa).

SINEMET 100 mg + 25 mg tablets

One tablet contains 100 mg of levodopa and 27 mg of hydrated carbidopa (equivalent to 25 mg of anhydrous carbidopa).

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

SINEMET tablets are indicated for the treatment of Parkinson's disease and parkinsonian syndrome. It is useful in relieving many symptoms of parkinsonism, especially rigidity and bradykinesia. SINEMET tablets are useful in the treatment of tremor, dysphagia, drooling and postural instability associated with Parkinson's disease and syndrome.

When the therapeutic response to levodopa alone is irregular and the signs and symptoms of Parkinson's disease are not uniformly controlled throughout the day, substitution with SINEMET tablets is usually effective in reducing fluctuations in response.

By reducing some of the side effects of levodopa alone, SINEMET tablets help more patients get adequate relief from their Parkinson's disease symptoms.

SINEMET tablets are indicated for patients with Parkinson's disease and syndrome who are given vitamin preparations containing pyridoxine.

04.2 Posology and method of administration

SINEMET tablets, a combination of carbidopa and levodopa, are supplied as breakable tablets. SINEMET 250 mg + 25 mg tablets contains 250 mg of levodopa and 25 mg of anhydrous carbidopa (ratio of 10: 1); SINEMET 100 mg + 25 mg tablets contain 100 mg of levodopa and 25 mg of carbidopa (4: 1 ratio).

Tablets of the two presentations can be administered separately or jointly as needed to achieve the optimal dosage. Each tablet can be halved with minimal effort.

General consideration

Dosage should be titrated to individual patient needs and this may require adjustment of both the individual dose and the frequency of administration. Fully effective doses are usually achieved within 7 days. Some studies show that peripheral dopa-decarboxylase is saturated by carbidopa at a dose of approximately 70-100 mg / day. Patients receiving lower doses of carbidopa are more likely to experience nausea and vomiting.

As both therapeutic and undesirable responses occur more rapidly with administration of SINEMET tablets than with administration of levodopa, patients should be followed closely during the dose adjustment period. Specifically, involuntary movements occur more rapidly with SINEMET tablets than with levodopa. The onset of involuntary movements may require a reduction in dosage in some patients, blepharospasm may be a useful early sign of overdosing. In case of general anesthesia, SINEMET tablets can be continued as long as the patient is allowed to take fluids and medicines for If therapy is temporarily interrupted, the usual daily dosage can be given as soon as the patient is able to take medicine by mouth.

Patients who are not being treated with levodopa

The optimal starting dosage for SINEMET 100 mg + 25 mg tablets is one tablet three times a day, a dosing schedule that gives the patient 75 mg of carbidopa per day. The dosage may be increased by one tablet per day, or every other day, as needed, until a dosage equivalent to eight tablets of SINEMET 100 mg + 25 mg tablets is obtained. The usual starting dose for SINEMET 250 mg + 25 mg tablets is half a tablet once or twice a day, increasing if necessary half a tablet a day or every other day until optimal response is achieved.

Patients being treated with levodopa

Levodopa should be discontinued at least 12 hours before starting therapy with SINEMET tablets (24 hours for levodopa in delayed formulations). A daily dosage of SINEMET tablets that provides 20% of the previous daily dose of levodopa should be considered. Patients who are taking less than 1,500 mg of levodopa per day should start with one tablet of SINEMET 100 mg + 25 mg tablets three or four times a day. The suggested starting dosage for most patients taking more than 1,500 mg of levodopa is one tablet of SINEMET 250 mg + 25 mg tablets three or four times a day (for example, if the patient was receiving 4 g of levodopa / day). day, the dosage of SINEMET tablets should not exceed 3 tablets per day).

Maintenance therapy

Most patients can be maintained on 3 to 6 tablets per day; no patient should receive more than 8 tablets per day.

No benefit is gained by increasing the dose of carbidopa beyond that provided by 8 tablets. For optimal inhibition of extracerebral decarboxylation of levodopa, at least 70 to 100 mg of carbidopa per day should be taken. There is limited experience of a daily carbidopa dose greater than 200 mg. Some patients may require additional " dose of levodopa. The results obtained indicate that the other antiparkinsonian medicinal products (except levodopa) can be continued although the dosage may need to be adjusted.

