Active ingredients: Rasagiline
AZILECT 1 mg tablets
Why is Azilect used? What is it for?
AZILECT is used in the treatment of Parkinson's disease. It can be used with or without Levodopa (another medicine used to treat Parkinson's disease).
With Parkinson's disease, loss of dopaminergic cells occurs in certain areas of the brain. Dopamine is a brain substance responsible for controlling movement. AZILECT helps to increase and maintain dopamine levels in the brain.
Contraindications When Azilect should not be used
Do not take AZILECT:
- if you are allergic (hypersensitive) to rasagiline or any of the other ingredients of AZILECT.
- if you suffer from severe hepatic insufficiency.
Do not take the following medicines in combination with AZILECT:
- monoamine oxidase (MAO) inhibitors (used as antidepressants, to treat Parkinsin's disease or for any other indication), including non-prescription medicines and natural products, such as St. John's wort.
- pethidine (a strong analgesic).
Wait at least 14 days after stopping treatment with AZILECT before starting treatment with MAO inhibitors or pethidine.
Precautions for use What you need to know before taking Azilect
Take special care with AZILECT
- In case of mild to moderate impaired liver function.
- Contact your doctor in case of any suspected skin changes.
Children
The use of AZILECT in patients under 18 years of age is not recommended.
Interactions Which drugs or foods can modify the effect of Azilect
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription and if you are a smoker or intend to stop smoking.
Ask your doctor for advice before taking any of the following medicines in combination with AZILECT:
- some antidepressants (selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, tricyclic or tetracyclic antidepressants)
- the antibiotic ciprofloxacin used to treat infections
- dextromethorphan, a medicine used for cough
- sympathomimetics such as those found in eye drops, nasal and oral decongestants, and cold medications containing ephedrine or pseudoephedrine.
Avoid concomitant use of AZILECT and antidepressants containing fluoxetine or fluvoxamine. Before starting treatment with AZILECT, wait at least five weeks after stopping treatment with fluoxetine.
Before starting treatment with fluoxetine or fluvoxamine, wait at least 14 days after stopping treatment with AZILECT.
Tell your doctor if you, your family or caregivers notice that you are developing unusual behaviors that make you unable to resist the urge, urge or desire to engage in certain activities that are dangerous or harmful to you or them. others. These behaviors are called impulse control disorders. Behaviors such as compulsions, obsessive thoughts, gambling addiction, overspending, have been observed in patients taking AZILECT and / or other medicines used to treat Parkinson's disease. impulsive behaviors and abnormally high sexual desire or an increase in sexual thoughts or desires. Your doctor may need to change your dose or stop treatment
Taking AZILECT with food and drink
AZILECT can be taken with or without food.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed. Ask your doctor for advice before driving and using machines.
Dose, Method and Time of Administration How to use Azilect: Posology
Always take AZILECT exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The usual dose of AZILECT is 1 tablet of 1 mg taken by mouth, once a day. AZILECT can be taken with or without food.
Overdose What to do if you have taken too much Azilect
If you take more AZILECT than you should
If you think you have taken more AZILECT tablets than you should, contact your doctor or pharmacist immediately. Take the AZILECT blister / bottle with you to show the doctor or pharmacist.
If you forget to take AZILECT
Do not take a double dose to make up for a forgotten tablet. Take your next dose as normal, when it's time to take it.
If you stop taking AZILECT
If you have any further questions on the use of AZILECT, ask your doctor or pharmacist.
Side Effects What are the side effects of Azilect
Like all medicines, AZILECT can cause side effects, although not everybody gets them.
The following undesirable effects have been reported in placebo-controlled clinical trials.
The frequency of possible side effects listed below is defined using the following conventions:
- Very common (in more than 1 in 10 patients)
- Common (1 to 10 out of 100 patients)
- Uncommon (1 to 10 out of 1,000 patients)
- Rare (1 to 10 out of 10,000 patients)
- Very rare (less than 1 out of 10,000 patients)
- Not known (frequency cannot be estimated from the available data).
