Active ingredients: Levodopa, Carbidopa, Entacapone
Stalevo 50 mg / 12.5 mg / 200 mg film-coated tablets
Stalevo package inserts are available for pack sizes:- Stalevo 50 mg / 12.5 mg / 200 mg film-coated tablets
- Stalevo 75 mg / 18.75 mg / 200 mg film-coated tablets
- Stalevo 100 mg / 25 mg / 200 mg film-coated tablets
- Stalevo 125 mg / 31.25 mg / 200 mg film-coated tablets
- Stalevo 150 mg / 37.5 mg / 200 mg film-coated tablets
- Stalevo 200 mg / 50 mg / 200 mg film-coated tablets
Why is Stalevo used? What is it for?
Stalevo contains three active substances (levodopa, carbidopa and entacapone) in one film-coated tablet. Stalevo is used to treat Parkinson's disease.
Parkinson's disease is caused by low levels of a substance called dopamine in the brain. Levodopa increases the dopamine level and consequently reduces the symptoms of Parkinson's disease. Carbidopa and entacapone enhance the efficacy of the antiparkinsonian effects of levodopa.
Contraindications When Stalevo should not be used
Do not take Stalevo
- if you are allergic to levodopa, carbidopa or entacapone or any of the other ingredients of this medicine
- if you have narrow-angle glaucoma (an eye disorder)
- if you have adrenal gland cancer
- if you are taking antidepressants (combinations of selective MAO-A inhibitors and MAO-B inhibitors, or non-selective MAO inhibitors)
- if you have suffered from the rare reaction to certain antipsychotic medicines known as Neuroleptic Malignant Syndrome (NMS)
- if you have suffered from a rare form of muscle disease called rhabdomyolysis of non-traumatic origin
- if you have severe liver disease.
Precautions for use What you need to know before taking Stalevo
Talk to your doctor or pharmacist before taking Stalevo if you suffer or have suffered in the past:
- a heart attack, other heart disease including arrhythmias, or blood vessels
- asthma or other lung diseases
- liver problems, as the dose may need to be adjusted
- of kidney or hormonal disorders
- stomach ulcer or convulsions.
- if you have prolonged diarrhea consult your doctor as this may be a sign of inflammation of the colon
- of serious mental disorders of any kind such as psychosis
- of chronic open-angle glaucoma, as your dose may need to be adjusted and the pressure in your eyes controlled.
Talk to your doctor if you are taking:
- antipsychotic drugs (drugs used to treat psychosis)
- a medicine that may cause low blood pressure when getting up from a sitting or lying down position. You should be aware that Stalevo can make these reactions worse.
Talk to your doctor if during treatment with Stalevo:
- you notice the onset of muscle stiffness or severe contractions, or if you experience tremors, shaking, confusion, fever, increased heart rate or severe changes in blood pressure. In such cases you should seek immediate medical attention
- you feel depressed, have suicidal intentions, or if you notice any changes in your behavior
- have sudden fits of sleep, or are particularly drowsy. If this occurs, you should not drive or use other machines (see also section "Driving and using machines").
- if you notice uncontrolled movements or if they get worse after taking Stalevo. In this case you should contact your doctor as the dosage of your antiparkinsonian medicines may need to be changed
- have diarrhea: weight control is recommended to avoid possible excessive weight loss
- experience progressive anorexia, asthenia (weakness, fatigue) and weight loss over a relatively short period of time. In this case, a general medical check-up, including liver function check, should be considered
- feel the need to stop taking Stalevo; see section "If you stop taking Stalevo".
Tell your doctor if you notice, or your family / caregivers notice that you develop strong urges or desires to behave in unusual ways or cannot resist the urge, urge or temptation to perform activities that may be harmful to you. These behaviors are called impulse control disorders and may include gambling addiction, excessive spending and eating, abnormally high sex drive, apprehension of increased sexual thoughts or desires. Your doctor may review your treatment.
During prolonged treatment with Stalevo, your doctor may regularly request laboratory investigations.
If you need to have surgery, tell your doctor that you are taking Stalevo. The use of Stalevo is not recommended for the treatment of extrapyramidal symptoms (eg involuntary movements, tremors, muscle stiffness and muscle twitching) caused by other medicines.
Children and adolescents
There is limited experience in patients under 18 years of age treated with Stalevo. Therefore, the use of Stalevo in children is not recommended.
Interactions Which drugs or foods may change the effect of Stalevo
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Do not take Stalevo if you are taking certain antidepressants (combinations of selective MAO-A inhibitors and MAO-B inhibitors, or non-selective MAO inhibitors).
Stalevo can potentiate the effects and side effects of some medicines. These include:
- medicines used to treat depression such as moclobemide, amitriptyline, desipramine, maprotiline, venlafaxine and paroxetine
- rimiterol and isoprenaline, used to treat some respiratory diseases
- adrenaline, used in case of severe allergic reactions
- norepinephrine, dopamine and dobutamine, used to treat certain heart diseases and hypotension
- alpha-methyldopa, used to treat hypertension
- apomorphine, used to treat Parkinson's disease.
The effects of Stalevo may be diminished by some medicines. These include:
- dopaminergic antagonists used to treat some mental disorders, nausea and vomiting
- phenytoin, used to prevent seizures
- papaverine, used to relax muscles.
