Active ingredients: Pramipexole
MIRAPEXIN 0.088 mg tablets
MIRAPEXIN 0.18 mg tablets
MIRAPEXIN 0.35 mg tablets
MIRAPEXIN 0.7 mg tablets
MIRAPEXIN 1.1 mg tablets
Indications Why is Mirapexin used? What is it for?
MIRAPEXIN contains the active substance pramipexole and belongs to a group of medicines known as dopamine agonists which stimulate dopamine receptors located in the brain. Stimulation of dopamine receptors in the brain triggers nerve impulses that help control body movements.
MIRAPEXIN is used for:
- the treatment of symptoms of idiopathic Parkinson's disease in adults. It can be used alone or in combination with levodopa (another medicine for Parkinson's disease).
- the treatment of moderate to severe idiopathic Restless Legs Syndrome (RLS) in adults.
Contraindications When Mirapexin should not be used
Do not take MIRAPEXIN
- if you are allergic to pramipexole or any of the other ingredients of this medicine
Precautions for use What you need to know before taking Mirapexin
Talk to your doctor before taking MIRAPEXIN. Tell your doctor if you have (had) or develop any medical conditions or symptoms, especially if they belong to the following list:
- Kidney disease.
- Hallucinations (seeing, hearing or feeling things that are not there). Most hallucinations are visual.
- Dyskinesia (e.g. abnormal, uncontrolled limb movements). If you have advanced Parkinson's disease and are also taking levodopa, you may develop dyskinesia during the titration of MIRAPEXIN.
- Somnolence and sudden sleep episodes.
- Psychosis (e.g. comparable with symptoms of schizophrenia).
- Vision alteration. Your eyesight should be checked regularly during treatment with MIRAPEXIN.
- Severe diseases of the heart or blood vessels. Especially at the start of treatment, your blood pressure will need to be checked regularly. This is to avoid postural hypotension (the drop in blood pressure when standing up).
- Worsening. You may find that symptoms appear earlier than usual, are more intense, and involve other limbs.
Tell your doctor if you, your family or caregivers notice that you are developing an urge or desire to behave in ways that are unusual for you and that you cannot resist the urge, urge or temptation to do certain activities that can harm yourself or others. Such phenomena are called impulse control disorders and can include behaviors such as gambling addiction, excessive eating or spending, unusually high sexual desire or worry due to increased thoughts or of sexual sensations Your doctor may need to adjust your dose or discontinue therapy
Tell your doctor if you or a family member or caregiver notice that you are developing mania (agitation, feeling euphoric or over-excited) or delirium (reduced awareness, confusion, loss of sense of reality). The doctor may find it necessary to adjust the dose or discontinue therapy
Children and adolescents
The use of MIRAPEXIN is not recommended in children or adolescents below 18 years of age
Interactions Which drugs or foods may change the effect of Mirapexin
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Including medicines, herbal preparations, dietary products or supplements obtained without a prescription.
You should avoid taking MIRAPEXIN in combination with antipsychotic medicines.
Pay attention if you are taking the following medicines:
- cimetidine (to treat excess stomach acid and stomach ulcers);
- amantadine (which can be used to treat Parkinson's disease);
- mexiletine (to treat irregular heartbeats, a condition known as ventricular arrhythmia);
- zidovudine (which can be used to treat acquired immunodeficiency syndrome (AIDS), a disease of the human immune system);
- cisplatin (to treat various types of cancer);
- quinine (which can be used to prevent painful nocturnal cramps and to treat a type of malaria known as falciparum malaria (malignant malaria));
- procainamide (to treat irregular heartbeats).
If you are taking levodopa, it is recommended that the dose be reduced when starting treatment with MIRAPEXIN.
Pay attention if you are taking any calming medicine (sedative effect) or if you are drinking alcohol. In these cases MIRAPEXIN may impair your ability to drive or use machines.
MIRAPEXIN with food, drink and alcohol
You should be careful if you drink alcohol while taking MIRAPEXIN.
MIRAPEXIN can be taken with or without food.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Your doctor will discuss with you whether to continue taking MIRAPEXIN.
The effect of MIRAPEXIN on fetuses is not known. Therefore do not take MIRAPEXIN if you are pregnant unless your doctor tells you to.
MIRAPEXIN should not be taken during breastfeeding. MIRAPEXIN may reduce milk production. It may also pass into milk and reach the baby. If MIRAPEXIN is unavoidable, breastfeeding should be stopped.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
MIRAPEXIN can cause hallucinations (seeing, hearing or feeling things that are not there). If this happens, do not drive or use machines
MIRAPEXIN has been associated with somnolence and sudden sleep episodes, particularly in patients with Parkinson's disease. If you experience these side effects, avoid driving or using machines. Tell your doctor if this happens.
Dose, Method and Time of Administration How to use Mirapexin: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor. Your doctor will advise you on the correct dosage.