Very common:
- Abnormal movements (dyskinesia)
- headache.
Common:
- abdominal pain
- falls
- allergy,
- fever
- flu syndrome (flu)
- general feeling of unwell (malaise)
- neck pain
- chest pain (angina pectoris)
- decrease in blood pressure when standing upright accompanied by symptoms such as dizziness / light-headedness (orthostatic hypotension)
- decreased appetite
- constipation
- dry mouth
- nausea and vomit
- flatulence
- abnormality in blood test results (leukopenia)
- joint pain (arthralgia)
- musculoskeletal pain
- joint inflammation (arthritis)
- numbness and weakness of the hand muscle (carpal tunnel syndrome)
- loss of body weight
- abnormal dreams
- difficulty in muscle coordination (balance disorders)
- depression
- dizziness
- prolonged muscle contractions (dystonia)
- runny nose (rhinitis)
- skin irritation (dermatitis)
- erythema
- red eyes (conjunctivitis)
- urinary urgency.
Uncommon:
- stroke (cerebrovascular stroke)
- Heart attack (myocardial infarction)
- skin blistering (vesiculobullous erythema).
In addition, skin cancer was reported in approximately 1% of patients in placebo-controlled clinical trials. Scientific evidence suggests that Parkinson's disease, and not a particular drug, is associated with a higher risk of skin cancer ( not just melanoma) Report any suspected skin changes to your doctor.
Parkinson's disease is associated with symptoms such as hallucinations and confusion. In post marketing experience these symptoms have also been observed in Parkinson's disease patients treated with AZILECT.
There have been cases of patients who, while taking one or more drugs for the treatment of Parkinson's disease, were unable to resist the urge, desire or temptation to perform an action that could have been harmful to themselves or others. These behaviors are called impulse control disorders. The following behaviors have been observed in patients taking AZILECT and / or other medicines used to treat Parkinson's disease:
- Obsessive thoughts or impulsive behaviors.
- Strong impulse to gamble excessively despite serious personal or family consequences.
- Altered or increased sexual interest and behaviors of significant concern to oneself or others, for example an increase in sexual desire. - Uncontrollable and excessive spending or purchases.
Tell your doctor if any of these behaviors occur; you will discuss ways to manage or reduce symptoms.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Keep AZILECT out of the reach and sight of children.
Do not use AZILECT after the expiry date which is stated on the carton, bottle or carton. The expiry date refers to the last day of the month.
Do not store above 25 ° C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What AZILECT contains
- The active ingredient is rasagiline. Each tablet contains 1 mg of rasagiline (as mesylate).
- The other ingredients are mannitol, anhydrous colloidal silica, maize starch, pregelatinised maize starch, stearic acid, talc.
What AZILECT looks like and contents of the pack
AZILECT comes in the form of white-off-white tablets, round, flat and bevelled at the edges, smooth on one side and embossed with "GIL" and "1" on the other.
The tablets are available in packs of 7, 10, 28, 30, 100 and 112 tablets or in bottles of 30 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
AZILECT 1 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 1 mg of rasagiline (mesylate).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
White to off-white tablets, round, flat and bevelled at the edges, plain on one side and embossed with "GIL" and "1" on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
AZILECT is indicated for the treatment of Parkinson's disease both as monotherapy (without levodopa) and as combination therapy (with levodopa) in patients with end-of-dose fluctuations.
04.2 Posology and method of administration
Dosage
Rasagiline is administered orally at a dose of 1 mg, once daily, with or without levodopa.
It can be taken either on an empty stomach or on a full stomach.
Elderly: No dose adjustment is necessary in elderly patients.
Pediatric population: The use of Azilect in children and adolescents is not recommended due to a lack of data on safety and efficacy.
Patients with hepatic insufficiency: The use of rasagiline in patients with severe hepatic insufficiency is contraindicated (see section 4.3). The use of rasagiline in patients with moderate hepatic insufficiency should be avoided. Use caution when initiating treatment with rasagiline in patients with mild hepatic insufficiency. Discontinue treatment with rasagiline if mild to moderate hepatic insufficiency develops (see section 4.4).