Stalevo may make it more difficult for iron to be absorbed. It is therefore not recommended to take Stalevo at the same time as iron supplements. Stalevo and iron-containing medicines should be taken at least 2-3 hours apart.
Stalevo with food and drink
Stalevo can be taken with or without food. For some patients, Stalevo may not be well absorbed when taken with, or soon after, protein-rich foods (such as meat, fish, dairy, seeds and nuts). Consult your doctor if you think this is the case for you.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
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 taking this medicine.
Women should not breastfeed while being treated with Stalevo.
Driving and using machines
Stalevo can lower blood pressure and this can cause light-headedness and dizziness. Take special care when driving and using machines.
If you experience drowsiness or sudden sleep attacks, wait for a full recovery before resuming driving or doing anything else that requires vigilance. Failure to do so could expose himself and others to serious risk and even death.
Stalevo contains sucrose
Stalevo contains sucrose (1.2 mg / tablet). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Stalevo: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Adult and elderly patients:
- Your doctor will tell you exactly how many Stalevo tablets to take each day.
- The tablet is not meant to be divided into smaller parts.
- Take only one tablet at a time.
- Based on your response to therapy, your doctor may recommend a higher or lower dose.
- If you take Stalevo tablets 50 mg / 12.5 mg / 200 mg, 75 mg / 18.75 mg / 200 mg, 100 mg / 25 mg / 200 mg, 125 mg / 31.25 mg / 200 mg or 150 mg / 37 , 5 mg / 200 mg, do not take more than 10 tablets a day.
If you have the impression that the effect of Stalevo is too strong or too weak, or if you get possible side effects, talk to your doctor or pharmacist.
Opening the bottle for the first time: Open the closure and then press the seal with your thumb until it breaks.
Overdose What to do if you have taken too much Stalevo
If you take more Stalevo than you should
Tell your doctor or pharmacist immediately if you have accidentally taken more Stalevo tablets than you should have taken. In the event of an overdose you may feel confused or agitated, your heart rate may speed up or slow down, or the color of your skin, tongue, eyes or urine may change.
If you forget to take Stalevo
Do not take a double dose to make up for a forgotten tablet.
If it is more than an hour until the next dose:
Take one tablet as soon as you remember and the next one at the scheduled time.
If it is less than an hour until your next dose:
Take a tablet as soon as you remember, wait one "now, then take" another tablet. Then carry on as normal.
Always leave at least one hour between successive doses of Stalevo to avoid possible side effects.
If you stop taking Stalevo
Do not stop taking Stalevo unless your doctor tells you to. In this case, your doctor may find that you need to adjust the dose of the other antiparkinsonian medicines you are taking, especially levodopa, to adequately control your symptoms. Abrupt discontinuation of treatment with Stalevo and other antiparkinsonian medicines may result in undesirable effects.
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 Stalevo
Like all medicines, this medicine can cause side effects, although not everybody gets them. Many of the side effects can be reduced simply by adjusting the dose.
If you experience the following symptoms while being treated with Stalevo, please contact your doctor immediately:
- Muscle stiffness or severe twitching, tremors, shaking, confusion, fever, increased heart rate or severe changes in blood pressure. These may represent symptoms of neuroleptic malignant syndrome (NMS, a rare and severe reaction to medicines used to treat central nervous system disorders) or rhabdomyolysis (a rare and severe muscle disorder).
- An allergic reaction, the signs of which may include hives, itching, rash, swelling of the face, lips, tongue or throat. The latter can cause difficulty in breathing or swallowing.
Very common (may affect more than 1 in 10 people)
- involuntary movements (dyskinesia)
- feeling sick (nausea)
- harmless reddish-brown staining of urine
- muscle aches
- diarrhea
Common (may affect up to 1 in 10 people)
- lightheadedness or fainting due to low blood pressure, increased blood pressure - worsening of Parkinsonian symptoms, dizziness, sleepiness
- vomiting, abdominal pain and discomfort, heartburn, dry mouth, constipation,
- insomnia, hallucinations, confusion, abnormal dreams (including nightmares), tiredness
- mental disorders including memory problems, anxiety and depression (including suicidal intentions)
- heart disease or artery problems (e.g. chest pain), irregular heart rhythm or rate
- higher frequency of falls
- shortness of breath
- increased sweating, rash
- muscle cramps, swelling in the legs
- blurred vision
- anemia
- decreased appetite, weight decreased
- headache, joint pain
- urinary tract infection
Uncommon (may affect up to 1 in 100 people)
- heart attack
- intestinal bleeding
- changes in blood cells which can cause bleeding, abnormal liver function tests
- convulsions
- agitation
- psychotic symptoms
- colitis (inflammation of the colon)
- discoloration other than urinary (e.g. skin, nails, hair, sweat)
- difficulty swallowing, difficulty urinating
The following side effects have also been reported:
- hepatitis (inflammation of the liver)
- itch
You may develop the following side effects:
- Inability to resist the urge to perform an action that could be harmful, which may include:
- strong urge to gamble excessively, despite serious personal or family consequences;
- altered or increased sexual interests and behaviors that are of significant concern to you or others, for example an increased sex drive;
- uncontrollable excessive purchases or spending;
- binge eating (eating large amounts of food in a short time) or compulsive eating (eating more food than usual and more than is necessary to satisfy hunger).