MIRAPEXIN can be taken with or without food. The tablets should be swallowed with water.
Parkinson's disease
The daily dose should be taken divided into 3 equal doses.
During the first week, the usual dose is 1 tablet of MIRAPEXIN 0.088 mg three times a day (equivalent to 0.264 mg a day):
This dose will be increased every 5 to 7 days as directed by your doctor until symptoms are controlled (maintenance dose).
The usual maintenance dose is 1.1 mg per day. However, its dose can also be further increased. If necessary, your doctor may increase the dose of tablets up to a maximum of 3.3 mg per day of pramipexole. A lower maintenance dose of three MIRAPEXIN 0.088 mg tablets per day is also possible.
Patients with kidney disease
If you have moderate or severe kidney disease your doctor will prescribe a lower dose for you. In this case, you will only need to take the tablets once or twice a day. If you have moderate kidney disease, the usual starting dose is 1 tablet of MIRAPEXIN 0.088 mg twice a day. In the case of severe kidney disease, the usual starting dose is only 1 tablet of MIRAPEXIN 0.088 mg per day.
Restless Legs Syndrome
The dose is usually taken once a day in the evening, 2 - 3 hours before going to bed. During the first week, the usual dose is 1 MIRAPEXIN 0.088 mg tablet once a day (equivalent to 0.088 mg a day):
This dose will be increased every 4 to 7 days as directed by your doctor until symptoms are controlled (maintenance dose).
The daily dose should not exceed 6 tablets of MIRAPEXIN 0.088 mg or a dose of 0.54 mg (0.75 mg of pramipexole salt).
If you stop taking it for more than a few days and intend to resume treatment, you must start again at the lower dose. You can then return to your dose as you did the first time. Ask your doctor for advice.
Your doctor will review your treatment after 3 months to decide whether to continue it or not.
Patients with kidney disease
If you have severe kidney disease, treatment with MIRAPEXIN may not be suitable for you.
Overdose What to do if you have taken an overdose of Mirapexin
If you take more MIRAPEXIN than you should
If you take too many tablets by mistake,
- contact your doctor immediately or go to the emergency room of the nearest hospital.
- Vomiting, restlessness or any of the side effects described in the chapter (Possible side effects) may occur.
If you forget to take MIRAPEXIN
Do not worry. Simply skip the dose completely then take the next one at the usual time.
Do not take a double dose to make up for a forgotten dose.
If you stop taking MIRAPEXIN
Do not stop taking MIRAPEXIN without talking to your doctor first. If you have to stop taking this medicine, your doctor will reduce your dose gradually. This reduces the risk of your symptoms getting worse.
If you suffer from Parkinson's disease, you should not stop treatment with MIRAPEXIN abruptly. A "sudden stop could lead to the development of a medical condition called neuroleptic malignant syndrome which can pose a greater health risk. Symptoms include:
- akinesia (loss of muscle movement),
- muscle stiffness,
- fever,
- unstable blood pressure,
- tachycardia (increased heart rate),
- confusion,
- reduced level of consciousness (e.g. coma).
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 Mirapexin
Like all medicines, this medicine can cause side effects, although not everybody gets them. The evaluation of these side effects is based on the following frequencies:
Very common, it may affect more than 1 in 10 people
Common may affect up to 1 in 10 people
Uncommon, it may affect up to 1 in 100 people
Rare may affect up to 1 in 1,000 people
Very rare, it may affect up to 1 in 10,000 people
S.and suffer from Parkinson's disease, you may develop the following side effects:
Very common:
- Dyskinesia (e.g. involuntary, abnormal limb movements)
- Drowsiness
- Dizziness
- Nausea (feeling sick)
Common:
- An impulse to behave in an unusual way
- Hallucinations (seeing, hearing or feeling things that are not there)
- Confusion
- Tiredness (feeling of fatigue)
- Lack of sleep (insomnia)
- Fluid retention, usually in the legs (peripheral edema)
- Headache
- Hypotension (low blood pressure)
- Abnormal dreams
- Constipation
- Changes in vision
- Vomiting (feeling sick)
- Weight loss accompanied by decreased appetite
Uncommon:
- Paranoia (e.g. excessive fear of one's own well-being)
- Delirium
- Excessive daytime sleepiness and sudden sleep episodes
- Amnesia (memory disturbances)
- Hyperkinesia (increased movement and inability to remain calm)
- Weight gain
- Allergic reactions (e.g. rash, itching, hypersensitivity)
- Fainting
- Heart failure (heart problems which can cause shortness of breath or swollen ankles) *
- Inappropriate antidiuretic hormone secretion *
- Restlessness
- Dyspnea (difficulty breathing)
- Hiccup
- Pneumonia (infection of the lungs)
- Inability to resist the urge, urge or temptation to take an action that may be harmful to you or others, which can include:
- Strong impulse to gamble excessively despite serious personal or family consequences.