04.3 Contraindications

SINEMET tablets are contraindicated in patients with hypersensitivity to the active substances (levodopa and carbidopa) or to any of the excipients listed in section 6.1, in narrow-angle glaucoma and in the acute phase of myocardial infarction. Since levodopa can activate a malignant melanoma. , should not be used in patients with suspected undiagnosed skin lesions or a history of melanoma.

Monoamine oxidase inhibitors (except low dose selective monoamine oxidase B inhibitors - see sections 4.4 and 4.5) and SINEMET tablets should not be administered concurrently and therapy with these inhibitors should be discontinued at least two weeks prior to initiation of SINEMET tablets.

SINEMET tablets should not be administered to patients under the age of 18, pregnant and breastfeeding patients.

04.4 Special warnings and appropriate precautions for use

SINEMET tablets can be administered to patients already being treated with levodopa alone; however levodopa alone must be stopped at least 12 hours before therapy with SINEMET tablets is started. SINEMET tablets should be administered at a dose that provides approximately 20% of the previous levodopa dose (see section 4.2). Patients being treated with SINEMET tablets should absolutely avoid taking additional doses of levodopa, unless prescribed by their doctor.

SINEMET tablets can be administered concomitantly with the recommended dose of an MAO inhibitor with selectivity for MAO type B used for the treatment of Parkinson's disease (e.g. selegiline hydrochloride) (see sections 4.3 and 4.5).

Since selegiline potentiates the effects of levodopa, adverse reactions to levodopa may be amplified, especially if patients are on high dose levodopa therapy. These patients should be observed. Adding selegiline to levodopa therapy may lead to involuntary movements and / or agitation. These undesirable effects disappear following a reduction in the levodopa dose.

SINEMET tablets are not recommended for the treatment of drug-induced extrapyramidal reactions.

Patients with current or history of psychosis should be treated with caution. Like levodopa, SINEMET tablets may cause involuntary movement and mental disturbance. Patients with a history of severe involuntary movement or psychotic episodes when treated with levodopa alone should be carefully observed. when SINEMET tablets are replaced.

These reactions are thought to be due to an increase in brain dopamine following levodopa administration; consequently, the use of SINEMET tablets can cause a relapse.

All patients should be carefully monitored for the development of mental changes, suicidal depression or other severe antisocial behaviors. The faster onset of elevated dopamine levels achieved with SINEMET tablets compared to levodopa alone may result in early dyskinesias. Such disorders require a reduction in the dosage of SINEMET tablets.

SINEMET tablets should be administered with caution to patients with severe cardiovascular or lung disease, bronchial asthma, renal, hepatic or endocrine disease. Care should be taken when administering SINEMET tablets to patients with a history of myocardial infarction who have residual atrial, nodal or ventricular arrhythmias. In such patients, cardiac function should be monitored with particular care during the initial dosage adjustment period.

As with levodopa, there is a possibility of upper gastrointestinal bleeding in patients with a history of peptic ulcer.

Complex neuroleptic malignant syndrome-like symptoms manifesting as muscle stiffness, elevated body temperature, mental changes and elevated serum creatine kinase have been reported when antiparkinsonian medicinal products were withdrawn abruptly. Therefore, patients should be closely observed when the dosage of SINEMET tablets is abruptly reduced or discontinued, especially if the patient is receiving neuroleptics. Patients with a history of seizures should be treated with caution.

Levodopa-carbidopa treatment has been associated with somnolence and episodes of sudden sleep attacks, in some cases without awareness and no warning signs. Patients being treated with SINEMET tablets should be informed of these events and advised to use caution when driving or using machines. Patients who have experienced episodes of somnolence and / or an episode of sudden sleep should refrain from driving and operating machinery. use of machinery. In addition, a reduction in dosage or discontinuation of therapy may be considered.

As for levodopa, in case of prolonged treatments it is advisable to carry out periodic tests of the blood formula and of the hepatic, renal and cardiovascular function. Patients with open-angle glaucomachronic can be treated with caution with SINEMET tablets, provided that intraocular pressure is well compensated and the patient is closely monitored during therapy.