Patients with renal insufficiency: No dose adjustment is necessary in patients with renal insufficiency.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
Concomitant treatment with other monoamine oxidase (MAO) inhibitors (including non-prescription medicines and natural products, such as St. John's wort) or pethidine (see section 4.5). Wait at least 14 days between stopping treatment. with rasagiline and initiation of therapy with MAO inhibitors or pethidine.
The use of rasagiline is contraindicated in patients with severe hepatic insufficiency.
04.4 Special warnings and appropriate precautions for use
Avoid concomitant use of rasagiline and fluoxetine or fluvoxamine (see section 4.5). Wait at least five weeks after stopping fluoxetine treatment before starting rasagiline therapy. Wait at least 14 days between stopping treatment with rasagiline and starting treatment with fluoxetine or fluvoxamine.
Impulse control disorders (ICDs) can occur in patients treated with dopamine agonists and / or dopaminergic treatments. Similar reports of impulse control disorders (ICDs) have been received in post-marketing experience in patients treated with rasagiline. Patients should be monitored regularly for the development of impulse control disorders.Patients and their carers should be aware of the behavioral symptoms of impulse control disorders that have been observed in patients treated with rasagiline, which include cases of compulsions, obsessive thoughts, pathological gambling, increased libido , hypersexuality, impulsive behavior, and compulsive spending or buying.
Since rasagiline potentiates the effects of levodopa, the side effects of levodopa may be increased and pre-existing dyskinesia aggravated. Reducing the dose of levodopa can improve this side effect.
There have been reports of hypotensive effects when rasagiline is taken concomitantly with levodopa. Patients with Parkinson's disease are particularly vulnerable to the side effects of hypotension due to the presence of walking problems.
The concomitant use of rasagiline and dextromethorphan or sympathomimetics, including nasal and oral decongestants and medicinal products containing ephedrine or psudoephedrine used to treat colds is not recommended (see section 4.5).
During the clinical development program of rasagiline, a few cases of melanoma were observed which could suggest a possible association with rasagiline. The data collected indicate that Parkinson's disease, and not a particular drug, is associated with a higher risk of skin cancer (not just melanoma). In case of suspected skin lesion, consult a specialist.
Use caution when initiating rasagiline treatment in patients with mild hepatic insufficiency.
Avoid the use of rasagiline in patients with moderate hepatic insufficiency. Discontinue treatment with rasagiline if mild to moderate hepatic insufficiency develops (see section 5.2).
04.5 Interactions with other medicinal products and other forms of interaction
There are a number of known interactions between non-selective MAO inhibitors and other medicinal products.
Rasagiline should not be administered in combination with other MAO inhibitors (including non-prescription medicines and natural products, such as "St. John's wort) as there is a risk of" non-selective MAO inhibition with possible onset of seizures. hypertensive (see section 4.3).
Serious adverse reactions have been reported with concomitant use of pethidine and MAO inhibitors, as well as another selective MAO-B inhibitor. Concomitant administration of rasagiline and pethidine is contraindicated (see section 4.3).
The concomitant use of MAO inhibitors and sympathomimetic drugs has resulted in drug interaction phenomena. Therefore, given the MAO inhibiting activity of rasagiline, concomitant administration of rasagiline and sympathomimetics, such as those present in nasal decongestants and oral and cold medicines containing ephedrine or psudoephedrine (see section 4.4).
Drug interactions have been reported with concomitant use of dextromethorphan and non-selective MAO inhibitors. Therefore, due to the MAO inhibitory activity of rasagiline, concomitant use of rasagiline and dextromethorphan is not recommended (see section 4.4).
Avoid concomitant use of rasagiline and fluoxetine or fluvoxamine (see section 4.4).
For concomitant use of rasagiline and selective serotonin reuptake inhibitors (SSRIs) / selective serotonin and norepinephrine reuptake inhibitors (SNRIs) in clinical trials, see section 4.8.