Tell your doctor if you experience any of these behaviors; will discuss a way to address or reduce these symptoms.
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 listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the bottle and carton after "EXP". The expiry date refers to the last day of that month
This medicine does not require any special storage conditions.
Do not throw 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.
What Stalevo contains
- The active substances in Stalevo are levodopa, carbidopa and entacapone.
- Each Stalevo 50 mg / 12.5 mg / 200 mg tablet contains 50 mg of levodopa, 12.5 mg of carbidopa and 200 mg of entacapone.
- The other ingredients of the tablet core are croscarmellose sodium, magnesium stearate, maize starch, mannitol (E421) and povidone (E1201).
- The other ingredients in the tablet coating are glycerol (85 percent) (E422), hypromellose, magnesium stearate, polysorbate 80, red iron oxide (E172), sucrose, titanium dioxide (E171) and yellow iron oxide (E172).
What Stalevo looks like and contents of the pack
Stalevo 50 mg / 12.5 mg / 200 mg: round, convex, brown or reddish-gray, non-divisible film-coated tablets engraved with 'LCE 50' on one side.
Stalevo 50 mg / 12.5 mg / 200 mg tablets are available in six packs (containing 10, 30, 100, 130, 175 or 250 tablets). Not all pack sizes may be marketed.
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
STALEVO 50 MG / 12.5 MG / 200 MG
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 50mg of levodopa, 12.5mg of carbidopa and 200mg of entacapone.
Excipient with known effects:
Each tablet contains 1.2 mg of sucrose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Round, convex, unbreakable, brown or reddish-gray film-coated tablet, engraved with "LCE 50" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Stalevo is indicated for the treatment of adult patients with Parkinson's disease who have "end-of-dose" motor fluctuations that are not stabilized on levodopa / dopa decarboxylase (DDC) inhibitor treatment.
04.2 Posology and method of administration
Dosage
The optimal daily dose should be determined after careful adjustment of levodopa for each patient. The daily dose should preferably be optimized using one of the seven strengths available for the product (50mg / 12.5mg / 200mg, 75mg / 18.75mg / 200mg, 100mg / 25mg / 200mg, 125mg / 31.25 mg / 200 mg, 150 mg / 37.5 mg / 200 mg, 175 mg / 43.75 mg / 200 mg or 200 mg / 50 mg / 200 mg levodopa / carbidopa / entacapone).
Patients should be instructed to take only one Stalevo tablet for each administration.Patients who receive a carbidopa dosage of less than 70-100 mg per day are more likely to experience nausea and vomiting. While experience using a total daily dose of carbidopa greater than 200 mg is limited, the maximum recommended dose for entacapone is 2000 mg, so the maximum dose is 10 tablets per day for Stalevo 50 mg / 12.5 doses. mg / 200 mg, 75 mg / 18.75 mg / 200 mg, 100 mg / 25 mg / 200 mg, 125 mg / 31.25 mg / 200 mg, and 150 mg / 37.5 mg / 200 mg. Ten tablets of Stalevo 150 mg / 37.5 mg / 200 mg corresponds to 375 mg of carbidopa per day. Based on this daily dose of carbidopa, the maximum recommended dose for Stalevo 175 mg / 43.75 mg / 200 mg is 8 tablets per day, and for Stalevo 200 mg / 50 mg / 200 mg it is 7 tablets per day.
In general, Stalevo should be used in patients treated with corresponding doses of standard levodopa / dopa decarboxylase inhibitor and entacapone preparations.
How to change the therapy from levodopa preparations / DDC inhibitors (carbidopa or benserazide) and entacapone tablets to Stalevo.
to. Patients undergoing treatment with entacapone and standard levodopa / carbidopa preparations in doses equal to the corresponding strengths of Stalevo can be given the correspondingly strengthened Stalevo tablets directly. For example, a patient taking one 50 mg / 12.5 mg levodopa / carbidopa tablet and one 200 mg entacapone tablet four times a day may take one Stalevo 50 mg / 12.5 mg / 200 mg tablet for four times a day instead of the usual dose of levodopa / carbidopa and entacapone.
b. When initiating therapy with Stalevo in patients receiving entacapone and levodopa / carbidopa in doses not corresponding to the Stalevo 50 mg / 12.5 mg / 200 mg (or 75 mg / 18.75 mg / 200 mg or 100 mg / 25 mg / 200 mg or 125 mg / 31.25 mg / 200 mg or 150 mg / 37.5 mg / 200 mg or 175 mg / 43.75 mg / 200 mg or 200 mg / 50 mg / 200 mg ), the dose of Stalevo should be carefully adjusted for optimal clinical response. In the beginning, Stalevo should be adjusted to correspond as closely as possible to the total daily dose being used.
c. When initiating therapy with Stalevo in patients who are already being treated with entacapone and levodopa / benserazide in a standard release formulation, it is advisable to stop the administration of levodopa / benserazide the previous evening and start the administration of Stalevo the following morning. The starting dose of Stalevo should contain the same or slightly (5-10%) higher amount of levodopa.