- Altered or increased sexual interest and behavior that causes you or others significant concern, for example, an increase in sex drive.
- Excessive and uncontrollable shopping or spending.
- Binge eating (eating large amounts of food in a short period of time) or compulsive eating (eating more food than normal and more than is needed to satisfy your appetite) *
- Delirium (reduced awareness, confusion, loss of a sense of reality)
Rare:
- Mania (agitation, feeling of euphoria or overexcitement)
Tell your doctor if you experience any of these behaviors; will explain how to manage or reduce your symptoms.
For undesirable effects marked with * it is not possible to make a precise frequency estimate as these undesirable effects were not observed in clinical studies among 2,762 patients treated with pramipexole. The frequency category is probably not greater than "uncommon".
If you suffer from Restless Legs Syndrome, you may develop the following side effects:
Very common:
- Nausea (feeling sick)
Common:
- Sleep disturbances, such as difficulty sleeping (insomnia) and sleepiness
- Tiredness (feeling of fatigue)
- Headache
- Abnormal dreams
- Constipation
- Dizziness
- Vomiting (feeling sick)
Uncommon:
- Impulse to behave in an unusual way *
- Heart failure (heart problems which can cause shortness of breath or swollen ankles) *
- Inappropriate antidiuretic hormone secretion *
- Dyskinesia (e.g. involuntary, abnormal limb movements)
- Hyperkinesia (increased movement and inability to remain calm) *
- Paranoia (e.g. excessive fear for one's own well-being) *
- Delirium*
- Amnesia (memory disturbances) *
- Hallucinations (seeing, hearing or feeling things that are not there)
- Confusion
- Excessive daytime sleepiness and sudden sleep episodes
- Weight gain
- Hypotension (low blood pressure)
- Fluid retention, usually in the legs (peripheral edema)
- Allergic reactions (e.g. rash, itching, hypersensitivity)
- Fainting
- Restlessness
- Changes in vision
- Weight loss accompanied by decreased appetite
- Dyspnea (difficulty breathing)
- Hiccup
- Pneumonia (infection of the lungs) *
- Inability to resist the urge, urge or temptation to take an action that may be harmful to you or others, which can include:
- Strong urge to gamble excessively despite serious personal or family consequences. *
- Altered or increased sexual interest and behavior that causes you or others significant concern, for example, an increased sex drive. *
- Shopping or excessive and uncontrollable spending. *
- Binge eating (eating large amounts of food in a short period of time) or compulsive eating (eating more food than normal and more than is needed to satisfy your appetite) *
- Mania (agitation, feeling of euphoria or overexcitement) *
- Delirium (reduced awareness, confusion, loss of sense of reality) *
Tell your doctor if you experience any of these behaviors; will explain how to manage or reduce your symptoms.
For undesirable effects marked with * it is not possible to make a precise frequency estimate as these undesirable effects were not observed in clinical studies among 1,395 patients treated with pramipexole. The frequency category is probably not greater than "uncommon".
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
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 carton after EXP. The expiry date refers to the last day of that month.
Do not store above 30 ° C.
Store in the original package to protect the medicine from light.
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 MIRAPEXIN contains
The active ingredient is pramipexole
Each tablet contains 0.088 mg, 0.18 mg, 0.35 mg, 0.7 mg or 1.1 mg of pramipexole as 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, or 1.5 mg, respectively. of pramipexole dihydrochloride monohydrate.
The other ingredients are: mannitol, maize starch, anhydrous colloidal silica, povidone K25, magnesium stearate
What MIRAPEXIN looks like and contents of the pack
MIRAPEXIN 0.088 mg tablets are white, round, flat and are not breakable
MIRAPEXIN 0.18 mg and MIRAPEXIN 0.35 mg tablets are white, oval-shaped and flat. They are engraved on both sides and can be divided in half.
MIRAPEXIN 0.7 mg and MIRAPEXIN 1.1 mg tablets are white, round and flat. They are engraved on both sides and can be divided in half.
All tablets have the Boehringer Ingelheim logo embossed on one face and the codes P6, P7, P8, P9, or P11 on the other, represent the strength of the tablet, 0.088 mg, 0.18 mg, 0.35 mg, 0 respectively. , 7 mg and 1.1 mg.
All strengths of MIRAPEXIN are available in aluminum blisters of 10 tablets each, packed in cartons containing 3 or 10 blisters (30 or 100 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
MIRAPEXIN 0.7 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 1.0 mg of pramipexole dihydrochloride monohydrate equivalent to 0.7 mg of pramipexole.
Note:
The doses of pramipexole published in the literature refer to the salt, therefore the doses will be expressed in terms of both pramipexole base and pramipexole salt (in brackets).
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Tablet.
