Active ingredients: Levodopa, Benserazide
Madopar 100 mg + 25 mg hard capsules
Madopar 200 mg + 50 mg divisible tablets
Madopar 100 mg + 25 mg prolonged-release hard capsules
Madopar 100 mg + 25 mg dispersible tablets
Indications Why is Madopar used? What is it for?
Pharmacotherapeutic group
Antiparkinsonian - dopaminergic substance
Therapeutic indications
Parkinson's disease. Symptomatic Parkinsonism (post-encephalitic, arteriosclerotic, toxic), excluding that of medicinal origin.
Madopar 100 mg + 25 mg dispersible tablets it is particularly suitable for those patients with dysphagia (difficulty in swallowing) or who need a formulation with a faster onset of action, for example patients who suffer from akinesia in the early morning or in the afternoon, or who manifest the phenomena of "response" delayed "or" end of dose deterioration ".
Madopar 100 mg + 25 mg prolonged-release hard capsules it is indicated in all those patients who present an oscillating trend in the response to levodopa therapy, especially when this trend is linked to changes in plasma levels (for example: "with dyskinesia at peak dose" and "deterioration from end of dose") and to better control nocturnal symptoms.
Further studies will be needed to determine whether the use of prolonged-release Madopar is also beneficial in the initial therapy of parkinsonian patients who have not previously been treated with levodopa alone or in combination with a decarboxylase inhibitor in a conventional dosage form. .
Contraindications When Madopar should not be used
Hypersensitivity to the active substances or to any of the excipients.
Madopar must not be administered in combination with non-selective monoamine oxidase (MAO) inhibitors. Conversely, selective MAO-B inhibitors, such as selegiline or rasagiline, or selective MAO-A inhibitors, such as moclobemide, are not contraindicated. The combination of an MAO-A inhibitor with a MAO-B is equivalent to the administration of a non-selective inhibitor and therefore should not be prescribed concomitantly with Madopar (see Interactions).
Madopar has the same contraindications as sympathomimetics (adrenaline, noradrenaline and their derivatives).
It is also contraindicated in endocrine diseases (e.g. pheochromocytoma, hyperthyroidism, Cushing's syndrome), renal (except dialysis patients with Restless Legs Syndrome), severely decompensated liver and heart diseases (e.g. severe cardiac arrhythmias and heart failure), in the acute myocardial infarction, in severe psychoses and psychoneuroses, in malignant melanoma (possible activation by levodopa) and suspected undiagnosed skin lesions, in acute angle glaucoma.
It should not be given to patients under the age of 25 (due to incompleteness of skeletal development)
Madopar must not be administered to pregnant women or women of childbearing potential in the absence of adequate contraceptive protection (see Pregnancy and breastfeeding). Should a woman being treated with Madopar become pregnant, administration of the drug should be discontinued.
Precautions for use What you need to know before taking Madopar
Patients with a history of myocardial infarction, rhythm alterations, coronary heart disease and blood pressure changes, should undergo periodic cardiovascular checks, in particular electrocardiography.
In diabetic patients it is advisable to carry out numerous blood glucose checks and to adapt the dosage of antidiabetic drugs to glycemic levels.
Hypersensitivity reactions may occur in predisposed individuals.
Patients with open angle glaucoma should have regular intraocular pressure checks as levodopa has the potential to increase intraocular pressure.
Particular care should be taken when Madopar is administered to patients with coronary artery disease, cardiac arrhythmias or heart failure. Cardiac functions should be monitored with particular attention in these patients, both during the initial period of treatment and regularly during the later stages of therapy.
For patients with predisposing risk factors (e.g. elderly, or on antihypertensive or other drugs with orthostatic potential) or with a previous history of orthostatic hypotension, careful monitoring is recommended especially at the start of treatment or following dose increases. .
Treatment with Madopar has been reported to lead to decreased blood counts (haemolytic anemia, thrombocytopenia and leukopenia). In some cases agranulocytosis and pancytopenia have been reported for which the intake of Madopar cannot be considered the cause but not completely excluded. Therefore during the treatment it is necessary to carry out periodic checks of the blood count.
Depression may be part of the clinical picture in patients with Parkinson's disease and Restless Legs Syndrome and may also arise in patients treated with Madopar.
All patients should be carefully monitored for psychological changes and depression associated or not with suicidal ideation.
Madopar can induce dopaminergic dysregulation syndrome resulting in overuse of the drug. A small subgroup of patients with Parkinson's disease has cognitive behavioral disorders that can be directly attributed to taking the drug in quantities greater than those recommended by the physician and well beyond the dosages required to treat their motor alterations.
If the patient is to undergo general anesthesia, normal Madopar treatment should be continued for as long as possible before surgery, except in the case of halothane. In general anesthesia with halothane, Madopar administration should be stopped between 12 and 48 hours before surgery as blood pressure fluctuations and / or arrhythmias may occur in patients taking Madopar. Thereafter, the treatment will be resumed by reaching the previous dosage of the drug through a progressive increase in doses.
Madopar administration should not be stopped abruptly. An abrupt interruption may lead to the onset of a malignant neuroleptic syndrome (hyperpyrexia and muscle stiffness, in some cases alterations of the psyche and increase in creatine phosphokinase, further symptoms, in severe cases, may include myoglobinuria, rhabdomyolysis and acute renal failure), which can jeopardize the patient's survival. Faced with the onset of some of these signs and symptoms, it is necessary to keep the patient under observation, if necessary in a hospital setting, and promptly administer adequate symptomatic treatment; this may also include the resumption of the administration of Madopar, after an accurate evaluation of the case.
Patients should be monitored regularly for the development of impulse control disorders. Patients and caregivers should be aware that behavioral symptoms of impulse control disorder including pathological gambling, increased libido, hypersexuality, compulsive shopping or overspending, binge eating, and compulsive eating can occur in patients. patients treated with dopamine agonists and / or other dopaminergic treatments containing levodopa including Madopar If such symptoms develop, re-evaluation of treatment is recommended.
Interactions Which drugs or foods can modify the effect of Madopar
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Pharmacokinetic interactions
Concomitant administration of the anticholinergic drug trihexyphenidyl hydrochloride with standard doses of madopar capsules or scored tablets reduces the rate, but not the extent, of absorption of levodopa. Trihexyphenidyl hydrochloride co-administered with prolonged-release Madopar does not change the pharmacokinetics of levodopa.
Concomitant administration of antacids with Madopar prolonged-release capsules reduces the absorption of levodopa by 32%.
Ferrous sulfate reduces the maximum plasma concentration and AUC of levodopa by 30-50%. Pharmacokinetic changes observed during concomitant treatment with ferrous sulfate are clinically evident in some, but not all patients.
Metoclopramide increases the rate of absorption of levodopa.
Pharmacodynamic interactions
Neuroleptics, opioids and antihypertensive agents containing reserpine inhibit the activity of Madopar. Concomitant administration of antipsychotic drugs with dopamine receptor blocking properties, in particular D2 receptor antagonists, could antagonize the antiparkinsonian effects of Madopar. Therefore, such administration should be done with caution, and the patient should be carefully observed for loss of the "antiparkinsonian effect" and worsening of symptoms.