How to transfer patients not treated with entacapone to Stalevo
Stalevo therapy can be initiated at a dose matching that of current therapy in some patients with Parkinson's disease who have "end-of-dose" motor fluctuations who are not stabilized on levodopa / DDC inhibitor treatment. However, direct switching from levodopa / DDC inhibitors to Stalevo is not recommended for patients with dyskinesia or taking a levodopa daily dose greater than 800 mg. In such patients it is advisable to introduce entacapone treatment as a separate treatment (entacapone tablets) and then adjust the levodopa dose if necessary, before switching to Stalevo.
Entacapone potentiates the effects of levodopa. Therefore, it may be necessary, especially in patients presenting with dyskinesia, to reduce the levodopa dose by 10-30% in the first days or weeks after starting treatment with Stalevo. The daily dose of levodopa can be reduced by extending the dose. interval between doses and / or reducing the amount of levodopa with each administration, taking into account the patient's clinical condition.
Dose adjustment during treatment
When more levodopa is required, an increase in the frequency of administration and / or the use of a different strength of Stalevo, within the recommended dose limits, should be considered.
When less levodopa is required, the total daily dose of Stalevo should be decreased by reducing the frequency of administration by extending the interval between doses, or by decreasing the dosage of Stalevo at one dose.
In case of concomitant use of Stalevo and other levodopa medicinal products, the maximum dose recommendations should be followed.
Discontinuation of Stalevo therapy: If treatment with Stalevo (levodopa / carbidopa / entacapone) is stopped and the patient is switched to levodopa / DDC inhibitor therapy without entacapone, the dosage of the other antiparkinsonian therapies should be adjusted to achieve sufficient control of parkinsonian symptoms.
Pediatric population: The safety and efficacy of Stalevo in children below the age of 18. There are no data available.
Elderly patients: No dose adjustment of Stalevo is necessary for elderly patients.
Patients with hepatic insufficiency: It is recommended that Stalevo be administered with caution in patients with mild to moderate hepatic impairment. The dosage may need to be reduced (see section 5.2). In case of severe hepatic insufficiency, see section 4.3.
Patients with renal insufficiency: Renal insufficiency does not affect the pharmacokinetics of entacapone. No special studies on the pharmacokinetics of levodopa and carbidopa have been reported in patients with renal insufficiency, therefore therapy with Stalevo should be administered with caution to patients with severe renal insufficiency, including those on dialysis (see section 5.2).
Method of administration
Each tablet should be taken orally with or without food (see section 5.2). One tablet contains one dose for treatment and should only be administered whole.
04.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Severe hepatic insufficiency.
- Closed-angle glaucoma.
- Pheochromocytoma.
- Concomitant administration of Stalevo with a non-selective monoamine oxidase inhibitor (MAO-A and MAO-B) (e.g. phenelzine, tranylcypromine).
- Concomitant administration with a selective MAO-A inhibitor and with a selective MAO-B inhibitor (see section 4.5).
- Previous history of Neuroleptic Malignant Syndrome (NMS) and / or rhabdomyolysis of non-traumatic origin.
04.4 Special warnings and appropriate precautions for use
- Stalevo is not recommended for the treatment of drug-induced extrapyramidal reactions.
- Stalevo therapy should be administered with caution in patients with ischemic disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal or endocrine disease, or with a history of peptic ulcer or seizures.
- In patients with a history of myocardial infarction, who have residual arrhythmias in the atrial or ventricular node: cardiac function should be closely monitored during the first dose adjustment period.
- All patients treated with Stalevo should be carefully monitored for the development of mental disorders, depression with suicidal intentions and other severe antisocial behaviors. Patients with past or current episodes of psychosis should be treated with caution.
- The concomitant administration of antipsychotic drugs with dopaminergic receptor blocking properties, especially D2 receptor antagonists, must be performed with great caution and the patient must be carefully observed for the loss of the antiparkinsonian effect or for the aggravation of his symptoms.
- Patients with chronic open angle glaucoma can be treated with Stalevo with caution as long as the intraocular pressure is well controlled and the patient is followed closely for any changes in intraocular pressure.
- Stalevo can cause orthostatic hypotension. Therefore Stalevo should be administered with caution to patients who are taking other medicinal products that can cause orthostatic hypotension.
- Entacapone in combination with levodopa has been associated with somnolence and episodes of sudden sleep onset in patients with Parkinson's disease. Therefore, caution should be exercised when driving or using machines (see section 4.7).
- In clinical trials, dopaminergic-type adverse reactions (e.g. dyskinesia) were more frequent in patients receiving entacapone and dopamine agonists (e.g. bromocriptine), selegiline or amantadine, compared to those receiving placebo and the same combination. . Doses of other antiparkinsonian therapies may need to be adjusted when entacapone treatment is initiated.