The tablets are white, flat, round, scored on both sides and have a code embossed (on one side the code P9 and on the other the Boehringer Ingelheim logo).
The tablets can be divided into equal halves.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
MIRAPEXIN is indicated in adults for the symptomatic treatment of idiopathic Parkinson's disease, either alone (without levodopa) or in combination with levodopa, i.e. during the course of the disease, in an advanced stage when the effect of levodopa wears off or becomes discontinuous and fluctuations of the "therapeutic effect (fluctuations at end of dose or" on / off ").
MIRAPEXIN is indicated in adults for the symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome in doses up to 0.54 mg of base (0.75 mg of salt) (see section 4.2).
04.2 Posology and method of administration
Dosage
Parkinson's disease
The daily dose is administered 3 times a day in equal doses.
Initial treatment
Doses should be gradually increased starting with 0.264 mg of base (0.375 mg of salt) per day and then increased every 5-7 days. For each patient it is necessary to gradually increase the dose until the maximum therapeutic benefit is achieved, provided that no serious side effects appear.
If a further dose increase is required, the daily dose may be increased by 0.54 mg of base (0.75 mg of salt) at weekly intervals up to a maximum dose of 3.3 mg of base (4.5 mg of salt) per day. However, it is noted that at doses above 1.5 mg / day (of salt) cases of somnolence are more frequent (see section 4.8 Undesirable effects).
Maintenance treatment
The individual dose of pramipexole for each patient should be between 0.264 mg of base (0.375 mg of salt) and a maximum of 3.3 mg of base (4.5 mg of salt) per day. In clinical studies, during dose escalation, pramipexole was shown to be effective starting at a dose of 1.1 mg of base (1.5 mg of salt) per day. Further dose adjustments should be made taking into account the clinical response and the incidence of adverse reactions. In clinical studies, approximately 5% of patients were treated with doses below 1.1 mg of base (1.5 mg of salt). In advanced Parkinson's disease, daily doses above 1.1 mg of base (1.5 mg of salt) may be effective in patients where a reduction in levodopa therapy is desired. It is recommended that the levodopa dose be reduced both during dose escalation of MIRAPEXIN and during maintenance therapy, based on individual patient response (see section 4.5).
Discontinuation of treatment
Abrupt discontinuation of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome. Pramipexole should be gradually decreased in amounts of 0.54 mg of base (0.75 mg of salt per day until the daily dose is reduced to 0.54 mg of base (0.75 mg of salt) Thereafter the dose should be reduced by 0.264 mg of base (0.375 mg of salt) per day (see section 4.4).
Patients with renal impairment
Elimination of pramipexole is dependent on renal function. The following dosage schedule is suggested to initiate therapy:
Patients with creatinine clearance greater than 50 ml / min do not require a reduction in daily dose or frequency of administration.
In patients with creatinine clearance between 20 and 50 ml / min the daily dose of MIRAPEXIN should be divided into two doses, starting with 0.088 mg of base (0.125 mg of salt) twice daily (0.176 mg of base / 0.25 mg of salt per day). The maximum daily dose of 1.57 mg of base (2.25 mg of salt) should not be exceeded.
In patients with creatinine clearance less than 20 ml / min MIRAPEXIN should be administered as a once daily dose starting at 0.088 mg of base (0.125 mg of salt) per day.
If renal function decreases during maintenance therapy, the daily dose of MIRAPEXIN should be reduced by the same percentage decrease in creatinine clearance; for example if creatinine clearance decreases by 30%, the daily dose of MIRAPEXIN should be reduced by 30%. The daily dose should be administered twice if creatinine clearance is between 20 and 50ml / min, and once daily if creatinine clearance is less than 20ml / min.
Patients with hepatic impairment
The presence of hepatic impairment is unlikely to require any dose reduction, as approximately 90% of the absorbed active substance is excreted via the kidneys. However, the potential influence of hepatic insufficiency on the pharmacokinetics of MIRAPEXIN is not known.
Pediatric population
The safety and efficacy of MIRAPEXIN in children below 18 years of age have not been established. There is no relevant use of MIRAPEXIN in the pediatric population in Parkinson's disease.
Restless Legs Syndrome
The recommended starting dose of MIRAPEXIN is 0.088 mg of base (0.125 mg of salt) taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days to a maximum of 0.54 mg of base (0.75 mg of salt) per day (as indicated in the table below).
The patient's response should be evaluated after 3 months of treatment and the need for continued treatment should be reconsidered. If treatment is interrupted for more than a few days, it should be restarted with dose titration as indicated above.
Discontinuation of treatment
Since the daily dose for the treatment of Restless Legs Syndrome does not exceed 0.54 mg of base (0.75 mg of salt) MIRAPEXIN administration can be discontinued without tapering off. In a 26-week placebo-controlled study, after abrupt discontinuation of treatment, a rebound effect (worsening of RLS symptom severity compared to baseline) was seen in 10% of patients (14 out of 135). This effect was similar for all doses.