Serious adverse reactions have been reported with concomitant use of SSRIs, SNRIs, tricyclic and tetracyclic antidepressants and MAO inhibitors. Given the MAO inhibitory activity of rasagiline, caution is therefore advised in case of treatment with antidepressants. .
No clinically significant effect of levodopa on rasagiline clearance has been reported in patients with Parkinson's disease on chronic treatment with levodopa as a combination drug.
Education in vitro on metabolism showed that cytochrome P4501A2 (CYP1A2) is the main enzyme responsible for the metabolism of rasagiline. Concomitant administration of rasagiline and ciprofloxacin (a CYP1A2 inhibitor) resulted in an 83% increase in rasagiline AUC. Concomitant administration of rasagiline and theophylline (a substrate of CYP1A2) had no effect on the pharmacokinetics of the two products. Hence, potent CYP1A2 inhibitors may alter the plasma levels of rasagiline and should be administered with caution.
In smoking patients there is a risk of decreased plasma levels of rasagiline due to induction of the metabolising enzyme CYP1A2.
Education in vitro demonstrated that rasagiline concentrations equal to 1 mcg / ml (equivalent to a level 160 times the mean Cmax of ≈5.9-8.5 ng / ml in Parkinson's disease patients after multiple doses of 1 mg rasagiline), did not inhibit the cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A. These results show that therapeutic concentrations of rasagiline are unlikely to significantly interfere with substrates of these enzymes.
Co-administration of rasagiline and entacapone resulted in a 28% increase in the oral clearance of rasagiline.
Tyramine / rasagiline interaction: the results of five tyramine stimulation studies (in volunteers and patients with Parkinson's disease) together with data from daily blood pressure monitoring after meals (in 464 patients treated with 0.5 mg / day or 1 mg / day of rasagiline or placebo as combination therapy with levodopa for six months without tyramine restrictions), and the absence of reports of an interaction between tyramine and rasagiline in unrestricted clinical trials of tyramine indicate that rasagiline can be used safely and without dietary restrictions for tyramine.
04.6 Pregnancy and lactation
No clinical data are available on the use of rasagiline in pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development, parturition and postnatal development (see section 5.3.). Caution is needed when prescribing the drug to pregnant women.
Experimental data indicate that rasagiline inhibits prolactin secretion and thus may inhibit lactation.
It is not known whether rasagiline is excreted in human milk. Particular attention should be paid to the administration of the drug in lactating women.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
Patients should be warned about the risk of using machinery, including motor vehicles, until they are satisfied that Azilect has no effect on their abilities.
04.8 Undesirable effects
In the rasagiline clinical development program, a total of 1,361 patients received 3,076.4 patient-years with rasagiline. In double-blind placebo-controlled studies, 529 patients equal to 212 patient-years were treated with rasagiline 1 mg / day and 539 patients equal to 213 patient-years received placebo.
Monotherapy
Adverse reactions reported with a higher incidence in placebo-controlled studies in patients treated with rasagiline 1 mg / day (rasagiline group n = 149, placebo group n = 151) are listed below.
Adverse reactions with at least 2% difference from placebo are reported in italics
The number in brackets (% of patients) indicates the incidence of the adverse reaction in the rasagiline vs. placebo group, respectively.