- Onset of rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has rarely been observed in patients with Parkinson's disease. Therefore any abrupt reduction in dose or discontinuation of levodopa treatment should be observed with caution, especially in treated patients. simultaneously with neuroleptics. NMS, including rhabdomyolysis and hyperthermia, is characterized by motor symptoms (rigidity, myoclonia, tremor), mental status changes (eg agitation, confusion, coma), hyperthermia, autonomic nervous system dysfunction (tachycardia , blood pressure instability) and elevated serum creatine phosphokinase levels. In special cases, only some of these signs and / or symptoms may be manifest. Early diagnosis is important for appropriate treatment of NMS. After abrupt discontinuation of antiparkinsonian agents, a syndrome resembling neuroleptic malignant syndrome has been described and includes muscle stiffness, elevated body temperature, altered mental status and increased serum creatine phosphokinase. In controlled clinical trials in which entacapone is abruptly stopped, no cases of NMS or rhabdomyolysis have been reported in association with entacapone treatment. Since marketing, isolated cases of NMS have been reported in association with entacapone treatment, especially after abrupt reduction or discontinuation entacapone and other concomitant dopaminergic drugs. When necessary, the replacement of Stalevo with levodopa and DDC inhibitor without entacapone or other dopaminergic medicinal products should occur progressively and an increase in the levodopa dose may be required.
- If general anesthesia is required, Stalevo therapy can be continued as long as the patient can take fluids and medicines by mouth. In case of need for temporary suspension of therapy, treatment with Stalevo can be resumed at the same dose as soon as the patient is able to take oral medicines again.
- During prolonged therapy with Stalevo, periodic monitoring of hepatic, haematopoietic, cardiovascular and renal function is recommended.
- In patients who have experienced episodes of diarrhea, monitoring of body weight is recommended to avoid excessive weight loss. Persistent or prolonged diarrhea that appears during the use of entacapone may be a sign of colitis. In case of persistent or prolonged diarrhea, the drug should be discontinued and appropriate medical investigation and therapy considered. .
- Patients should be monitored regularly for the development of impulse control disorders. Patients and their carers should be aware that behavioral symptoms of impulse control disorders, including pathological gambling, may occur in patients treated with dopamine agonists and / or other dopaminergic treatments containing levodopa including Stalevo. increased libido, hypersexuality, compulsive shopping or shopping, binge eating and compulsive eating If these symptoms develop, it is recommended that treatment be reviewed.
- For patients who experience progressive anorexia, asthenia and weight loss over a relatively short period of time, a general medical check-up, including liver function check, should be considered.
- The combination of levodopa / carbidopa may be responsible for false positive test results for urinary ketones using dipstick. This reaction does not change by bringing the urine sample to a boil. The use of glucose oxidase methods may cause false negative results for glycosuria.
- Stalevo contains sucrose, therefore patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase deficiency should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Other antiparkinsonian medicines: To date, there is no indication of interactions that could preclude the use of standard antiparkinsonian medicinal products concomitantly with Stalevo. In high doses, entacapone may interfere with the absorption of carbidopa. However, no interaction has been observed with the recommended treatment regimen (200 mg entacapone up to 10 times daily). Interactions between entacapone and selegiline were investigated in repeat dose studies in patients with Parkinson's disease treated with levodopa / DDC inhibitor. No findings were found. interaction: When combined with Stalevo, the daily dose of selegiline should not exceed 10 mg.
Particular care should be taken with concomitant administration of the following drugs and levodopa therapy.
Antihypertensives: Symptomatic postural hypotension may occur if levodopa is added to the treatment of patients already receiving antihypertensive agents. The dose of the antihypertensive agent may need to be adjusted.
Antidepressants: Rarely, reactions including hypertension and dyskinesia have been reported with concomitant use of tricyclic antidepressant agents and levodopa / carbidopa. In single-dose studies in healthy volunteers, interactions between entacapone and imipramine, and between entacapone and moclobemide have been studied. no drug interaction was observed. A significant number of patients with Parkinson's disease were treated with the combination levodopa, carbidopa and entacapone and several other drugs, including MAO-A inhibitors, tricyclic antidepressants, reuptake inhibitors norepinephrine, such as desipramine, maprotiline and venlafaxine, medicines that are metabolized by COMTs (e.g. compounds containing a catechol group, paroxetine). No pharmacodynamic interactions were observed. However, special care should be taken when these medicinal products are combined with Stalevo (see sections 4.3 and 4.4).
Other drugs: Dopamine receptor antagonists (eg some antipsychotic and antiemetic agents), phenytoin and papaverine may decrease the therapeutic effect of levodopa. Patients treated with these products concomitantly with Stalevo should be followed closely for loss of response. therapeutic.
Because of the affinity shown in vitro against cytochrome P450 2C9 (see section 5.2), Stalevo has the potential to interfere with drugs whose metabolism depends on this isoenzyme, such as the S-warfarin isomer. However, in an interaction study performed in healthy volunteers, entacapone did not changed plasma levels of S-warfarin, while the AUC value for the R-warfarin isomer increased on average by 18% [CI90 11-26%]. INR values increased on average by 13% [CI90 11-26%]. CI90 6-19%] Therefore, in patients receiving warfarin, it is recommended that INR checks be carried out when starting the administration of Stalevo.
Other forms of interaction: As levodopa competes with some amino acids, the absorption of Stalevo may be impaired in some patients on a high protein diet.
Levodopa and entacapone can form chelates with iron in the gastrointestinal tract. Therefore Stalevo and iron preparations should be taken at least 2-3 hours apart (see section 4.8).