Patients with renal impairment
Elimination of pramipexole is dependent on renal function. Patients with creatinine clearance greater than 20 ml / min do not require a reduction in daily dose.
The use of MIRAPEXIN has not been studied in patients undergoing hemodialysis or in patients with severe renal impairment.
Patients with hepatic impairment
No dosage adjustment is required in patients with hepatic insufficiency, as approximately 90% of the absorbed active substance is excreted via the kidneys.
Pediatric population
The use of MIRAPEXIN is not recommended in children and adolescents below 18 years due to a lack of data on safety and efficacy.
Tourette's syndrome
Pediatric population
The use of MIRAPEXIN is not recommended in children and adolescents below 18 years as safety and efficacy have not been established in this population. MIRAPEXIN should not be used in children or adolescents with Tourette's syndrome due to a negative benefit-risk balance for this disease (see section 5.1).
Method of administration
The tablets should be administered orally, swallowed with water, with or without food.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
When prescribing MIRAPEXIN to patients with renal impairment with Parkinson's disease, a dose reduction is suggested as described in section 4.2.
Hallucinations
A known undesirable effect of treatment with dopamine agonists and levodopa is the onset of hallucinations. Patients should be advised that hallucinations (especially visual) may occur.
Dyskinesia
In advanced Parkinson's disease, dyskinesia may occur in combination with levodopa during the initial titration of MIRAPEXIN. If this happens the levodopa dose should be decreased.
Sudden onset of sleep and somnolence episodes
Pramipexole can cause somnolence and sudden sleep episodes, particularly in patients with Parkinson's disease. In rare cases, sudden onset sleep has been reported during daytime activities, sometimes without warning or warning signs. Patients being treated with MIRAPEXIN should be informed of this and cautioned to exercise caution while driving or operating machines. Patients who have experienced somnolence and / or a sudden onset of sleep should refrain. driving or using machines while being treated with MIRAPEXIN. In addition, dose reduction or discontinuation of therapy may be considered. Due to possible additive effects, caution should be advised when patients take sedative medicinal products or alcohol in combination with pramipexole (see sections 4.5, 4.7 and 4.8).
Impulse control disorders
Patients should be monitored regularly for the development of impulse control disorders. Patients and their carers should be advised that behavioral symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive shopping or shopping, eating, may occur in patients treated with dopamine agonists, including MIRAPEXIN. binge eating and compulsive eating If such symptoms develop, dose reduction / gradual withdrawal should be considered.
Mania and delirium
Patients should be monitored regularly for the development of mania and delirium. Patients and their carers should be aware that mania and delirium can occur in patients treated with pramipexole. If such symptoms develop, dose reduction / gradual withdrawal should be considered.
Patients with psychotic disorders
Patients with psychotic disorders should be treated with dopamine agonists only if the potential benefits outweigh the potential risks.
Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see section 4.5).
Ophthalmological checks
Ophthalmological checks are recommended at regular intervals or if vision changes occur.
Severe cardiovascular disease
In case of severe cardiovascular disease, special attention is required. Blood pressure monitoring is recommended, especially at the start of treatment, due to the general risk of postural hypotension associated with dopaminergic therapy.
Neuroleptic malignant syndrome
Symptoms of neuroleptic malignant syndrome have been reported following abrupt discontinuation of dopaminergic therapy (see section 4.2).
Worsening
Literature data indicate that treatment of Restless Legs Syndrome with dopaminergic drugs can cause it to worsen.
Worsening involves early onset of symptoms in the evening (or even in the afternoon), exacerbation of symptoms, and spread of symptoms to involve other extremities. The phenomenon of worsening (augmentation) was specifically studied in a controlled clinical study lasting 26 weeks. Augmentation was observed in 11.8% of patients on pramipexole therapy (N = 152) and in 9.4% of patients on placebo (N = 149). The Kaplan-Meier analysis evaluating the time required for the onset of worsening (augmentation) did not reveal significant differences between the two treatment groups, pramipexole and placebo.
04.5 Interactions with other medicinal products and other forms of interaction
Plasma protein binding
Pramipexole has very low affinity for plasma proteins (biotransformation observed in humans is minimal. Therefore, interactions with other medicinal products affecting plasma protein binding or elimination by biotransformation are unlikely. Since anticholinergics are eliminated mainly by biotransformation, the possibility of interaction is limited, although an "interaction with anticholinergics has not been studied. There is no" pharmacokinetic interaction with selegiline and levodopa.
Inhibitors / competitors of active renal elimination
Cimetidine resulted in a reduction in the renal clearance of pramipexole by approximately 34%, presumably through inhibition of secretion by the cationic transport system of the renal tubules. Therefore, medicinal products that inhibit this active renal elimination mechanism or are eliminated via this pathway, such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine and procainamide, can interact with pramipexole resulting in a decrease in clearance. opportunity for a reduction in the dose of pramipexole.