Administration of levodopa in combination with a decarboxylase inhibitor may cause symptomatic orthostatic hypotension in patients on antihypertensive drug therapy. Madopar should therefore be introduced with caution in patients treated with antihypertensive drugs. Blood pressure should be monitored to allow for dosage adjustments of both drugs if required.
The concomitant administration of Madopar with sympathomimetic drugs (such as adrenaline, noradrenaline, isoproterenol or amphetamines, capable of stimulating the sympathetic nervous system), may enhance the activity of the latter, therefore these combinations are not recommended.
In the event that concomitant administration should prove necessary, a close control of the cardio-circulatory function and a possible reduction in the dose of sympathomimetic drugs are essential.
Irreversible and non-selective MAO inhibitors should not be combined with Madopar; treatment with the latter should not be started before at least 2 weeks have elapsed from the discontinuation of irreversible and non-selective anti-MAO, otherwise undesirable effects (hypertensive crisis) are likely to appear (see Contraindications).
Selective MAO-B inhibitors, such as selegiline and rasagiline, and selective MAO-A inhibitors, such as moclobemide, can be prescribed to patients receiving Madopar; it is recommended to modify the levodopa dosage according to the needs of the individual patient, in terms of efficacy and tolerability. The combination of an MAO-A inhibitor with a MAO-B is equivalent to the administration of a non-selective inhibitor and therefore should not be prescribed concomitantly with Madopar (see Contraindications).
The concomitant administration of other antiparkinsonian drugs such as anticholinergics, amantadine and dopamine agonists is possible, but the potential for intensification of both therapeutic and unwanted effects must be taken into account. It may be necessary to reduce the dosage of Madopar or the other. drug. When initiating adjuvant treatment with a COMT inhibitor, the Madopar dosage may need to be reduced.
Switching to Madopar should not lead to abrupt discontinuation of previously used antiparkinsonian anticholinergics, as the effect of levodopa occurs after a latency period of several days.
Levodopa can alter laboratory test results for catecholamines, creatinine, uric acid and blood sugar. Coombs' test may give a false positive result in patients taking Madopar.
The therapeutic effect of Madopar is reduced if the drug is taken in conjunction with a protein-rich meal.
The concomitant intake of levodopa and Madopar must be carried out under medical supervision as the additionally administered levodopa could also be enhanced by benserazide with a consequent risk of overdose.
Vitamin B6 in medium or high doses should not be administered together with Madopar as it antagonizes the effects of levodopa: this antagonistic activity has no clinical significance in the case of vitamin B6 in low doses, such as those contained in polyvitamin preparations.
General anesthesia with halothane: Madopar administration should be discontinued between 12 and 48 hours prior to surgery requiring general anesthesia with halothane as blood pressure fluctuations and / or arrhythmias may occur.
In the case of general anesthesia with other anesthetics, see Precautions for use.
Warnings It is important to know that:
In prolonged treatments with Madopar it is advisable to carry out periodic checks of the blood count and of the hepatic, renal and cardiovascular function.
In diabetic patients it is advisable to carry out numerous blood glucose checks and to adapt the dosage of antidiabetic drugs to glycemic levels.
Both levodopa and benserazide are largely metabolised and less than 10% of levodopa is excreted unchanged via the kidney. Therefore, no dosage reduction is necessary in cases of mild or moderate renal insufficiency.
No pharmacokinetic data are available with levodopa in patients with renal insufficiency.
Levodopa is mainly metabolized by aromatic amino acid decarboxylase which is abundantly present in the intestinal tract, kidney and heart, as well as in the liver.
No pharmacokinetic data are available with levodopa in patients with hepatic insufficiency. Madopar has been associated with somnolence and episodes of sudden sleep attacks.
Sudden sleep attacks have been reported very rarely during daily activity, in some cases without awareness or warning signs. Patients taking Madopar should be informed of these events and advised to use caution while driving or operating machinery. .
Patients who have experienced episodes of somnolence and / or an episode of sudden sleep should refrain from driving and operating machinery. In addition, dose reduction or discontinuation of therapy may be considered (see Effects on the ability to drive or the use of machinery). Epidemiological studies have shown that patients with Parkinson's disease have a higher risk of developing melanoma than the rest of the population (approximately 2-6 times higher). It is unclear whether the increased risk observed is associated with Parkinson's disease or other factors such as the use of levodopa to treat it. Therefore, both patients and physicians are required to regularly monitor the presence of melanoma during treatment with Madopar for any indication. recommends that you periodically undergo a skin examination carried out by qualified medical personnel (for example dermatologists).
A small subgroup of patients with Parkinson's disease have cognitive-behavioral disorders that can be directly attributed to taking the drug in greater quantities than those recommended by the physician and well beyond the dosages required to treat their motor alterations.
Tell your doctor if you or someone in your family or caregiver becomes aware 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 they could harm yourself or others. These are called impulse control disorders and can include behaviors such as gambling addiction, excessive eating or spending, an abnormal exaggerated sexual desire, or an increase in sexual thoughts or feelings. Your doctor may find it necessary to change or discontinue your dose.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine
Pregnancy
Animal studies have shown the possible presence of fetal skeletal development disorders. Based on these results Madopar is absolutely contraindicated during pregnancy and in women of childbearing age who do not practice adequate contraception (see Contraindications).
Feeding time
Since it is unclear whether benserazide is able to pass into breast milk or not, mothers requiring treatment with Madopar should not breastfeed, as the risk of skeletal malformations in infants cannot be excluded and it is therefore prudent to resort to artificial breastfeeding.
Effects on ability to drive or use machines
Patients being treated with levodopa who experience episodes of drowsiness and / or sudden sleep attacks should refrain from driving or engaging in any activity in which impaired attention could expose themselves or others to the risk of serious harm or death (eg. . use of machinery) until these recurrent episodes and sleepiness have resolved (see Special warnings).
Dosage and method of use How to use Madopar: Dosage
The capsules should be swallowed whole and unopened or dissolved in liquid.
The dispersible tablets can be swallowed whole or after having been mixed with a quarter of a glass of water (about 25-50 ml) (do not use orange juice, as the effectiveness of the product would be reduced); the tablets disperse. completely within a few minutes, giving the liquid an opalescent appearance. Drink the liquid within half an hour from when it was prepared, remembering to mix well before taking.
Madopar should possibly be taken 30 minutes before or one hour after meals.
Gastrointestinal side effects, which may occur especially in the initial stages of treatment, can be well controlled by taking the drug together with a snack (e.g. biscuits) or liquids, or by gradually increasing the dosage.
With Madopar it is essential to individually determine the optimal daily dosage and achieve it with a gradual increase in individual doses.
Initial therapy
For the above, it will be advisable to start administration with a capsule or a dispersible tablet of Madopar 100 mg + 25 mg or with 1/2 tablet of Madopar 200 mg + 50 mg once a day and then increase this dosage with a capsule or tablet. Madopar 100 mg + 25 mg dispersible or 1/2 Madopar 200 mg + 50 mg tablet every 3 days until the effective individual dose is reached.
