Active ingredients: Rivastigmine
Exelon 1.5 mg hard capsules
Exelon 3.0 mg hard capsules
Exelon 4.5 mg hard capsules
Exelon 6.0 mg hard capsules
Exelon package inserts are available for pack sizes: - Exelon 1.5 mg hard capsules, Exelon 3.0 mg hard capsules, Exelon 4.5 mg hard capsules, Exelon 6.0 mg hard capsules
- Exelon 2 mg / ml oral solution
- Exelon 4.6 mg / 24 h transdermal patch Exelon 9.5 mg / 24 h transdermal patch Exelon 13.3 mg / 24 h transdermal patch
Why is Exelon used? What is it for?
Exelon contains the active substance rivastigmine.
Rivastigmine belongs to a class of substances called cholinesterase inhibitors. In patients with Alzheimer's dementia or dementia associated with Parkinson's disease, some brain cells die, resulting in low levels of acetylcholine (a substance that allows nerve cells to communicate with each other). Rivastigmine works by blocking the enzymes that break down acetylcholine: acetylcholinesterase and butyrylcholinesterase. By blocking these enzymes, Exelon increases acetylcholine levels in the brain, improving the symptoms of Alzheimer's disease or the dementia associated with Parkinson's disease.
Exelon is used to treat adult patients with mild to moderate Alzheimer's dementia, a progressive disorder of the central nervous system that gradually affects memory, learning and behavior. The hard capsules and oral solution are also used for the treatment of dementia in adult patients with Parkinson's disease.
Contraindications When Exelon should not be used
Do not take Exelon
- if you are allergic to rivastigmine (the active substance in Exelon) or any of the other ingredients of this medicine (listed in section 6).
- if you have had a skin reaction when using the patch that extended beyond the area where the patch was applied, if you have had a more intense local reaction (such as blisters, increased skin inflammation, swelling) that did not improve in the next 48 hours when removing the patch.
If this applies to you, tell your doctor and do not take Exelon.
Precautions for use What you need to know before taking Exelon
Talk to your doctor before taking Exelon:
- if you have or have ever had an irregular heartbeat.
- if you have or have ever had an active stomach ulcer.
- if you have or have ever had difficulty passing urine.
- if you have or have ever had seizures.
- if you have or have ever had asthma or severe breathing problems.
- if you have or have ever had changes in kidney function.
- if you have or have ever had changes in liver function.
- if you suffer from tremors.
- if it weighs little.
- if you experience gastrointestinal complaints such as feeling sick, vomiting and diarrhea. If the vomiting and diarrhea persist, you may become dehydrated (excessive fluid loss).
If you recognize one of these situations, your doctor will be able to see you more frequently during therapy with this medicine.
If you have not taken Exelon for several days, consult your doctor before resuming treatment.
Use in children and adolescents
There is no indication for a specific use of Exelon in the pediatric population in the treatment of Alzheimer's disease.
Interactions Which drugs or foods may change the effect of Exelon
Other medicines and Exelon
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. Exelon must not be given together with other medicines that have similar effects.
Exelon may interfere with anticholinergic medicines (medicines used to relieve stomach cramps or spasms, to treat Parkinson's disease or to prevent travel sickness).
If you are undergoing surgery and are being treated with Exelon, please inform your doctor before undergoing anesthesia, as Exelon may increase the effects of some muscle relaxants during anesthesia.
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.
If you are pregnant, the benefits of using Exelon should be weighed against the possible effects on the unborn child. Exelon should not be used during pregnancy unless clearly necessary.
You must not breastfeed while being treated with Exelon.
Driving and using machines
Your doctor will tell you if your illness allows you to drive and use machines with a certain degree of safety. Exelon may cause dizziness and sleepiness, especially at the start of treatment or when the dose is increased. If you feel dizzy or sleepy, do not drive, operate machinery or do any other activity that requires vigilance.
Dose, Method and Time of Administration How to use Exelon: Posology
Always take this medicine exactly as stated in this leaflet and your doctor's instructions. If in doubt, consult your doctor, pharmacist or nurse.
How to start treatment
Your doctor will tell you which dose of Exelon to take.
- Treatment usually starts with a low dose.
- Your doctor will slowly increase the dose based on your response to treatment.
- The highest dose that can be taken is 6.0 mg twice a day.
Your doctor will check regularly if the medicine is working.
Your doctor will also monitor your weight while you are taking this medicine.
If you have not taken Exelon for several days, consult your doctor before resuming treatment.
Taking the medicine
- Tell the person taking care of you that you are being treated with Exelon.
- To benefit from the treatment, take your medicine every day.
- Take Exelon twice a day, in the morning and in the evening, with food.
- Take the capsules whole with a drink.
- Do not open or break the capsules.
Overdose What to do if you have taken too much Exelon
If you take more Exelon than you should
If you accidentally take more Exelon than you should, tell your doctor. He may need medical attention. Some people who have taken too much Exelon by mistake have experienced feelings of nausea, vomiting, diarrhea, high blood pressure and hallucinations. Slow heart rate and fainting can also occur.
If you forget to take Exelon
If you find that you have forgotten to take your dose of Exelon, wait and take the next dose at the usual time. Do not take a double dose to make up for a forgotten dose.
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 Exelon
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Side effects may be more frequent when you start taking the medicine or when the dose is increased. Usually the side effects will slowly disappear as the body gets used to the medicine.