Combination with levodopa
When MIRAPEXIN is given in combination with levodopa it is recommended to reduce the dose of levodopa and to keep the dose of the other antiparkinsonian medicinal products constant while increasing the dose of MIRAPEXIN.
Due to possible additive effects, caution should be advised when patients take sedative medicinal products or alcohol in combination with pramipexole (see sections 4.4, 4.7 and 4.8).
Antipsychotic Medicines
Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see section 4.4) for example if antagonistic effects can be expected.
04.6 Pregnancy and lactation
Pregnancy
Effects on pregnancy and lactation in women have not been studied. Pramipexole was not teratogenic in rats and rabbits, but was embryotoxic in rats at maternally toxic dosages (see section 5.3). MIRAPEXIN should not be used. during pregnancy unless clearly necessary, i.e. only if the potential benefits justify the potential risks to the fetus.
Feeding time
Since treatment with pramipexole inhibits the secretion of prolactin in humans, inhibition of lactation may occur.
In women, no studies on the excretion of pramipexole in human milk have been performed. In rats, the concentration of the active substance, assessed by radiolabelling, in milk is higher than in blood. As no clinical data are available, MIRAPEXIN should not be administered during lactation. "feeding time. However, if its administration is necessary, breastfeeding should be discontinued.
Fertility
No studies on the effects of pramipexole on human fertility have been conducted. In animal studies, pramipexole altered oestrus cycles and reduced fertility in females, as expected for a dopamine agonist. However, these studies did not show direct or indirect effects on male fertility.
04.7 Effects on ability to drive and use machines
MIRAPEXIN affects the ability to drive or use machines.
Hallucinations or drowsiness may occur.
Patients treated with MIRAPEXIN who experience somnolence and / or sudden onset sleep episodes should be advised not to drive or engage in activities where insufficient alertness could put them or others at risk of serious accident or death ( eg.running machines) until the recurrence of such episodes and somnolence have disappeared (see also sections 4.4, 4.5 and 4.8).
04.8 Undesirable effects
Adverse reactions expected
The following adverse reactions are expected with the use of MIRAPEXIN: abnormal dreams, amnesia, behavioral symptoms of impulse control disorders and compulsions such as binge eating, compulsive shopping, hypersexuality, pathological gambling, heart failure, mental confusion, constipation , delirium, dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, hypotension, inappropriate antidiuretic hormone secretion, insomnia, libido changes, nausea, paranoia, peripheral edema, pneumonia, pruritus, rash and other hypersensitivity reactions; restlessness, somnolence, sudden sleep episodes, syncope, visual changes including diplopia, blurred vision and visual acuity decreased, vomiting, weight loss accompanied by decreased appetite, weight gain.
Based on the pooled data analysis of the placebo studies, comprising a total of 1923 patients treated with pramipexole and 1,354 patients treated with placebo, adverse reactions were frequently reported in both groups. 63% of patients treated with pramipexole and 52% of placebo-treated patients reported at least one adverse reaction.
Tables 1 and 2 show the frequency of adverse drug reactions from placebo-controlled clinical trials for both Parkinson's disease and Restless Legs Syndrome. The adverse drug reactions reported in these tables are those that occurred in 0.1% or more of patients treated with pramipexole and that were reported significantly more often in patients treated with pramipexole than in those treated with placebo, or where the reaction was deemed clinically relevant. Most adverse drug reactions have been mild to moderate, they usually occur at the start of therapy and then mostly disappear with continued treatment.
Within the system organ classes, adverse reactions are listed by frequency (number of patients expected to experience the reaction), using the following values: (very common (≥ 1/10); common (≥ 1/100,
Parkinson's disease, most common adverse events
The most commonly reported adverse drug reactions (≥ 5%) in patients with Parkinson's disease more frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache and feeling of fatigue. The incidence of somnolence is higher at doses greater than 1.5 mg of salt per day (see section 4.2). A more frequent adverse drug reaction in association with levodopa has been dyskinesia. Hypotension may occur early in the day. treatment, especially if pramipexole is titrated too quickly.
Table 1: Parkinson's disease
1 This undesirable effect has been observed in post-marketing experience. With 95% certainty, the frequency category is not greater than uncommon, but could be lower. An accurate estimate of frequency is not possible as the undesirable effect is not occurred in the clinical trial database of 2,762 Parkinson's disease patients treated with pramipexole.
Restless Legs Syndrome, most common adverse reactions
The most commonly reported adverse drug reactions (≥ 5%) in patients with Restless Legs Syndrome treated with pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were reported more often in female patients treated with pramipexole (20.8% and 10.5%, respectively) when compared with men (6.7% and 7.3% respectively).