Adverse reactions have been ranked by frequency using the following conventions: very common (> 1/10), common (> 1/100 to 1 / 1,000 to 1 / 10,000 to
Infections and infestations
Common: influenza (4.7% vs. 0.7%)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common: skin cancer (1.3% vs. 0.7%)
Disorders of the blood and lymphatic system
Common: leukopenia (1.3% vs. 0%)
Disorders of the immune system
Common: allergic reactions (1.3% vs. 0.7%)
Metabolism and nutrition disorders
Uncommon: decreased appetite (0.7% vs. 0%)
Psychiatric disorders
Common: depression (5.4% vs. 2%), hallucinations (1.3% vs. 0.7%)
Nervous system disorders
Very common: migraine (14.1% vs. 11.9%)
Uncommon: cerebrovascular stroke (0.7% vs. 0%)
Eye disorders
Common: conjunctivitis (2.7% vs. 0.7%)
Ear and labyrinth disorders
Common: dizziness (2.7% vs. 1.3%)
Cardiac pathologies
Common: angina pectoris (1.3% vs. 0%)
Uncommon: myocardial infarction (0.7% vs. 0%)
Respiratory, thoracic and mediastinal disorders
Common: rhinitis (3.4% vs. 0.7%)
Gastrointestinal disorders
Common: flatulence (1.3% vs. 0%)
Skin and subcutaneous tissue disorders
Common: dermatitis (2.0% vs. 0%)
Uncommon: vesiculobullous erythema (0.7% vs. 0%)
Musculoskeletal and connective tissue disorders
Common: musculoskeletal pain (6.7% vs. 2.6%), neck pain (2.7% vs. 0%), arthritis (1.3% vs. 0.7%)
Renal and urinary disorders
Common: urinary urgency (1.3% vs. 0.7%)
General disorders and administration site conditions
Common: fever (2.7% vs. 1.3%), malaise (2% vs. 0%)
Association therapy
The following are adverse reactions seen with a higher incidence in placebo-controlled studies in patients receiving rasagiline 1 mg / day (rasagiline group n = 380, placebo group n = 388). The number in brackets (% of patients) indicates the incidence of the adverse reaction in the rasagiline vs. placebo group, respectively.
Adverse reactions with at least 2% difference from placebo are reported in italics.
Adverse reactions have been ranked by frequency using the following conventions: very common (> 1/10), common (> 1/100 to 1 / 1,000 to 1 / 10,000 to
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon: cutaneous melanoma (0.5% vs. 0.3%)
Metabolism and nutrition disorders
Common: decreased appetite (2.4% vs. 0.8%)
Psychiatric disorders
Common: hallucinations (2.9% vs. 2.1%), abnormal dreams (2.1% vs. 0.8%)
Uncommon: confusion (0.8% vs. 0.5%)
Nervous system disorders
Very common: dyskinesia (10.5% vs. 6.2%)
Common: dystonia (2.4% vs. 0.8%), carpal tunnel syndrome (1.3% vs. 0%), balance disorders (1.6% vs. 0.3%)
Uncommon: cerebrovascular stroke (0.5% vs. 0.3%)
Cardiac pathologies
Uncommon: angina pectoris (0.5% vs. 0%)
Vascular pathologies
Common: orthostatic hypotension (3.9% vs. 0.8%)
Gastrointestinal disorders
Common: abdominal pain (4.2% vs 1.3%), constipation (4.2% vs 2.1%), nausea and vomiting (8.4% vs 6.2%), dry mouth (3.4% vs. 1.8%)
Skin and subcutaneous tissue disorders
Common: Skin rash (1.1% vs. 0.3%)
Musculoskeletal and connective tissue disorders
Common: arthralgia (2.4% vs. 2.1%), neck pain (1.3% vs. 0.5%)
Diagnostic tests
Common: decrease in body weight (4.5% vs. 1.5%)
Injury, poisoning and complications from trauma
Common: Fall (4.7% vs. 3.4%)
Parkinson's disease is associated with symptoms such as hallucinations and confusion. In post marketing experience, these symptoms have also been seen in patients with Parkinson's disease treated with rasagiline.
The occurrence of serious adverse reactions is known with the concomitant use of SSRIs, SNRIs, tricyclic and tetracyclic antidepressants and MAO inhibitors. In post-marketing experience, cases of serotonin syndrome associated with agitation, confusion, rigidity have been reported. , pyrexia and myoclonus in patients treated with antidepressants / SNRIs concomitantly with rasagiline.