In the rare cases in which badly tolerated side effects occur, the dose increase or dose will be reduced. At the disappearance or attenuation of the side effects, the increase will resume at a slower rate: for example, it will increase by a single capsule or a dispersible tablet of Madopar 100 mg + 25 mg or 1/2 tablet of Madopar 200 mg + 50 mg per week.
The average effective maintenance dose is usually between 600 mg of levodopa + 150 mg of benserazide and 800 mg of levodopa + 200 mg of benserazide per day, i.e. between 3-4 tablets of Madopar 200 mg + 50 mg per day, divisible into 3-4 administrations. However, the dose must be closely tailored to the individual patient's response.
Should it be necessary to exceed this average dose, it is recommended to wait a few weeks, because a fairly long period may elapse before the effect of the drug manifests itself.
Only rarely is it necessary to administer more than 5 tablets / day of Madopar 200 mg + 50 mg.
For the determination of the optimal posology, the following dosage schedule can be used as a guideline.
* the two administrations at noon and at 4 pm can be replaced with a single administration at noon of 1 tablet of Madopar 200 mg + 50 mg divisible tablets.
Maintenance therapy
As soon as the optimal dose is reached, switching from Madopar 100 mg + 25 mg to Madopar 200 mg + 50 mg becomes useful.
That is, when said optimal dose is equivalent to 6 or 8 (or more) capsules or dispersible tablets of Madopar 100 mg + 25 mg, these can be replaced with 3 or 4 (or more) tablets of Madopar 200 mg + 50 mg.
Since the improvement obtainable with the therapy may vary, the distribution of the pro / day dose in 3 or 4 administrations must be adapted to individual needs, both in terms of the number of single administrations and their distribution during the day.
Transition from levodopa to Madopar
When Madopar is to be administered to patients who have hitherto been treated with levodopa alone, the following schedule should be followed:
- decrease the levodopa dose progressively until parkinsonian symptoms reappear or worsen;
- then replace each single dose of 500 mg of levodopa with a capsule or a dispersible tablet of Madopar 100 mg + 25 mg or with 1/2 tablet of Madopar 200 mg + 50 mg divisible tablets, whose effectiveness corresponds precisely to that of 500 mg of levodopa.
- observe the patient for a week and, if necessary, then increase the dose of Madopar until a satisfactory improvement is achieved (scheme identical to that valid for patients never treated with levodopa).
Switch to Madopar 100 mg + 25 mg prolonged-release hard capsules
In all those patients who exhibit large fluctuations in therapeutic response during the course of the day it is recommended to divide the daily dose into a larger number of administrations or preferably to use prolonged-release Madopar.
Switching to prolonged-release Madopar therapy can be done from one day to the next, maintaining the same daily dose and the same frequency of intake. After 2-3 days the dose should be gradually increased by approximately 50% due to the lower bioavailability of this special slow-release form.
Patients should be informed of the possible occurrence of a temporary worsening of their condition.
Prolonged-release Madopar, due to its pharmacokinetic properties, begins its activity in about 3 hours. Effective plasma levels can be achieved more rapidly by administering prolonged-release Madopar in combination with conventional capsules or tablets. This can be particularly beneficial in administering the morning dose, which should preferably be a little higher than the following ones.
Finding the optimal individual dose of prolonged-release Madopar should be done slowly and very carefully, waiting at least 2-3 days before varying doses. If the response to prolonged-release Madopar is unsatisfactory even at daily doses corresponding to 1500 mg levodopa, it is preferable to return to the previous treatment with conventional capsules or tablets.
In the case of patients who over-respond to treatment, rather than intervening by reducing single doses, the interval between administrations will have to be increased.
Positive results have been reported in patients with nocturnal hypokinesia following the gradual increase of the last evening dose to 3 Madopar prolonged-release capsules to be taken at bedtime.
Patients must be carefully monitored in order to highlight the possible onset of side effects affecting the psychic sphere.
The dosing regimen should be carefully considered individually in all patients. Madopar administration should last at least six months before a judgment of ineffectiveness can be made at medium doses.
As with all replacement therapies, treatment must be continuous.
Overdose What to do if you have taken too much Madopar
Symptoms
The symptoms of overdose are qualitatively similar to the side effects of Madopar at therapeutic doses, but more severe in magnitude. Overdose can lead to: cardiovascular side effects (e.g. cardiac arrhythmias), psychiatric disorders (e.g. confusion and insomnia), gastrointestinal effects (e.g. nausea and vomiting) and abnormal involuntary movements (see Side Effects).
A small subgroup of patients with Parkinson's disease have cognitive-behavioral disorders that can be directly attributed to taking the drug in greater quantities than those recommended by the physician and well beyond the dosages required to treat their motor alterations.
If a patient has taken an overdose of Madopar in a controlled-release form (prolonged-release capsules), the onset of symptoms may be delayed due to delayed absorption of the active substance from the stomach.
Treatment
Monitor the patient's vital signs and institute supportive measures appropriate to his clinical condition. In particular, patients may require symptomatic treatment of cardiovascular effects (eg with antiarrhythmics), or central nervous system effects (eg with respiratory stimulants, neuroleptics).
In addition, in the case of the controlled release formulation, further absorption of the drug must be prevented by an appropriate method.
In case of accidental intake of an excessive dose of Madopar, notify your doctor immediately or go to the nearest hospital.
IF YOU HAVE ANY DOUBTS ABOUT THE USE OF MADOPAR, CONTACT YOUR DOCTOR OR PHARMACIST.
Side Effects What are the side effects of Madopar
Like all medicines, Madopar can cause side effects, although not everybody gets them. The undesirable effects due to the peripheral activity of dopamine and observed during therapy with levodopa are significantly reduced in frequency and severity with the use of Madopar.
The following side effects have been reported to occur following administration of Madopar
(frequency not known: cannot be predicted from the available data):
The categories of attendance are as follows:
Very common (≥1 / 10)
Common (≥1 / 100,
Uncommon (≥1 / 1,000 to
Rare (≥1 / 10,000,
Very rare (
Not known (frequency cannot be predicted from the available data)
* These events may occur in particular in elderly patients and in patients who have already suffered from these disorders.
Impulse Control Disorders:
Pathological gambling, increased libido, hypersexuality, compulsive shopping or overspending, binge eating, and compulsive eating may occur in patients treated with dopamine agonists and / or other dopamine-containing treatments containing levodopa including Madopar.
Tell your doctor if any of these behaviors occur so he can decide what to do to manage or reduce symptoms.
Nervous system disorders: in a later phase of the treatment, involuntary movements, of a choreiform or athetotic type, may appear. During prolonged treatments, fluctuations in the therapeutic response may also arise, including motor block phenomena, end-of-dose deterioration and the "on-off" phenomenon. All these secondary effects are related to the posology and disappear or are significantly reduced by decreasing the doses, while drug discontinuation is a measure only rarely necessary. If, following these measures, the response to treatment becomes unsatisfactory, a new dose increase or resumption of therapy in case of discontinuation.