In vitro data: Entacapone binds to the binding site II of human albumin to which several other medicinal products also bind, including diazepam and ibuprofen. Considering the in vitro studies, no significant displacement is expected at therapeutic concentrations of the medicinal products. no indication of such interactions.
04.6 Pregnancy and lactation
Pregnancy
There are no adequate data from the use of the levodopa / carbidopa / entacapone combination in pregnant women. Studies in animals have shown reproductive toxicity of the individual components (see section 5.3). The potential risk for humans is unknown.
Stalevo should not be used during pregnancy unless the possible benefits to the mother outweigh the possible risk to the fetus.
Feeding time
Levodopa is excreted in milk. There is evidence that breastfeeding is inhibited during levodopa treatment. In animal studies, carbidopa and entacapone were excreted in milk, but it is not known whether these products are also excreted in human milk. The safety of levodopa is not known. carbidopa and entacapone in infants Women should not breastfeed during treatment with Stalevo.
Fertility
No adverse reactions on fertility were observed in separate preclinical studies with entacapone, carbidopa or levodopa.Animal fertility studies involving the combination of entacapone, levodopa and carbidopa have not been conducted.
04.7 Effects on ability to drive and use machines
Stalevo may impair the ability to drive or use machines. Levodopa, carbidopa and entacapone given in combination can cause dizziness and symptomatic standing. Therefore, caution should be exercised when driving and operating machinery.
Patients being treated with Stalevo who experience 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 serious risk or death (for eg use of machines), until these recurrent episodes have resolved (see section 4.4).
04.8 Undesirable effects
to. Summary of the safety profile
The most frequently reported side effects with Stalevo are dyskinesias, which occur in approximately 19% of patients; gastrointestinal symptoms including nausea and diarrhea, which occur in approximately 15% and 12% of patients, respectively; muscle, musculoskeletal and connective tissue pain, occurring in approximately 12% of patients; and harmless reddish-brown discoloration of the urine (chromaturia), which occurs in approximately 10% of patients. Serious adverse reactions such as gastrointestinal haemorrhage (uncommon) and angioedema (rare) have been reported from clinical trials with Stalevo or entacapone used in combination with levodopa / DDC inhibitor. Severe hepatitis, mainly cholestatic in nature, rhabdomyolysis and neuroleptic malignant syndrome can occur with Stalevo, although no cases have emerged from clinical trial data.
b. Table of adverse reactions
The following adverse drug reactions, listed in Table 1, were collected from both data from eleven double-blind clinical studies involving 3230 patients (1810 treated with Stalevo or entacapone in combination with levodopa / DDC inhibitor, and 1420 treated with placebo in combination with levodopa / DDC inhibitor or with cabergoline in combination with levodopa / DDC inhibitor), and from post-marketing reports of entacapone for use in combination with levodopa / DDC inhibitors.
Adverse reactions are ranked by frequency, starting with the most frequent and according to the following conventional scale: Very common (≥ 1/10); common (≥ 1/100,
Table 1. Adverse reactions
Disorders of the blood and lymphatic system
Common: Anemia
Uncommon: Thrombocytopenia
Metabolism and nutrition disorders
Common: Weight loss *, decreased appetite *
Psychiatric disorders
Common: Depression, hallucinations, confusional state *, abnormal dreams *, anxiety, insomnia
Uncommon: Psychosis, agitation *
Not known: Suicidal behavior
Nervous system disorders
Very common: Dyskinesia *
Common: Worsening of parkinsonism (e.g. slowness of movement) *, tremor, on-off phenomenon, dystonia, cognitive dysfunction (e.g. memory impairment, dementia), somnolence, dizziness *, headache
Not known: Neuroleptic malignant syndrome *
Eye disorders
Common: Vision blurred
Cardiac pathologies
Common: Ischemic events other than myocardial infarction (eg angina pectoris) **, heart rhythm irregularity
Uncommon: Myocardial infarction **
Vascular pathologies
Common: Orthostatic hypotension, hypertension
Uncommon: Gastrointestinal haemorrhage
Respiratory, thoracic and mediastinal disorders
Common: Dyspnoea
Gastrointestinal disorders
Very common: Diarrhea *, nausea *
Common: Constipation *, vomiting *, dyspepsia, abdominal pain and discomfort *, dry mouth *
Uncommon: Colitis *, dysphagia
Hepatobiliary disorders
Uncommon: Abnormal liver function test values *
Not known: Hepatitis mainly cholestatic type (see section 4.4) *
Skin and subcutaneous tissue disorders
Common: Rash *, hyperhidrosis
Uncommon: Discolouration of skin, nails, hair or sweat *
Rare: Angioedema
Not known: Urticaria *
Musculoskeletal and connective tissue disorders
Very common: Muscle, musculoskeletal and connective tissue pain *
Common: Muscle cramps, arthralgia
Not known: Rhabdomyolysis *
Renal and urinary disorders:
Very common: Chromaturia *
Common: Urinary tract infection
Uncommon: Urinary retention
General disorders and administration site conditions
Common: Chest pain, peripheral edema, falls, gait abnormalities, asthenia, fatigue
Uncommon: Malaise
* Adverse reactions attributable mainly to entacapone or which are more frequent (according to frequency difference of at least 1% from clinical studies) with entacapone compared to levodopa / DDC inhibitors. See section c.