In clinical trials of rasagiline, concomitant use of fluoxetine or fluvoxamine and rasagiline was not permitted, but the use of the following antidepressants was authorized at the following doses: amitriptyline ≤ 50 mg per day, trazodone ≤ 100 mg per day, citalopram ≤ 20 mg per day, sertraline ≤ 100 mg per day and paroxetine ≤ 30 mg per day. No cases of serotonin syndrome were reported during the rasagiline clinical program, in which 115 patients were treated concomitantly with rasagiline and tricyclics and 141 patients were treated with rasagiline and SSRI / SNRI.
In post-marketing experience, cases of increased blood pressure have been reported in patients receiving rasagiline, including rare cases of hypertensive crisis following ingestion of tyramine-rich foods in unknown quantities.
Cases of drug interactions with concomitant use of sympathomimetic medicinal products have been reported with MAO inhibitors.
In post-marketing experience, a case of increased blood pressure was reported in a patient who was also using a tetrahydrozoline hydrochloride ophthalmic vasoconstrictor during treatment with rasagiline.
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 and / or other dopaminergic treatments. a similar picture of impulse control disorders was recorded which also included compulsions, obsessive thoughts and impulsive behaviors (see section 4.4).
04.9 Overdose
Overdose: Symptoms reported following overdose with Azilect in doses ranging from 3 mg to 100 mg included dysphoria, hypomania, hypertensive crisis and serotonin syndrome.
Overdose may be associated with significant inhibition of MAO-A and MAO-B.
Healthy volunteers were treated with 20 mg / day of the product in a single dose study, or with 10 mg / day in a ten-day study. Adverse events observed were rated as mild or moderate and unrelated to rasagiline treatment. Cardiovascular adverse reactions (including hypertension and postural hypotension) were reported in a dose escalation study in patients on chronic levodopa therapy treated with rasagiline 10 mg / day and disappeared upon discontinuation of treatment. they are similar to those observed for non-selective MAO inhibitors.
There is no specific antidote. In case of overdose, monitor patients and intervene with "adequate symptomatic and supportive therapy."
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiparkinsonian drugs, monoamine oxidase inhibitors -B
ATC code: N04BD02
Mechanism of action:
Rasagiline has been shown to be a potent and irreversible selective MAO-B inhibitor, which can lead to an increase in extracellular dopamine levels in the striatum. The increase in dopamine levels and the consequent increase in dopaminergic activity may be responsible for the beneficial effects observed with rasagiline in dopaminergic-based models of motor dysfunction.
1-Aminoindane is the major active metabolite of rasagiline and is not a MAO-B inhibitor.
Clinical studies:
The efficacy of rasagiline was documented by the results of three studies: as monotherapy in Study I and as combination therapy in Studies II and III.
Monotherapy:
In study I, 404 patients were randomized and treated for 26 weeks with placebo (138 patients) with rasagiline 1 mg / day (134 patients) or rasagiline 2 mg / day (132 patients), with no other active comparator.
In this study, the primary efficacy endpoint was the change from baseline in total score on the Unified Parkinson's Disease Rating Scale (UPDRS, parts I-III). The difference between the mean change between baseline and that at 26 weeks / end of treatment (LOCF, Last Observation Carried Forward) was statistically significant (UPDRS, parts I-III: for rasagiline 1 mg compared to placebo -4, 2, 95% CI [-5.7 -2.7];
Association therapy:
In study II, patients were randomized and treated for 18 weeks with placebo (229 patients) or rasagiline 1 mg / day (231 patients) or entacapone 200 mg (227 patients), a catechol-O-methyltransferase inhibitor ( COMT), taken together with the scheduled dose of levodopa (LD) / decarboxylase inhibitor. In study III, patients were randomized and treated for 26 weeks with placebo (159 patients), rasagiline 0.5 mg / day (164 patients), or rasagiline 1 mg / day (149 patients).
In both studies, the main measure of effectiveness was the change between baseline and treatment period in the mean number of hours spent in the "off" state during the day (based on journals compiled at home for 24 hours and compiled for three days before each assessment visit).