Madopar can cause drowsiness; very rarely it has been associated with excessive daytime sleepiness and episodes of sudden sleep attacks.
Vascular disorders: orthostatic disturbances usually improve with reducing Madopar dosage.
Gastrointestinal disorders:
Gastrointestinal side effects, which may occur especially during the early stages of treatment, can be considerably limited by administering Madopar at mealtimes and, in any case, with some food or drink; it is also indicated to reach the optimal dose of the drug gradually.
Musculoskeletal and connective tissue disorders: Restless Legs Syndrome: Increased symptomatology (with temporal shift of symptoms from evening / night to early afternoon and evening before taking the next dose) is the most common adverse event in long-term dopaminergic treatment.
Diagnostic tests: in case of treatment with Madopar, a reddish discoloration of the urine may appear, which tends to darken with time.
Madopar tolerance is identical to that observed for levodopa given alone.
Without speaking of addiction in the strict sense of the word, after several years of continuous treatment with Madopar, a decrease in the therapeutic efficacy of the product has been observed. Madopar, but to the evolution of Parkinson's disease.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
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. Side effects can also be reported 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
Madopar 100 mg + 25 mg dispersible tablets: store at a temperature not exceeding 30 ° C. Keep the bottle tightly closed to protect the medicine from moisture.
Madopar 200 mg + 50 mg divisible tablets: do not store above 25 ° C. Keep the bottle tightly closed to protect the medicine from moisture.
Madopar 100 mg + 25 mg hard capsules: do not store above 30 ° C. Keep the bottle tightly closed to protect the medicine from moisture.
Madopar 100 mg + 25 mg prolonged-release hard capsules: Do not store above 30 ° C.
Keep the bottle tightly closed to protect the medicine from moisture.
Expiry: see the expiry date indicated on the package.
The expiry date refers to the product in intact packaging, correctly stored. Warning: do not use the medicine after the expiry date shown on the package.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN.
Composition
Madopar 100 mg + 25 mg hard capsules
One capsule contains: active ingredients: levodopa 100 mg, benserazide 25 mg (as benserazide hydrochloride 28.5 mg
Excipients:
Capsule contenta: povidone K90, talc, magnesium stearate, microcrystalline cellulose.
Capsule operculum: gelatin, titanium dioxide (E171), red iron oxide (E172), indigo carmine (E132), food grade printing ink (shellac gum, potassium hydroxide, black iron oxide (E172)).
Madopar 200 mg + 50 mg divisible tablets
One divisible tablet contains: active ingredients: levodopa 200 mg, benserazide 50 mg (as benserazide hydrochloride 57 mg).
Excipients: mannitol (E421), anhydrous dibasic calcium phosphate, microcrystalline cellulose, pregelatinised starch, crospovidone, magnesium stearate, ethylcellulose, red iron oxide (E172), anhydrous colloidal silica, docusate sodium.
Madopar 100 mg + 25 mg prolonged-release hard capsules
One capsule contains: active ingredients: levodopa 100 mg, benserazide 25 mg (as benserazide hydrochloride 28.5 mg).
Excipients:
Capsule contents: hypromellose, hydrogenated vegetable oil, anhydrous dibasic calcium phosphate, mannitol (E421), talc, povidone K30, magnesium stearate.
Capsule operculum: gelatin, titanium dioxide (E171), yellow iron oxide (E172), indigo carmine (E132), food grade printing ink (shellac gum, potassium hydroxide, red iron oxide (E172)).
Madopar 100 mg + 25 mg dispersible tablets
One dispersible tablet contains: active ingredients: levodopa 100 mg, benserazide 25 mg (as 28.5 mg benserazide hydrochloride).
Excipients: anhydrous citric acid, pregelatinised maize starch, microcrystalline cellulose, magnesium stearate.
Pharmaceutical form and content
Hard capsules, prolonged-release hard capsules, divisible tablets and dispersible tablets for oral use.
Madopar 100 mg + 25 mg hard capsules - 30 capsules
Madopar 200 mg + 50 mg divisible tablets - 50 divisible tablets
Madopar 100 mg + 25 mg prolonged-release hard capsules - 30 capsules
Madopar 100 mg + 25 mg dispersible tablets - 30 dispersible 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.
01.0 NAME OF THE MEDICINAL PRODUCT
MADOPAR
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Madopar 100 mg + 25 mg hard capsules
One capsule contains: 100 mg levodopa, 25 mg benserazide (as 28.5 mg benserazide hydrochloride).
Madopar 200 mg + 50 mg divisible tablets
One divisible tablet contains: 200 mg levodopa, 50 mg benserazide (as 57 mg benserazide hydrochloride).
Madopar 100 mg + 25 mg prolonged-release hard capsules
One capsule contains: 100 mg levodopa, 25 mg benserazide (as 28.5 mg benserazide hydrochloride).
Madopar 100 mg + 25 mg dispersible tablets
One dispersible tablet contains: 100 mg levodopa, 25 mg benserazide (as 28.5 mg benserazide hydrochloride).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsules, prolonged-release hard capsules, divisible tablets and dispersible tablets for oral use.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Parkinson's disease. Symptomatic Parkinsonism (post-encephalitic, arteriosclerotic, toxic), excluding that of medicinal origin.
Madopar 100 mg + 25 mg dispersible tablets it is particularly suitable for those patients with dysphagia (difficulty in swallowing) or who need a formulation with a more rapid onset of action, for example patients who suffer from akinesia in the early morning or in the afternoon, or who manifest the phenomena of "response" delayed "or" end of dose deterioration ".
Madopar 100 mg + 25 mg prolonged-release hard capsules it is indicated in all those patients who present an oscillating trend in the response to levodopa therapy, especially when this trend is linked to changes in plasma levels (for example: "with dyskinesia at peak dose" and "deterioration from end of dose") and to better control nocturnal symptoms.
Further studies will be needed to determine whether the use of prolonged-release Madopar is also beneficial in the initial therapy of parkinsonian patients who have not previously been treated with levodopa alone or in combination with a decarboxylase inhibitor in a conventional dosage form. .
04.2 Posology and method of administration
The capsules should be swallowed whole and unopened or dissolved in liquid.
The dispersible tablets can be swallowed whole or after having been mixed with a quarter of a glass of water (about 25-50 ml) (do not use orange juice, as the effectiveness of the product would be reduced); the tablets disperse. completely within a few minutes, giving the liquid an opalescent appearance. Drink the liquid within half an hour from when it was prepared, remembering to mix well before taking.
Madopar should possibly be taken 30 minutes before or one hour after meals.
Gastrointestinal side effects, which may occur especially in the initial stages of treatment, can be well controlled by taking the drug together with a snack (e.g. biscuits) or liquids, or by gradually increasing the dosage.
With Madopar it is essential to individually determine the optimal daily dosage and achieve it with a gradual increase in individual doses.