Melanoma: Epidemiological studies have shown that patients with Parkinson's disease are at a higher risk of developing melanoma (2 to approximately 6 times greater) than the general population. It is not clear whether the increased risk observed is due to Parkinson's disease or to other factors, such as the use of medicines to treat the disease.

For the above reasons, it is recommended that patients and healthcare professionals have monitoring for melanoma prevention frequently and regularly when using Sinemet for any indication.

Ideally, periodic skin examinations should be carried out by qualified personnel (eg dermatologists).

Impulse control disorders

Patients should be monitored regularly for the development of impulse control disorders.

Patients and caregivers should be aware that the behavioral symptoms of impulse control disorder including pathological gambling, increased libido, hypersexuality, compulsive shopping or overspending, bulimia, and the urge to eat may occur in patients treated with dopamine agonists and / or other dopaminergic treatments containing levodopa including SINEMET If such symptoms develop, re-evaluation of treatment is recommended.

The safety and efficacy of SINEMET tablets have not been demonstrated in infants and children, therefore use in patients below 18 years of age is contraindicated (see section 4.3).

Lab test

Laboratory test abnormalities include: increases in SGOT, SGPT, LDH, bilirubin, alkaline phosphatase, as well as increases in BUN, creatinine, uric acid and positive Coombs test.

Hemolytic anemia is extremely rare.

The following have been reported: decreased hemoglobin and hematocrit, increased serum glucose and white blood cells and the presence of blood and bacteria in the urine.

If any unusual signs or symptoms occur during treatment with SINEMET tablets, you should immediately consult your doctor or pharmacist.

Keep out of reach of children.

04.5 Interactions with other medicinal products and other forms of interaction

Caution should be exercised when the following medicinal products are co-administered with SINEMET tablets.

Antihypertensives

Symptomatic postural hypotension may occur when SINEMET tablets are administered to a patient already being treated with antihypertensive medicinal products. Therefore, when initiating therapy with SINEMET tablets, dosage adjustment of the antihypertensive medicinal product may be required.

Antidepressants

For patients taking monoamine oxidase inhibitors, see sections 4.3 and 5.

Undesirable reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and SINEMET tablets have been reported rarely.

Iron

Studies show a reduction in the bioavailability of carbidopa and / or levodopa when ingested with ferrous sulfate or ferrous gluconate.

Other Medicines

Phenothiazines and butyrophenones may reduce the therapeutic effects of levodopa. Furthermore, it has been reported that the therapeutic effects of levodopa in Parkinson's disease are canceled out by phenytoin and papaverine. Patients taking these medicinal products with SINEMET tablets should be carefully monitored for any loss of therapeutic response. As levodopa competes with certain amino acids, its absorption may be impaired in some patients on a high protein diet.

The use of SINEMET tablets with dopamine depleting agents (eg reserpine and tetrabenazine) or with other medicinal products known to deplete monoamine stores is not recommended.

Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone (see section 4.3).

Monoamine oxidase inhibitors (except low dosages of selective monoamine oxidase B inhibitors) and SINEMET tablets should not be administered and therapy with these inhibitors should be discontinued at least two weeks prior to initiation of therapy with SINEMET tablets.

04.6 Pregnancy and lactation

SINEMET tablets should not be administered during pregnancy, presumed pregnancy or breastfeeding.

04.7 Effects on ability to drive and use machines

Patients being treated with SINEMET tablets who have episodes of drowsiness and / or sudden sleep attacks should be advised to refrain from driving or from engaging in any activity in which impaired attention could expose themselves or others to the risk of serious harm or harm. death (eg use of machines) until these recurrent episodes and somnolence have resolved (see also section 4.4).

04.8 Undesirable effects

The undesirable effects that may frequently occur in patients treated with SINEMET tablets are those due to the central neuropharmacological activity of dopamine. These effects can usually be reduced by reducing the dosage. The most common undesirable effects are: dyskinesias, including movements choreiform, dystonic and other involuntary movements and nausea.Muscle spasm and blepharospasm can be considered as warning symptoms to decide on a reduction of the dosage.