In study II, the mean difference in the number of hours spent in the "off" state compared to placebo was -0.78 hours, 95% CI [-1.18 -0.39 hours], p = 0.0001. The mean total daily reduction in "off" time observed in the entacapone group (-0.80 hours, 95% CI [-1.20 -0.41], p
Secondary efficacy measures included the examiner's overall assessment of the degree of improvement, the Activities of Daily Living (ADL) subscale score in the "off" state, and the UPDRS score in the "on" state. Compared to placebo, treatment with rasagiline resulted in a statistically significant benefit.
05.2 "Pharmacokinetic properties
Absorption: Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 0.5 hours.The absolute bioavailability of single dose rasagiline is approximately 36%.
Food does not affect rasagiline's Tmax, although there is a decrease in Cmax and exposure (AUC) of approximately 60% and 20%, respectively, if the drug is taken with a high-fat meal. The AUC is not substantially changed, rasagiline can be taken on either a full stomach or an empty stomach.
Distribution: The mean volume of distribution of rasagiline following single dose intravenous injection is 243 l. Plasma protein binding after single oral dose of 14C-labeled rasagiline is approximately 60% -70%.
Metabolism: Before being excreted, rasagiline undergoes almost complete biotransformation in the liver. The main metabolic pathways of rasagiline are two: N-dealkylation and / or hydroxylation with the formation of: 1-Aminoindane, 3-hydroxy-N-propargyl-1 aminoindane and 3-hydroxy-1-aminoindane. The experiments in vitro indicate that both metabolic pathways of rasagiline are dependent on the cytochrome P450 system; CYP1A2 is the major isoenzyme involved in the metabolism of rasagiline. It has also been found that the conjugation of rasagiline and its metabolites is one of the main elimination pathways with the formation of glucuronides.
Excretion: After oral administration of 14C-labeled rasagiline, the drug was eliminated primarily via urine (62.6%) and faeces (21.8%) with a total recovery of 84.4% of the dose over a 38-day period. Less than 1% of rasagiline is excreted in the urine as unchanged drug.
Linearity / non-linearity: Rasagiline pharmacokinetics are linear over doses in the range of 0.5 to 2 mg. Its final half-life is 0.6-2 hours.
Characteristics in patients
Patients with hepatic insufficiency: In subjects with mild hepatic insufficiency, AUC and Cmax were increased by 80% and 38%, respectively. In subjects with moderate hepatic impairment, AUC and Cmax were increased by 568% and 83%, respectively (see section 4.4).
Patients with renal insufficiency: Rasagiline pharmacokinetics in subjects with mild (CLcr 50-80 ml / min) to moderate (CLcr 30-49 ml / min) renal insufficiency were similar to that in healthy subjects.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety, repeated dose toxicity and reproductive toxicity.
Rasagiline has no genotoxic potential in vivo and in numerous systems in vitro using bacteria and / or hepatocytes. In the presence of active metabolites, rasagiline induces an increase in chromosomal aberrations at excessive cytotoxic concentrations which are not utilized in the conditions of clinical use.
Rasagiline was not carcinogenic in rats at a systemic exposure 84-339 times the expected human plasma concentration at the 1 mg / day dose.
In mice, an increase in the incidence of combined bronchiolar / alveolar adenoma and / or carcinoma was observed, with a systemic exposure 144-213 times greater than the expected human plasma concentration at the 1 mg / day dose.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Mannitol
Cornstarch
Pregelatinised maize starch
Anhydrous colloidal silica
Stearic acid
Talc
06.2 Incompatibility
Not relevant.
06.3 Period of validity
Blister: 3 years
Bottles: 3 years
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Blisters: Aluminum / aluminum blisters, packs of 7, 10, 28, 30, 100 or 112 tablets.
Bottles: White, high-density polyethylene bottle with or without child-resistant safety cap containing 30 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Teva Pharma GmbH
Graf-Arco-Str. 3
89079 Ulm
Germany
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/04/304 / 001-007
036983017
036983029
036983031
036983043
036983056
036983068
036983070
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 21 February 2005
Date of last renewal: 21 September 2009
10.0 DATE OF REVISION OF THE TEXT
D.CCE November 2013