Initial therapy
For the above, it will be advisable to start administration with a capsule or a dispersible tablet of Madopar 100 mg + 25 mg or with ½ tablet of Madopar 200 mg + 50 mg once a day and then increase this dosage with a capsule or a dispersible tablet of Madopar 100 mg + 25 mg or ½ tablet of Madopar 200 mg + 50 mg every 3 days until the individual effective dose is reached.
In the rare cases in which badly tolerated side effects occur, the dose increase or dose will be reduced. When the side effects disappear or lessen, the increase will resume at a slower rate: for example, one capsule or one dispersible tablet of Madopar 100 mg + 25 mg or ½ tablet of Madopar 200 mg + 50 mg will resume. a week.
The average effective maintenance dose is usually between 600 mg of levodopa + 150 mg of benserazide and 800 mg of levodopa + 200 mg of benserazide per day, i.e. between 3-4 tablets of Madopar 200 mg + 50 mg per day, divisible into 3-4 administrations. However, the dose must be closely tailored to the individual patient's response.
Should it be necessary to exceed this average dose, it is recommended to wait a few weeks, because a fairly long period may elapse before the effect of the drug manifests itself.
Only rarely is it necessary to administer more than 5 tablets / day of Madopar 200 mg + 50 mg.
For the determination of the optimal posology, the following dosage schedule can be used as a guideline.
* the two administrations at noon and at 4 pm can be replaced with a single administration at noon of 1 tablet of Madopar 200 mg + 50 mg divisible tablets.
Maintenance therapy
As soon as the optimal dose is reached, switching from Madopar 100 mg + 25 mg to Madopar 200 mg + 50 mg becomes useful.
That is, when said optimal dose is equivalent to 6 or 8 (or more) capsules or dispersible tablets of Madopar 100 mg + 25 mg, these can be replaced with 3 or 4 (or more) tablets of Madopar 200 mg + 50 mg.
Since the improvement obtainable with the therapy may vary, the distribution of the pro / day dose in 3 or 4 administrations must be adapted to individual needs, both in terms of the number of single administrations and their distribution during the day.
Transition from levodopa to Madopar
When Madopar is to be administered to patients who have hitherto been treated with levodopa alone, the following schedule should be followed:
- decrease the dose of levodopa progressively until the parkinsonian symptoms reappear or worsen;
- then replace each single dose of 500 mg of levodopa with a capsule or a dispersible tablet of Madopar 100 mg + 25 mg or with ½ tablet of Madopar 200 mg + 50 mg divisible tablets, the effectiveness of which corresponds precisely to that of 500 mg of levodopa.
- observe the patient for a week and, if necessary, then increase the dose of Madopar until a satisfactory improvement is achieved (scheme identical to that valid for patients never treated with levodopa).
Switch to Madopar 100 mg + 25 mg prolonged-release hard capsules
In all those patients who exhibit large fluctuations in therapeutic response during the course of the day it is recommended to divide the daily dose into a larger number of administrations or preferably to use prolonged-release Madopar.
Switching to prolonged-release Madopar therapy can be done from one day to the next, maintaining the same daily dose and the same frequency of intake. After 2-3 days the dose should be gradually increased by approximately 50% due to the lower bioavailability of this special slow-release form.
Patients should be informed of the possible occurrence of a temporary worsening of their condition.
Prolonged-release Madopar, due to its pharmacokinetic properties, begins its activity in about 3 hours. Effective plasma levels can be achieved more rapidly by administering prolonged-release Madopar in combination with conventional capsules or tablets. This can be particularly beneficial in administering the morning dose, which should preferably be a little higher than the following ones.
Finding the optimal individual dose of prolonged-release Madopar should be done slowly and very carefully, waiting at least 2-3 days before varying doses.
If the response to prolonged-release Madopar is unsatisfactory even at daily doses corresponding to 1500 mg levodopa, it is preferable to return to the previous treatment with conventional capsules or tablets.
In the case of patients who over-respond to treatment, rather than intervening by reducing single doses, the interval between administrations will have to be increased.
Positive results have been reported in patients with nocturnal hypo-akinesia following the gradual increase of the last evening dose to 3 Madopar prolonged-release capsules to be taken at bedtime.
Patients must be carefully monitored in order to highlight the possible onset of side effects affecting the psychic sphere.
The dosing regimen should be carefully considered individually in all patients.
Madopar administration should last at least six months before a judgment of ineffectiveness can be made at medium doses.
As with all replacement therapies, treatment must be continuous.
04.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients. Madopar must not be administered in combination with non-selective monoamine oxidase (MAO) inhibitors. Conversely, selective MAO-B inhibitors, such as selegiline or rasagiline, or selective MAO-A inhibitors, such as moclobemide, are not contraindicated. The combination of an MAO-A inhibitor with an MAO-B is equivalent to the administration of a non-selective inhibitor and therefore should not be prescribed concomitantly with Madopar (see section 4.5).
Madopar has the same contraindications as sympathomimetics (adrenaline, noradrenaline and their derivatives).
It is also contraindicated in endocrine diseases (e.g. pheochromocytoma, hyperthyroidism, Cushing's syndrome), renal (except dialysis patients with Restless Legs Syndrome), severely decompensated liver and heart diseases (e.g. severe cardiac arrhythmias and heart failure), in the acute myocardial infarction, in severe psychoses and psychoneuroses, in malignant melanoma (possible activation by levodopa) and suspected undiagnosed skin lesions, in acute angle glaucoma. the incompleteness of skeletal development).
Madopar must not be administered to pregnant women or women of childbearing potential in the absence of adequate contraceptive protection (see section 4.6). Should a woman being treated with Madopar become pregnant, administration of the drug should be discontinued.
04.4 Special warnings and appropriate precautions for use
Patients with a history of myocardial infarction, rhythm alterations, coronary heart disease and blood pressure changes, should undergo periodic cardiovascular checks, in particular electrocardiography. Strict checks should also be performed in the case of patients with a positive history of gastro-duodenal ulcer and osteomalacia.
Hypersensitivity reactions may occur in predisposed individuals.
Patients with open angle glaucoma should have regular intraocular pressure checks as levodopa has the potential to increase intraocular pressure.
Particular care should be taken when Madopar is administered to patients with coronary artery disease, cardiac arrhythmias or heart failure (see section 4.3). Cardiac functions should be monitored with particular attention in these patients, both during the initial period of treatment and regularly during the later stages of therapy.
For patients with predisposing risk factors (e.g. elderly, or on antihypertensive or other drugs with orthostatic potential) or with a previous history of orthostatic hypotension, careful monitoring is recommended especially at the start of treatment or following dose increases. .
Treatment with Madopar has been reported to lead to decreased blood counts (haemolytic anemia, thrombocytopenia and leukopenia). In some cases agranulocytosis and pancytopenia have been reported for which the intake of Madopar cannot be considered the cause but not completely excluded. Therefore during the treatment it is necessary to carry out periodic checks of the blood count.