** The incidence rates of "myocardial infarction and other ischemic events (0.43% and 1.54%, respectively) are derived from an" analysis of 13 double-blind studies involving 2082 patients with daily motor fluctuations of " end of dose "who were taking entacapone.
c. Description of particular adverse reactions
Adverse reactions mainly attributable to entacapone, or which are more frequent with entacapone than levodopa / DDC, are indicated with an asterisk in Table 1, section 4.88b. Some of these adverse reactions are related to increased dopaminergic activity (eg, dyskinesia, nausea and vomiting) and occur more commonly at initiation of therapy. Reducing the levodopa dose reduces the severity and frequency of these dopaminergic reactions. Some adverse reactions are known to be attributable to the active substance entacapone, including diarrhea and a reddish-brown discoloration of the urine. Sometimes entacapone can also lead to discolouration, eg of skin, nails, hair and sweat. Other adverse reactions, indicated with an asterisk in Table 1, section 4.8b, are reported based on their major frequency (frequency difference of at least 1%) observed in clinical trials using entacapone versus levodopa / DDCI therapy, or from post-marketing individual case safety reports of entacapone.
Seizures have rarely occurred with levodopa / carbidopa; however a causal relationship with levodopa / carbidopa therapy has not been established.
Impulse Control Disorders: Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating, and compulsive eating may occur in patients treated with dopamine agonists and / or other dopaminergic treatments containing levodopa including Stalevo ( see section 4.4).
Entacapone combined with levodopa has been associated with isolated cases of excessive daytime sleepiness and episodes of sudden sleep onset.
04.9 Overdose
The data collected after the marketing of the product include some isolated cases of overdose in which the maximum daily doses reported for levodopa and entacapone were at least 10,000 mg and 40,000 mg respectively. Acute symptoms and signs observed in such overdose cases included agitation, confusion, coma, bradycardia, ventricular tachycardia, Cheyne-Stoke's breath, pigmentation changes in the skin, tongue and conjunctiva, and chromaturia. Treatment of acute overdose with Stalevo is similar to levodopa overdose. However, pyridoxine is not effective in reversing the action of Stalevo. Hospitalization of the patient with the application of general supportive measures is recommended, as well as gastric lavage and repeated doses of charcoal: this can speed up the "elimination of entacapone" in particular by decreasing its absorption / reabsorption by the gastrointestinal tract. The adequacy of the respiratory, circulatory and renal systems should be carefully monitored, applying suitable support measures. ECG monitoring should be instituted and the patient monitored closely for possible cardiac arrhythmias. If necessary, appropriate antiarrhythmic therapy should be given. Consideration should also be given to whether the patient may have taken some other medicinal product besides Stalevo. The utility of dialysis in the treatment of overdose is unknown.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmaco-therapeutic category: antiparkinsonian drugs, dopa and its derivatives.
ATC code: N04BA03.
In light of current knowledge, the symptoms of Parkinson's disease are related to dopamine depletion in the striatum. Dopamine does not cross the blood brain barrier. Levodopa, a precursor of dopamine, crosses the blood-brain barrier and relieves the symptoms of the disease. Since levodopa is extensively metabolised peripherally, only a small amount of a given dose reaches the central nervous system when levodopa is administered without metabolic enzyme inhibitors.
Carbidopa and benserazide are peripheral DDC inhibitors which reduce the peripheral metabolism of levodopa to dopamine, thereby increasing the amount of levodopa available in the brain. When levodopa decarboxylation is decreased with concomitant administration of a DDC inhibitor, a lower dosage of levodopa can be used, and consequently the incidence of adverse reactions such as nausea is also reduced.
With decarboxylase inhibition by a DDC inhibitor, catechol-O-methyltransferase (COMT) becomes the major metabolic pathway that catalyzes the conversion of levodopa to 3-O-methyldopa (3-OMD), a potentially harmful metabolite of levodopa Entacapone is a reversible and specific inhibitor of COMT with mainly peripheral action, designed to be administered in combination with levodopa preparations. Entacapone slows the clearance of levodopa from the bloodstream resulting in an increase in the AUC in the pharmacokinetic profile of levodopa. As a result, the clinical response to each dose is increased and prolonged.
The evidence for the therapeutic effects of Stalevo is based on two double-blind phase III studies conducted in a total of 376 Parkinson's disease patients with "end-of-dose" motor fluctuations daily, to whom entacapone or placebo were administered with each dose. of levodopa / decarboxylase inhibitor preparations. The daily "on" period with and without entacapone was recorded in daily patient diaries. In the first study, entacapone increased the mean daily "on" period by 1 h and 20 min (95% CI 45 min, 1 h 56 min) from baseline This corresponds to an 8.3% increase in the daily "on" period. Likewise, the decrease in the daily "off" period was 24% in the entacapone group and 0% in the placebo group. In the second study, the mean daily "on" period increased 4.5% (95% CI 0.93%, 7.97%) from baseline. This corresponds to an average increase of 35 min in the daily "on" period. Likewise, the daily "off" period decreased by 18% in patients treated with entacapone and by 5% in those treated with placebo. Since the effects of the Stalevo tablets are equal to those of the entacapone 200 mg tablet administered in combination with standard commercially available carbidopa / levodopa preparations in equivalent doses, these results can also be applied to the description of the effects of Stalevo.