Other undesirable effects reported in clinical trials or during post-marketing experience are:

Body in general: syncope, chest pain, anorexia.

Cardiovascular pathologies: cardiac irregularities and / or palpitation, orthostatic effects including hypotensive episodes, hypertension, phlebitis.

Gastrointestinal disorders: vomiting, gastrointestinal bleeding, development of duodenal ulcer, diarrhea, dark saliva.

Haematological disorders: leukopenia, haemolytic and non-haemolytic anemia, thrombocytopenia, agranulocytosis.

Hypersensitivity. angioedema, urticaria, pruritus, Henoch-Schonlein purpura.

Nervous system disorders / Psychiatric disorders: neuroleptic malignant syndrome (see section 4.4), episodes of bradykinesia (the on-off phenomenon), dizziness, somnolence including very rarely excessive daytime sleepiness and episodes of sudden sleep onset, paraesthesia, psychotic episodes including delirium, hallucinations and paranoid ideation, depression with and without development of suicidal tendencies, dementia, disturbances of dream activity, agitation, confusion.

Impulse control disorders

Pathological gambling, increased libido, hypersexuality, compulsive shopping or overspending, bulimia and binge eating may occur in patients treated with dopamine agonists and / or with other dopamine-containing treatments containing levodopa including SINEMET (see section 4.4). .

Respiratory disorders: dyspnea.

Skin disorders: alopecia, rash, dark sweat.

Urogenital disorders: dark urine.

Convulsions have rarely been observed; however, a causal correlation with SINEMET has not been demonstrated.

DIAGNOSTIC TESTS

Alterations in various laboratory tests have occurred with carbidopa-levodopa preparations and can occur with SINEMET. These changes include increases in liver function test values such as alkaline phosphatase, SGOT (AST), SGPT (ALT), LDH, bilirubin, BUN, creatinine, uric acid, and positive Coombs test.

The following have been reported: decreased hemoglobin and hematocrit, hyperglycemia, leukocytosis, presence of bacteria and blood in the urine.

Carbidopa-levodopa preparations can cause a false positive reaction for urinary ketone bodies when using a test strip test for the determination of ketonuria. This reaction will not be affected by boiling the urine sample. False negativity tests can occur when glucose-oxidase methods are used to detect glucose in the urine.

Other undesirable effects which have been reported with levodopa or with the levodopa / carbidopa combinations and which could be potential undesirable effects of SINEMET therapy are the following:

Gastrointestinal disorders: dyspepsia, dry mouth, altered taste, drooling, dysphagia, bruxism, hiccups, abdominal discomfort and pain, constipation, flatulence, burning sensation of the tongue.

Metabolism and nutrition disorders: weight reduction or gain, edema.

Nervous system disorders / Psychiatric disorders: asthenia, decreased mental acuity, disorientation, ataxia, numbness, increased hand tremor, muscle cramps, trismus, activation of latent Horner syndrome, insomnia, anxiety, euphoria, easy falling and abnormal gait.

Skin disorders: flushing, increased sweating.

Sensory organs: diplopia, blurred vision, dilated pupils, oculogyric crisis.

Urogenital disorders: urinary retention, urinary incontinence, priapism.

Miscellaneous: weakness, fainting, tiredness, headache, hoarseness, malaise, flushing, feeling of excitement, irregular breathing rhythm, malignant melanoma (see section 4.3).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

04.9 Overdose

In the event of overdose, appropriate supportive therapy should be given along with immediate gastric lavage. Intravenous fluid should be administered with caution and a patent airway should be maintained. An electrocardiographic examination should be performed and the patient should be carefully monitored for possible development of arrhythmias; appropriate antiarrhythmic therapy should be given if necessary. The possibility that the patient may have taken other medicinal products together with SINEMET tablets should be considered. To date, no experience with dialysis has been reported; therefore its value in overdose is not known.

Pyridoxine has no effect in "canceling" the action of SINEMET tablets.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antiparkinsonian drug, dopaminergic substance.

ATC code: N04BA02.

SINEMET tablets are a combination of carbidopa, an aromatic amino acid decarboxylase inhibitor, and levodopa, the metabolic precursor of dopamine, for the treatment of Parkinson's disease and parkinsonian syndrome.