Depression may be part of the clinical picture in patients with Parkinson's disease and Restless Legs Syndrome and may also arise in patients treated with Madopar. All patients should be carefully monitored for psychological changes and depression associated or not with suicidal ideation.
Madopar can induce dopaminergic dysregulation syndrome resulting in overuse of the drug. A small subset of patients with Parkinson's disease have cognitive-behavioral disturbances that can be directly attributed to taking the drug in quantities greater than those recommended by the physician and well beyond the dosages required to treat their motor disabilities.
If the patient is to undergo general anesthesia a patient, normal treatment with Madopar should be continued for as long as possible before surgery, except in the case of halothane. In general anesthesia with halothane, Madopar administration should be stopped between 12 and 48 hours before surgery as blood pressure fluctuations and / or arrhythmias may occur in patients taking Madopar. Thereafter, the treatment will be resumed by reaching the previous dosage of the drug through a progressive increase in doses.
Both levodopa and benserazide are largely metabolised and less than 10% of levodopa is excreted unchanged via the kidney (see section 5.2). Therefore, no dosage reduction is necessary in cases of mild or moderate renal insufficiency.
No pharmacokinetic data are available with levodopa in patients with renal insufficiency (see section 5.2).
Levodopa is mainly metabolised by aromatic amino acid decarboxylase (see section 5.2) which is abundantly present in the intestinal tract, kidney and heart, as well as in the liver.
No pharmacokinetic data are available with levodopa in patients with hepatic impairment (see section 5.2).
Madopar administration should not be stopped abruptly. Abrupt discontinuation may lead to the onset of a malignant neuroleptic syndrome (hyperpyrexia and muscle stiffness, in some cases alterations of the psyche and increased creatine phosphokinase, in severe cases further symptoms may include myoglobinuria, rhabdomyolysis and acute renal failure), which may jeopardize the patient's survival. Faced with the onset of some of these signs and symptoms, it is necessary to keep the patient under observation, if necessary in a hospital setting, and promptly administer adequate symptomatic treatment; this may also include the resumption of the administration of Madopar, after an accurate evaluation of the case.
Levodopa has been associated with somnolence and episodes of sudden sleep attacks.
Sudden sleep attacks have been reported very rarely during daily activity, in some cases without awareness or warning signs. Patients being treated with Levodopa should be informed of these events and advised to use caution while driving or operating machinery. . Patients who have experienced episodes of somnolence and / or a sudden episode of sleep should refrain from driving and operating machinery. In addition, a reduction in dosage or discontinuation of therapy may be considered (see section 4.7).
Impulse control disorders
Patients should be monitored regularly for the development of impulse control disorders.Patients and caregivers should be aware that behavioral symptoms of impulse control disorder including pathological gambling, increased libido, hypersexuality, compulsive shopping or overspending, binge eating, and compulsive eating can occur in patients. patients treated with dopamine agonists and / or other dopaminergic treatments containing levodopa including Madopar If such symptoms develop, re-evaluation of treatment is recommended.
Diagnostic tests
During treatment with Madopar it is advisable to carry out periodic checks of the blood count and of the hepatic, renal and cardiovascular function.
In diabetic patients it is advisable to carry out numerous blood glucose checks and to adapt the dosage of antidiabetic drugs to glycemic levels.
Malignant melanoma
Epidemiological studies have shown that patients with Parkinson's disease have a higher risk of developing melanoma than the rest of the population (approximately 2-6 times higher). It is not clear whether the observed increased risk is associated with Parkinson's disease or with other factors such as the use of levodopa to treat it. Therefore, both patients and physicians are required to regularly monitor the presence of melanoma during treatment with Madopar for any indication. It is advisable to periodically undergo a skin examination carried out by qualified medical personnel (for example dermatologists).
04.5 Interactions with other medicinal products and other forms of interaction
Pharmacokinetic interactions
THE CONCOMITANT ADMINISTRATION OF THE ANTICOLINERGIC DRUG TRIESIPHENIDYL HYDROCHLORIDE WITH STANDARD DOSAGE OF MADOPAR CAPSULES OR DIVISIBLE TABLETS REDUCES THE SPEED, BUT NOT THE ENTITY, OF THE ABSORPTION OF LEVODOPA. PROLONGED-RELEASE TRIESIPHENIDYL HYDROCHLORIDE GIVEN TOGETHER WITH MADOPAR DOES NOT CHANGE THE PHARMACOKINETICS OF LEVODOPA.
Concomitant administration of antacids with Madopar prolonged-release capsules reduces the absorption of levodopa by 32%.
Ferrous sulfate reduces the maximum plasma concentration and AUC of levodopa by 30-50%. Pharmacokinetic changes observed during concomitant treatment with ferrous sulfate are clinically evident in some, but not all patients.
Metoclopramide increases the rate of absorption of levodopa.
Pharmacodynamic interactions
Neuroleptics, opioids and antihypertensives containing reserpine inhibit the activity of Madopar.
Concomitant administration of antipsychotic drugs with dopaminergic receptor blocking properties, in particular D2 receptor antagonists, could antagonize the antiparkinsonian effects of Madopar. Therefore, such administration should be performed with caution and the patient should be carefully monitored to evaluate the reduction of the anti-parkinsonian effect and the worsening of symptoms.
Administration of levodopa in combination with a decarboxylase inhibitor may cause symptomatic orthostatic hypotension in patients on antihypertensive drug therapy; Madopar should therefore be introduced with caution in patients treated with antihypertensive drugs. Blood pressure should be monitored to allow for dosage adjustments of both drugs if required.
The concomitant administration of Madopar with sympathomimetic drugs (such as adrenaline, noradrenaline, isoproterenol or amphetamine, capable of stimulating the sympathetic nervous system), may enhance the activity of the latter, therefore these combinations are not recommended. concomitant should it prove necessary a strict control of the cardiocirculatory function, and a possible reduction of the dose of sympathomimetic drugs is essential.
Irreversible and non-selective MAO inhibitors should not be combined with Madopar; treatment with the latter should not be started before at least 2 weeks have elapsed from the discontinuation of irreversible and non-selective MAOIs, otherwise undesirable effects (hypertensive crisis) are likely to appear (see section 4.3).
Selective MAO-B inhibitors, such as selegiline and rasagiline, and selective MAO-A inhibitors, such as moclobemide, can be prescribed to patients receiving Madopar; it is recommended to modify the levodopa dosage according to the needs of the individual patient, in terms of efficacy and tolerability. The combination of an MAO-A inhibitor with an MAO-B is equivalent to the administration of a non-selective inhibitor and therefore should not be prescribed concomitantly with Madopar (see section 4.3).
The concomitant administration of other antiparkinsonian drugs such as anticholinergics, amantadine and dopamine agonists is possible, but the potential for intensification of both therapeutic and unwanted effects must be taken into account. It may be necessary to reduce the dosage of Madopar or the other. drug. When initiating adjuvant treatment with a COMT inhibitor, the Madopar dosage may need to be reduced.
Switching to Madopar should not lead to abrupt discontinuation of previously used antiparkinsonian anticholinergics, as the effect of levodopa occurs after a latency period of several days.