Table 2: Restless Legs Syndrome
1 This undesirable effect has been observed in post-marketing experience. With 95% certainty, the frequency category is not greater than uncommon, but could be lower. An accurate estimate of frequency is not possible as the undesirable effect is not occurred in the clinical trial database of 1,395 patients with Restless Legs Syndrome treated with pramipexole.
Drowsiness
Pramipexole is commonly associated with somnolence and has been associated uncommonly with excessive daytime sleepiness and sudden sleep episodes (see also section 4.4).
Changes in libido
Pramipexole may uncommonly be associated with changes in libido (increase or decrease).
Impulse control disorders
Pathological gambling, increased libido, hypersexuality, compulsive shopping or shopping, binge eating and compulsive eating may occur in patients treated with dopamine agonists, including MIRAPEXIN (see section 4.4).
In a cross-sectional, retrospective screening and case-control study of 3,090 patients with Parkinson's disease, 13.6% of all patients treated with dopaminergic or non-dopaminergic drugs had symptoms of impulse control disorder during the past six months. Manifestations observed included pathological gambling, compulsive shopping, binge eating, and compulsive sexual behavior (hypersexuality). Possible independent risk factors for impulse control disorders included dopaminergic treatments and higher doses of dopaminergic treatment, younger age (≤ 65 years), being unmarried and patient-reported familiarity with pathological gambling.
Heart failure
In clinical trials and post-marketing experience, heart failure has been reported in patients treated with pramipexole. In a pharmacoepidemiological study the use of pramipexole was associated with an increased risk of heart failure when compared with the non-use of pramipexole (observed hazard ratio of 1.86; 95% CI, 1.21-2.85). .
04.9 Overdose
There is no direct experience of an overdose; however, the expected adverse reactions should be those related to the pharmacodynamic profile of a dopamine agonist, therefore: nausea, vomiting, hyperkinesis, hallucinations, agitation and hypotension. There is no established antidote for dopamine agonist overdose. If signs of central nervous system stimulation are present, a neuroleptic agent may be employed. Treatment of overdose may require general supportive measures along with gastric lavage, intravenous fluid administration, activated charcoal, and electrocardiographic monitoring.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code: N04BC05.
Mechanism of action
Pramipexole is a dopamine agonist and binds with high selectivity and specificity to the receptors of the D2 subfamily of dopamine, in which it has a preferential affinity for the D3 receptors; it is endowed with complete intrinsic activity.
Pramipexole alleviates Parkinsonian motor deficits by stimulating dopamine receptors in the striatum. Preclinical studies have shown that pramipexole inhibits dopamine synthesis, release and turnover.
The mechanism of action of pramipexole in the treatment of Restless Legs Syndrome is unknown. Neuropharmacological evidence suggests involvement of the primary dopaminergic system.
Pharmacodynamic effects
A dose-dependent decrease in prolactin was observed in healthy volunteers. In a clinical study in healthy volunteers, where MIRAPEXIN prolonged-release tablets were titrated faster than recommended (every 3 days) up to 3.15 mg pramipexole base (4.5 mg of salt) per day, it was An increase in blood pressure and heart rate was observed. This effect was not seen in patient studies.
Clinical efficacy and safety in Parkinson's disease
In patients, pramipexole relieves the signs and symptoms of idiopathic Parkinson's disease. Placebo-controlled clinical trials involved approximately 1,800 patients with Hoehn and Yahr stages I to V treated with pramipexole. Of these, approximately 1,000 patients were in the most advanced stage of the disease, received concomitant levodopa therapy, and suffered from motor complications.
In early and late stage Parkinson's disease, the efficacy of pramipexole in controlled clinical trials was maintained for approximately six months. In the open-label follow-up lasting more than three years, there was no sign of decrease in effectiveness.
In a two-year double-blind controlled clinical trial, initial treatment with pramipexole significantly delayed the onset of motor complications and when compared to initial levodopa treatment, reduced their frequency. The delayed motor complications achieved with pramipexole should counterbalance the greater efficacy of levodopa on motor function (as measured by the mean change in the UPDRS score). The overall incidence of hallucinations and somnolence was generally higher during the titration phase in the pramipexole group. However, there was no significant difference during the maintenance phase. These aspects should be considered when initiating treatment with pramipexole in patients with Parkinson's disease.
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with MIRAPEXIN in all subsets of the pediatric population in Parkinson's disease (see section 4.2 for information on pediatric use).
Clinical efficacy and safety in Restless Legs Syndrome
The efficacy of pramipexole was evaluated in four placebo-controlled clinical trials in approximately 1,000 patients with moderate to very severe idiopathic Restless Legs Syndrome.