05.2 "Pharmacokinetic properties
General characteristics of the active ingredient
Absorption / distribution: There are substantial variations between individuals and within the same individual in the absorption of levodopa, carbidopa and entacapone. Both levodopa and entacapone are rapidly absorbed and eliminated. Carbidopa is absorbed and eliminated somewhat more slowly than levodopa. When administered separately from the other two active substances, the bioavailability is 15-33% for levodopa, 40-70% for carbidopa, and 35% for entacapone after an oral dose of 200 mg. Foods rich in large neutral amino acids can delay and decrease the absorption of levodopa. Food does not significantly affect the absorption of entacapone. The volume of distribution of both levodopa (Vd 0.36-1.6 l / kg) that of entacapone (Vdss 0.27 l / kg) is relatively modest, while no corresponding data are available for carbidopa.
Levodopa binds to plasma proteins only to a lesser extent of 10-30% and carbidopa binds to an extent of approximately 36%, while entacapone binds extensively to plasma proteins (approximately 98%) - mainly albumin. serum. At therapeutic concentrations, entacapone does not displace other strongly bound drugs (such as warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it significantly displaced by any of these drugs at therapeutic or higher concentrations.
Biotransformation and elimination : Levodopa is extensively metabolised to various metabolites: the main pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT).
Carbidopa is reduced to two major metabolites which are excreted in the urine in the form of glucuronides and unconjugated compounds. Unchanged carbidopa accounts for approximately 30% of the total urinary excretion.
Entacapone is metabolised almost completely prior to its elimination via the urine (10-20%) and the bile and faeces (80-90%). The main metabolic pathway is the glucuronidation of entacapone and its active metabolite, the "cis- isomer, which represents about 5% of the total amount in plasma.
Total clearance for levodopa is in the range of 0.55 to 1.38 l / kg / h and for entacapone this is in the range of 0.70 l / kg / h. The elimination half-life (t½) it is 0.6-1.3 hours for levodopa, 2-3 hours for carbidopa and 0.4-0.7 hours for entacapone, each administered separately.
Due to the short elimination half-lives, no true accumulation of entacapone occurs after repeated administration.
Data from studies conducted in vitro on human liver microsome preparations indicate that entacapone inhibits cytochrome P450 2C9 (IC50 4 mcM). Entacapone demonstrated low or no inhibitory activity for other types of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19): (see section 4.5).
Characteristics in patients
Senior citizens: When administered without carbidopa and entacapone, the absorption of levodopa is higher and its elimination is slower in elderly subjects than in younger subjects. However, when combining carbidopa with levodopa, the absorption of levodopa is similar between elderly and young subjects. , but the AUC is still 1.5 times higher in the elderly due to increased DDC activity and reduced clearance due to age. There are no significant differences in the AUC of carbidopa or entacapone between younger (45-64 years) and older (65-75 years) subjects.
Sex: The bioavailability of levodopa is significantly higher in female than in male subjects. In the pharmacokinetic studies with Stalevo, the bioavailability of levodopa was higher in women than in men, mainly due to differences in body weight, while there was no gender difference with carbidopa and entacapone.
Liver failure: The metabolism of entacapone is slowed in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B), resulting in a higher plasma concentration of entacapone in both the absorption and elimination phases (see sections No particular studies on the pharmacokinetics of carbidopa and levodopa have been reported in patients with hepatic insufficiency, however it is recommended that Stalevo be administered with particular care in patients with mild or moderate hepatic insufficiency.
Kidney failure: Renal insufficiency does not affect the pharmacokinetics of entacapone. No special studies on the pharmacokinetics of levodopa and carbidopa have been reported in patients with renal insufficiency. However, a longer interval between administrations of
Stalevo in patients undergoing dialysis (see section 4.2).
05.3 Preclinical safety data
Preclinical data on levodopa, carbidopa and entacapone, studied alone or in combination, did not reveal any particular risk for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Cases of anemia have been observed in repeat dose toxicity studies, most likely due to entacapone's ability to chelate iron. Regarding reproductive toxicity, decreased fetal weight and a slight delay in bone development were observed in rabbits exposed to the therapeutic range. Both levodopa and combinations of carbidopa and levodopa caused visceral and skeletal malformations in rabbits.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet: Croscarmellose sodium; magnesium stearate; cornstarch; mannitol (E421); povidone K30 (E1201).
Coating: Glycerol (85%) (E422); hypromellose; magnesium stearate; polysorbate 80; red iron oxide (E172); sucrose; titanium dioxide (E171); yellow iron oxide (E172).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
High density polyethylene bottle with child resistant polypropylene closure.
Pack sizes: 10, 30, 100, 130, 175 or 250 tablets.
Not all pack sizes may be marketed
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations
07.0 MARKETING AUTHORIZATION HOLDER
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/03/260 / 001-004
036825014
036825026
036825038
036825040
EU / 1/03/260/013
036825139
EU / 1/03/260/016
036825166
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 17 October 2003
Date of most recent renewal: October 17, 2008
10.0 DATE OF REVISION OF THE TEXT
12/2012