Levodopa can alter laboratory test results for catecholamines, creatinine, uric acid and blood sugar. Coombs' test may give a false positive result in patients taking Madopar.
The therapeutic effect of Madopar is reduced if the drug is taken in conjunction with a protein-rich meal.
The concomitant intake of levodopa and Madopar must be carried out under medical supervision as the additionally administered levodopa could also be enhanced by benserazide with a consequent risk of overdose.
Vitamin B6 in medium or high doses should not be administered together with Madopar as it antagonizes the effects of levodopa: this antagonistic activity has no clinical significance in the case of vitamin B6 in low doses, such as those contained in polyvitamin preparations.
General anesthesia with halothaneMadopar should be discontinued between 12 and 48 hours prior to surgery requiring general anesthesia with halothane as blood pressure fluctuations and / or arrhythmias may occur.
In case of general anesthesia with other anesthetics, see section 4.4 (Special warnings and precautions for use).
04.6 Pregnancy and lactation
Pregnancy
Animal studies have shown the possible presence of fetal skeletal development disorders. Based on these results Madopar is absolutely contraindicated during pregnancy and in women of childbearing potential who are not practicing adequate contraception (see sections 4.3 and 5.3).
Feeding time
Since it is unclear whether benserazide is able to pass into breast milk or not, mothers requiring treatment with Madopar should not breastfeed, as the risk of skeletal malformations in infants cannot be excluded and it is therefore prudent to resort to artificial breastfeeding.
04.7 Effects on ability to drive and use machines
Patients being treated with levodopa 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 death. (eg using machines) until these recurrent episodes and sleepiness have resolved (see section 4.4).
04.8 Undesirable effects
The undesirable effects due to the peripheral activity of dopamine and observed during therapy with levodopa are significantly reduced in frequency and severity with the use of Madopar.
The following side effects have been reported to occur following administration of Madopar (frequency not known: cannot be predicted from the available data):
The categories of attendance are as follows:
Very common (≥1 / 10)
Common (≥1 / 100,
Uncommon (≥1 / 1,000 to
Rare (≥1 / 10,000,
Very rare (
Not known (frequency cannot be predicted from the available data)
* These events may occur in particular in elderly patients and in patients who have already suffered from these disorders.
Impulse control disorders: Pathological gambling, increased libido, hypersexuality, compulsive shopping or overspending, binge eating and compulsive eating may occur in patients treated with dopamine agonists and / or other dopaminergic treatments containing levodopa including Madopar (see section 4.4. Warnings special and precautions for use).
Nervous system disorders: In a later phase of the treatment, involuntary movements of the choreiform or athetotic type may appear. Fluctuations in the therapeutic response may also arise during prolonged treatments, including episodes of motor block, end-of-dose deterioration and the "on-off" phenomenon. All these secondary effects are related to the posology and disappear or are significantly reduced by decreasing the doses, while drug discontinuation is a measure only rarely necessary. If, following these measures, the response to treatment becomes unsatisfactory, a new dose increase or resumption of therapy in case of discontinuation.
Madopar can cause drowsiness; very rarely it has been associated with excessive daytime sleepiness and episodes of sudden sleep attacks.
Vascular pathologies: Orthostatic disorders usually improve with reduction of Madopar dosage.
Gastrointestinal disorders: Gastrointestinal side effects, which may occur especially during the early stages of treatment, can be considerably limited by administering Madopar at mealtimes and, in any case, with some food or drink; it is also indicated to reach the optimal dose of the drug gradually.
Musculoskeletal and connective tissue disorders: Restless Legs Syndrome: Increased symptomatology (with temporal shift of symptoms from evening / night to early afternoon and evening before taking the next dose) is the most common adverse event in long-term dopaminergic treatment.
Diagnostic tests: in the case of treatment with Madopar, a reddish color may appear in the urine, which tends to darken over time.
Madopar tolerance is identical to that observed for levodopa given alone.
Without speaking of addiction in the strict sense of the word, after several years of continuous treatment with Madopar, a decrease in the therapeutic efficacy of the product has been observed. Madopar, but to the evolution of Parkinson's disease.
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 http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Symptoms
The symptoms of overdose are qualitatively similar to the side effects of Madopar at therapeutic doses, but more severe in magnitude. Overdose can lead to: cardiovascular undesirable effects (e.g. cardiac arrhythmias), psychiatric disturbances (e.g. confusion and insomnia), gastrointestinal effects (e.g. nausea and vomiting) and abnormal involuntary movements (see section 4.8).
A small subgroup of patients with Parkinson's disease have cognitive-behavioral disorders that can be directly attributed to taking the drug in greater quantities than those recommended by the physician and well beyond the dosages required to treat their motor alterations.
If a patient has taken an overdose of Madopar in a controlled-release form (prolonged-release capsules), the onset of symptoms may be delayed due to delayed absorption of the active substance from the stomach.
Treatment
Monitor the patient's vital signs and institute supportive measures appropriate to his clinical condition. In particular, patients may require symptomatic treatment of cardiovascular effects (eg with antiarrhythmics), or central nervous system effects (eg with respiratory stimulants, neuroleptics).
In addition, in the case of the controlled release formulation, further absorption of the drug must be prevented by an appropriate method.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiparkinsonian - dopaminergic substance, ATC code: N04BA02
Dopamine, a substance that plays the role of chemical mediator at the level of the central gray nuclei, is found in the patient with Parkinson's disease in reduced concentration in the aforementioned structures. Levodopa is an intermediate of dopamine biosynthesis. As a precursor to dopamine, levodopa is used as a prodrug to increase dopamine levels, as it is able to pass the blood brain barrier, whereas dopamine cannot. Once in the central nervous system, levodopa is metabolized into dopamine by aromatic L-amino acid decarboxylase.
After administration, levodopa is rapidly decarboxylated to dopamine, and this transformation does not occur only in the brain. Hence the need to administer high doses of levodopa, which can, however, frequently cause secondary effects. It is therefore of particular therapeutic interest to block the decarboxylation process of levodopa only at the extra-cerebral level, which is obtained by administering, simultaneously with levodopa, benserazide, a decarboxylase inhibitor with peripheral action.
Clinical trials have shown that the best results are obtained by combining 4 parts of levodopa with 1 part of benserazide.
05.2 Pharmacokinetic properties
Madopar prolonged release is a special formulation that guarantees a prolonged release of the active ingredients in the stomach over time. It therefore ensures the permanence of therapeutic plasma levels of levodopa for several hours and a significant reduction in peak plasma concentrations.
Absorption
Madopar capsules and divisible tablets
Levodopa is mainly absorbed in the proximal regions of the small intestine, and absorption is site independent. The maximum plasma concentration of levodopa is reached approximately one hour after the ingestion of Madopar capsules or scored tablets.
The capsules and tablets are bioequivalent.
The maximum plasma concentration of levodopa and the extent of absorption (AUC) increase in a dose-proportional manner (50-200 mg of levodopa).