The mean change from baseline in the Restless Legs Syndrome (IRLS) measurement scale and the "Overall Clinical Impression-Improvement (CGI-I)" were the primary efficacy parameters of the results. Differences were observed for both primary parameters. statistically significant for the pramipexole 0.25 mg, 0.5 mg and 0.75 mg pramipexole salt groups compared to placebo. After 12 weeks of treatment the baseline IRLS score decreased from 23.5 to 14.1 points for placebo and 23.4 to 9.4 points for pramipexole (combined doses). The adjusted mean difference was -4.3 points (95% CI -6.4; -2.1 points, by p
In a placebo-controlled study with polysomnography over 3 weeks MIRAPEXIN significantly reduced the number of periodic limb movements during bed time.
In a placebo-controlled clinical trial, the "long-term efficacy of pramipexole was evaluated. After 26 weeks of treatment, c" was an adjusted mean reduction in the IRLS total score of 13.7 points and 11.1 points. in the pramipexole group and the placebo group, respectively, with a statistically significant mean difference (p = 0.008) of -2.6. Responder rates on the CGI-I scale (improved, much improved) were 50.3% (80/159) for placebo and 68.5% (111/162) for pramipexole (p = 0.001) which correspond to a number needed to treat (NNT) of 6 patients (95% CI: 3.5, 13.4).
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with MIRAPEXIN in one or more subsets of the pediatric population in Restless Legs Syndrome (see section 4.2 for information on pediatric use).
Clinical efficacy and safety in Tourette's syndrome
The efficacy of pramipexole (0.0625-0.5 mg / day) in pediatric patients aged 6-17 years with Tourette's syndrome was evaluated in a 6-week, double-blind, randomized, controlled versus placebo, flexible dose. A total of 63 patients (43 treated with pramipexole, 20 with placebo) were randomized. The primary endpoint was change from baseline in Total Tic Score (TTS) measured according to Yale Global Tic Severity Scales (YGTSS). No difference was observed between pramipexole and placebo for either the primary endpoint or any of the secondary efficacy endpoints including YGTSS total score, Patient Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI). -I) or the Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of patients belonging to the pramipexole group and most common in pramipexole-treated patients compared with placebo-treated patients are states: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%), nausea (18.6%, placebo 10.0%), vomiting (11.6% , placebo 0.0%), upper abdominal pain (7.0%, placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection (7.0%, placebo 5 , 0%). Other significant adverse events leading to discontinuation of study treatment for patients receiving pramipexole were confusion, speech disturbances and aggravated condition (see section 4.2).
05.2 Pharmacokinetic properties
Absorption
After oral administration, pramipexole is rapidly and completely absorbed. Absolute bioavailability is greater than 90% and maximum plasma concentration occurs between 1 and 3 hours. Food intake does not reduce the extent of absorption of pramipexole but does reduce its rate. Pramipexole exhibits linear kinetics and low inter-patient variability in plasma levels.
Distribution
In humans, the protein binding of pramipexole is very low (plasma).
Biotransformation
In humans, pramipexole is metabolised only to a small extent.
Elimination
The major route of elimination of pramipexole is renal excretion, in unchanged form.
About 90% of the absorbed 14C-labeled drug is excreted via the kidneys, while 2% is found in the faeces. Total clearance of pramipexole is approximately 500 mL / min and renal clearance is approximately 400 mL / min. The half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.
05.3 Preclinical safety data
Repeated dose toxicity studies have shown that pramipexole exerts functional effects, mainly involving the central nervous system and the female reproductive system, possibly due to the drug's excessive pharmacodynamic effect.
In the guinea pig, decreases in diastolic and systolic pressure and heart rate were observed; a tendency to a hypotensive effect was noted in the monkey.
The potential effects of pramipexole on reproductive function were studied in rats and rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in rats at maternally toxic doses. Given the animal species studied and the limited parameters evaluated, the adverse events of pramipexole on pregnancy and male fertility have not yet been fully elucidated.
Delayed sexual development (ie separation of the foreskin and opening of the vagina) was observed in rats. The relevance of these findings to humans is unknown.
Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell hyperplasia and adenomas, attributable to the inhibitory effect of pramipexole on prolactin secretion. These observations are not relevant for clinical use in humans. The same study demonstrated that at doses of 2 mg / kg (salt) or higher, pramipexole causes retinal degeneration in the albino rat. The latter effect was not observed in the normal pigmented rat or in a 2-year carcinogenicity study in the mouse. albino and all other species studied.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Mannitol
cornstarch
anhydrous colloidal silica
povidone K25
magnesium stearate
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Do not store above 30 ° C.
Store in the original package to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package
OPA / aluminum / PVC-aluminum blisters.
Each blister contains 10 tablets.
Cartons containing 3 or 10 blisters (30 or 100 tablets).
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/97/051 / 005-006
034090050
034090062
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 23 February 1998
Date of last renewal: 23 February 2008
10.0 DATE OF REVISION OF THE TEXT
February 28, 2014
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