Levodopa relieves the symptoms of Parkinson's disease by allegedly being decarboxylated to dopamine in the brain. Carbidopa, which does not cross the blood brain barrier, only inhibits the extracerebral decarboxylation of levodopa, thus providing more levodopa available for transport to the brain and for subsequent conversion into dopamine. This eliminates the need to administer high levodopa doses at frequent intervals and helps relieve some unwanted effects, such as nausea, which may be attributed to dopamine buildup in extracerebral tissues.

When used as recommended, SINEMET tablets improve the overall therapeutic response compared to levodopa.

SINEMET tablets induce effective and long-lasting plasma levels of levodopa at doses that are approximately 80% lower than those needed with levodopa alone. While pyridoxine hydrochloride (vitamin B6) is known to accelerate the peripheral metabolism of levodopa to dopamine, the carbidopa prevents this action. In a study in which patients received 100 to 500 mg of pyridoxine per day while being treated with carbidopa and levodopa in combination, there was no alteration of the antiparkinsonian effect.

05.2 Pharmacokinetic properties

Maximum recommended dose: 8 tablets of SINEMET 250 mg + 25 mg tablets per day (200 mg of carbidopa and 2 g of levodopa, i.e. approximately 3 mg / kg of carbidopa and 30 mg / kg of levodopa in a patient weighing 70 kg ).

Onset of action at recommended doses: Response was seen within one day and sometimes after a dose. Fully effective doses are usually achieved within 7 days.

Half-life : after oral administration, the plasma half-life for carbidopa is approximately 3 hours and for levodopa approximately 50 minutes. When carbidopa and levodopa are given together, the half-life of levodopa is prolonged to approximately 1.5 hours.

Carbidopa metabolism : after an oral dose of radiolabelled carbidopa to healthy subjects and to patients with Parkinson's disease, maximum plasma levels of radioactivity were reached in 2-4 hours in healthy subjects and in 1.5-5 hours in patients. Approximately equal amounts were excreted in urine and faeces from both groups. Comparison of the urinary metabolites of healthy subjects and patients indicated that the drug is metabolised in the same way in both groups. Urinary excretion of the unchanged drug was essentially complete within 7 hours and accounted for 35% of total urinary radioactivity. From then on, only metabolites were present. No hydrazine was found. Among the metabolites excreted by "humans, are the" α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid. These represented approximately 14 and 10% of the excreted radioactive metabolites, respectively. Two minor metabolites were found. One has been identified as 3,4-dihydroxyphenylacetone and the other, provisionally, as N-methylcarbidopa. They represented less than 5% of the urinary metabolites. Unchanged carbidopa is also present in the urine. They were not found married.

Levodopa metabolism: Levodopa is rapidly absorbed from the gastrointestinal tract and is extensively metabolised. Although more than 30 metabolites can be formed, it is mainly converted into dopamine, adrenaline, and noradrenaline and eventually into dihydroxyphenylacetic acid, homovanillic acid and vanylmandelic acid. 3-O-methyldopa appears in plasma and cerebrospinal fluid. Its meaning is not known. When single doses of radioactive levodopa are administered in the fasting state to patients with Parkinson's disease, peak plasma levels of radioactivity are reached in 0.5-2 hours and are detectable for 4-6 hours. At peak levels, about 30% of the radioactivity appears as catecholamines, 15% as dopamine, and 10% as dopa.

Radioactive compounds are rapidly excreted in the urine and one third of the dose appears within 2 hours. 80-90% of the urinary metabolites are phenylcarboxylic acids, mainly homovanillic acid. For 24 hours, 1-2% of the recovered radioactivity is dopamine and less than 1% is adrenaline, noradrenaline and unchanged levodopa.