Food intake reduces the rate and extent of levodopa absorption. The maximum plasma concentration of levodopa is 30% lower and is reached later if Madopar capsules or divisible tablets are administered after a normal meal. absorption of levodopa is reduced by 15%.
Madopar dispersible tablets
The pharmacokinetic profiles of levodopa following administration of Madopar dispersible tablets in healthy volunteers and parkinsonian patients are very similar to those obtained after administration of Madopar capsules and divisible tablets, but the time to reach peak plasma concentrations tends to be longer. short with the dispersible form, which if taken as a suspension also ensures a lower inter-individual variability of the absorption parameters.
Extended-release Madopar
The pharmacokinetic properties of the prolonged-release formulation differ from those of Madopar capsules and divisible tablets and the dispersible form. The active ingredients are in fact released slowly in the stomach. The peak plasma concentrations of levodopa, 20-30% lower than that of the other forms, is reached in about 3 hours after ingestion.
The pharmacokinetic profile shows a plasma semiconcentration duration (the time during which the plasma concentration is greater than or equal to half the maximum concentration) which is clearly greater than that of the other forms of Madopar, and this denotes the characteristic of a markedly controlled release. The bioavailability of prolonged-release Madopar is approximately 60% of that of other forms and is not affected by food. The maximum plasma concentration of levodopa is not changed by food but is reached more slowly (over 5 hours) if prolonged-release Madopar is administered after a meal.
Distribution
Levodopa crosses the blood brain barrier by means of a saturable transport system. It is not bound to plasma proteins and has a volume of distribution of 57 liters. The AUC of levodopa in CSF is 12% of that in plasma.
Unlike levodopa, benserazide does not cross the blood brain barrier at therapeutic doses. It is mainly concentrated in the kidney, lung, small intestine and liver.
Biotransformation
Levodopa follows two main metabolic processes (decarboxylation and O-methylation) and two secondary ones (transamination and oxidation).
Aromatic amino acid decarboxylase converts levodopa into dopamine. The main end products of this process are homovanillic acid and dihydrophenylacetic acid. Catechol-O-methyltransferase transforms levodopa into 3-O-methyldopa. This important plasma metabolite has an elimination half-life of 15 hours and results in an accumulation process in patients receiving therapeutic doses of Madopar.
The reduced peripheral decarboxylation of levodopa when administered together with benserazide is reflected in an increase in the plasma levels of levodopa and 3-O-methyldopa and in a decrease in the plasma levels of catecholamines (dopamine, noradrenaline) and phenolcarboxylic acids (acid homovanillic acid, dihydrophenylacetic acid).
Benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and in the liver. This metabolite is a potent inhibitor of aromatic amino acid decarboxylase.
Elimination
Under conditions of reduced peripheral decarboxylation, the elimination half-life of levodopa is approximately 1.5 hours.
Plasma clearance of levodopa is approximately 430 ml / min and less than 10% is excreted unchanged via the kidney.
Elimination of benserazide occurs almost completely by metabolism. The metabolites are excreted mainly in the urine (64%) and to a lesser extent in the faeces (24%).
Special populations
No pharmacokinetic data are available in uremic patients, with renal and hepatic insufficiency.
In elderly patients (65 - 78 years) with Parkinson's disease, both the elimination half-life and the AUC of levodopa are approximately 25% higher than in younger patients (34 - 64 years). The statistical significance linked to age is clinically negligible and is of minor importance for the dosage regimen.
05.3 Preclinical safety data
Carcinogenicity
Carcinogenicity studies have not been conducted with Madopar.
Mutagenicity
Madopar and its components (levodopa and benserazide) did not appear mutagenic in the Ames test. No further data are available.
Fertility
No fertility studies have been conducted with Madopar in animals.
Teratogenicity
Teratogenicity studies revealed no teratogenic effects or effects on skeletal development in mice, rats and rabbits.
At maternally toxic dosages, intrauterine deaths (rabbits) increased and / or fetal weight decreased (rats).
Other
General toxicology studies in rats have highlighted the possibility of alterations in skeletal development.
No further relevant data are available in the animal.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Madopar 100 mg + 25 mg hard capsules
Capsule contents:
Povidone K30
Talc
Magnesium stearate
Microcrystalline cellulose
Capsule operculum:
Jelly
Red iron oxide (E172)
Titanium dioxide (E171)
Indigo carmine (E132)
Food grade printing ink (shellac gum, potassium hydroxide, black iron oxide (E172))
Madopar 200 mg + 50 mg divisible tablets
Mannitol (E421)
Anhydrous dibasic calcium phosphate
Microcrystalline cellulose
Pregelatinised starch
Crospovidone
Magnesium stearate
Ethylcellulose
Red iron oxide (E172)
Anhydrous colloidal silica
Sodium docusate
Madopar 100 mg + 25 mg prolonged-release hard capsules
Capsule contents:
Hypromellose
Hydrogenated vegetable oil
Anhydrous dibasic calcium phosphate
Mannitol (E421)
Talc
Povidone K30
Magnesium stearate
Capsule operculum:
Jelly
Indigo carmine (E132)
Titanium dioxide (E171)
Yellow iron oxide (E172)
Food grade printing ink (shellac gum, potassium hydroxide, red iron oxide (E172))
Madopar 100 mg + 25 mg dispersible tablets
Anhydrous citric acid
Pregelatinised maize starch
Microcrystalline cellulose
Magnesium stearate
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Madopar 100 mg + 25 mg hard capsules
Do not store above 30 ° C.
Keep the bottle tightly closed to protect the medicine from moisture.
Madopar 100 mg + 25 mg prolonged-release hard capsules
Do not store above 30 ° C.
Keep the bottle tightly closed to protect the medicine from moisture.
Madopar 200 mg + 50 mg divisible tablets
Do not store above 25 ° C.
Keep the bottle tightly closed to protect the medicine from moisture.
Madopar 100 mg + 25 mg dispersible tablets
Store at a temperature not exceeding 30 ° C.
Keep the bottle tightly closed to protect the medicine from moisture.
06.5 Nature of the immediate packaging and contents of the package
Dark glass bottle, with safety cap in thermoplastic material, placed in a cardboard box together with the package leaflet.
Madopar 100 mg + 25 mg hard capsules - 30 capsules
Madopar 200 mg + 50 mg divisible tablets - 50 divisible tablets
Madopar 100 mg + 25 mg prolonged-release hard capsules - 30 capsules
Madopar 100 mg + 25 mg dispersible tablets - 30 dispersible tablets
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Roche S.p.A. - Piazza Durante 11 - 20131 Milan
08.0 MARKETING AUTHORIZATION NUMBER
"100 mg + 25 mg hard capsules" 30 capsules AIC n ° 023142019
"200 mg + 50 mg divisible tablets" 50 divisible tablets AIC n ° 023142033
"100 mg + 25 mg prolonged-release hard capsules" 30 capsules AIC n ° 023142045
"100 mg + 25 mg dispersible tablets" 30 dispersible tablets AIC n ° 023142058
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Renewal: June 2010
10.0 DATE OF REVISION OF THE TEXT
February 2014
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