Effect of carbidopa on levodopa metabolism: Carbidopa markedly increases plasma levels of levodopa in statistically significant amounts, as assessed versus placebo, in healthy subjects. This has been shown when carbidopa is given before levodopa and when the two medicines are given at the same time. In one study, carbidopa pretreatment increased the plasma levels of a single dose of levodopa by approximately 5-fold and prolonged the duration of detectable plasma concentrations of levodopa from 4 to 8 hours. In other studies, similar results were obtained when the two medicines were administered together. In a study in which a single dose of labeled levodopa was administered to patients with Parkinson's disease who had been pre-treated with carbidopa, there was an increase in the half-life of total plasma radioactivity derived from levodopa from 3 to 15 hours. The fraction of radioactivity remaining as unmetabolized levodopa increased at least three-fold with carbidopa.

Plasma and urinary dopamine and homovanillic acid both decreased with carbidopa pretreatment.

05.3 Preclinical safety data

Toxicology

The oral LDs of carbidopa are 1,750 mg / kg in adult female mice and 4,810 and 5,610 mg / kg in female and male rats, respectively.

The acute oral toxicity of carbidopa is similar in juvenile and adult rats, but the compound is more toxic in neonatal rats. The signs of drug action were similar in mice and rats and consisted of: ptosis, ataxia and decreased activity. sexes at 2,260 mg / kg in young female rats.

Signs of the drug's action were: vocalization, irritability, excitability, ataxia and increased activity followed within one to two hours by decreased activity. The oral LD50s of various combinations of carbidopa and levodopa in mice ranged from 1,930 mg / kg for a ratio of 1: 1 to 3,270 mg / kg for a 1: 3 ratio. These amounts are the sum of single doses of carbidopa and levodopa; ratios tested above 1: 3 (1: 4, 1: 5, 1:10) they did not appreciably change the value of the LD50 compared to that found with the ratio 1: 3. The ratios of 1: 3 and higher were less toxic than the ratios 1: 1 and 1: 2.

Chronic oral toxicity studies with carbidopa were conducted for one year in monkeys and for 96 weeks in rats, using doses ranging from 25 to 135 mg / kg. No drug-related effects were observed in monkeys.

In rats, flaccidity occurred in some animals of all dose groups.

Carbidopa administered to dogs resulted in a pyridoxine deficiency which was prevented with the concomitant administration of pyridoxine. With the exception of pyridoxine deficiency in dogs, carbidopa showed no hydrazine-associated toxicity.

Three dose ratios of carbidopa and levodopa given orally to monkeys for 54 weeks and rats for 106 weeks showed that the main physical effects were due to the pharmacological action of the compounds. The dosages studied were (carbidopa / levodopa): 10 / 20, 10/50 and 10/100 mg / kg / day. The dose of 10/20 mg / kg / day had no apparent physical effects. Hyperactivity occurred in monkeys at doses of 10/50 and 10/100 mg / kg / day, which continued for 32 weeks with the highest dose. With the dose of 10/50 mg / kg / day, hyperactivity decreased; the study continued and this phenomenon was no longer observed after the 14th week. Lack of muscle coordination and weakness were observed up to 22 weeks with the 10/100 mg / kg / day dose. Pathological anatomy studies have shown no morphological changes.

Rats receiving 10/50 and 10/100 mg / kg / day had decreased normal activity and exhibited abnormal body positions. The higher dose resulted in "excessive salivation. There was a decrease in" weight gain. Pathological anatomy studies revealed very slight hypertrophy of the follicular cells of the sub-maxillary glands of two rats that had received 10/100 mg / kg / day for 26 weeks. No histomorphological effects were found with any dose after 54 or 106 weeks. Salivary gland follicular cell hypertrophy was noted in rats with the higher doses of the combination for shorter periods and with levodopa alone.

Teratogenesis and Reproduction Studies

Carbidopa did not show teratogenicity in mice or rabbits at doses up to 120 mg / kg / day. Levodopa caused visceral and skeletal malformations in rabbits at doses of 125 and 250 mg / kg / day. With the combinations of carbidopa and levodopa, at doses ranging from 25/250 to 100/500 mg / kg / day, there was no evidence of teratogenicity in mice, but visceral and skeletal malformations were quantitatively and qualitatively similar to rabbits. those seen with levodopa alone. Combinations of carbidopa and levodopa at doses up to 10/100 mg / kg / day had no adverse effects on the reproductive performance of male or female rats, nor on the growth and survival of the offspring.