Very common (may affect more than 1 in 10 people)
- Feeling dizzy
- Loss of appetite
- Upset stomach such as feeling sick, vomiting, diarrhea
Common (may affect up to 1 in 10 people)
- Anxiety
- Sweating
- Headache
- Stomach ache
- Weight loss
- Stomach ache
- Feeling agitated
- Feeling tired or weak
- General feeling of being unwell
- Tremors or a feeling of confusion
Uncommon (may affect up to 1 in 100 people)
- Depression
- Sleep disorders
- Fainting or accidental falls
- Changes in the functioning of the liver
Rare (may affect up to 1 in 1,000 people)
- Chest pain
- Skin rash, itching
- Convulsions
- Stomach or intestinal ulcer
Very rare (may affect up to 1 in 10,000 people)
- High blood pressure
- Urinary tract infection
- Seeing things that aren't there (hallucinations)
- Heart rhythm disturbances, such as fast or slow heart rate
- Bleeding from the gut - this is manifested by the presence of blood in the stool or vomit
- Inflammation of the pancreas - manifested by severe pain in the upper stomach, often accompanied by a feeling of nausea or vomiting
- The signs of Parkinson's disease worsen or similar symptoms develop - such as muscle stiffness, difficulty in moving
Not known (frequency cannot be estimated from the available data)
- Severe vomiting which can lead to the rupture of the tract that connects the mouth to the stomach (esophagus)
- Dehydration (excessive loss of fluids)
- Liver problems (yellowing of the skin and whites of the eyes, abnormal darkening of the urine or unexplained nausea, vomiting, tiredness and loss of appetite)
- Aggression, feeling restless
- Irregular heartbeat
Patients with dementia and with Parkinson's disease
These patients experience some undesirable effects more frequently. They also experience some additional side effects:
Very common (may affect more than 1 in 10 people)
- Tremors
- Fainting
- Accidental falls
Common (may affect up to 1 in 10 people)
- Anxiety
- Feeling restless
- Slow and fast heartbeat
- Sleep disorders
- Excessive salivation and dehydration
- Unusual slowing of movements or movements that you cannot control
- The signs of Parkinson's disease worsen or similar symptoms develop - such as muscle stiffness, difficulty moving and muscle weakness
Uncommon (may affect up to 1 in 100 people)
- Irregular heartbeat and poor movement control
Other side effects seen with Exelon transdermal patches and which may occur with the capsules:
Common (may affect up to 1 in 10 people)
- Fever
- Serious confusion
- Loss of appetite
- Urinary incontinence (inability to hold urine properly)
Uncommon (may affect up to 1 in 100 people)
- Hyperactivity (high level of activity, restlessness)
Not known (frequency cannot be estimated from the available data)
- Allergic reactions at the patch application site, such as blistering or inflammation of the skin
If any of these symptoms occur, contact your doctor as you may need medical attention.
If you get any side effects, talk to your doctor, pharmacist or nurse. 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.
- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use.This will help protect the environment.
Composition and pharmaceutical form
What Exelon contains
- The active substance is rivastigmine hydrogen tartrate.
- The other ingredients are hypromellose, magnesium stearate, microcrystalline cellulose, precipitated silica, gelatin, yellow iron oxide (E172), red iron oxide (E172), titanium dioxide (E171) and shellac.
Each Exelon 1.5 mg capsule contains 1.5 mg of rivastigmine.
Each Exelon 3.0 mg capsule contains 3.0 mg of rivastigmine.
Each Exelon 4.5 mg capsule contains 4.5 mg of rivastigmine.
Each Exelon 6.0 mg capsule contains 6.0 mg of rivastigmine.
What Exelon looks like and contents of the pack
- Exelon 1.5 mg hard capsules, which contain an off-white to slightly yellow powder, have a yellow cap and a yellow body, with a red imprint "EXELON 1.5 mg" on the body.
- Exelon 3.0 mg hard capsules, which contain an off-white to slightly yellow powder, have an orange cap and orange body, with a red imprint "EXELON 3 mg" on the body.
- Exelon 4.5 mg hard capsules, which contain an off-white to slightly yellow powder, have a red cap and red body, with white imprint "EXELON 4.5 mg" on the body.
- Exelon 6.0 mg hard capsules, which contain an off-white to slightly yellow powder, have a red cap and an orange body, with a red imprint "EXELON 6 mg" on the body.
Exelon hard capsules are packaged in blister packs available in three different cartons (28, 56 or 112 capsules) and in plastic bottles of 250 capsules, but 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
EXELON 3.0 MG
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 3.0 mg.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsules.
Off-white to pale yellow powder in a capsule with orange body and orange cap, with red imprint "EXELON 3 mg" on body.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Symptomatic treatment of mild to moderately severe Alzheimer's type dementia.
Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.
04.2 Posology and method of administration
Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia or dementia associated with Parkinson's disease. Diagnosis should be made in accordance with current guidelines. Rivastigmine therapy should only be initiated if a 'caregiver' (the one who usually cares for the patient) is available to regularly monitor the patient's intake of the medicine.
Rivastigmine is given twice a day, with breakfast and dinner. The capsules should be swallowed whole.
Initial dose
1.5 mg twice a day.
Dosage titration:
The starting dose is 1.5 mg twice a day. If this dose is well tolerated for at least two weeks of treatment, it may be increased to 3 mg twice a day. Subsequent increases to 4.5 and then 6 mg twice daily should always be based on good tolerability, for at least two weeks, of the dose being administered.
If adverse reactions (eg nausea, vomiting, abdominal pain, loss of appetite), weight loss or worsening of extrapyramidal symptoms (eg tremor) occur during treatment in patients with dementia associated with Parkinson's disease, these may respond to discontinuation of one or more doses of the medicinal product If adverse reactions persist the daily dose should be temporarily reduced to the previous well tolerated dose, or treatment may be discontinued.
Maintenance dose:
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained at the highest well tolerated dosage. The maximum recommended dose is 6 mg twice a day.
Maintenance treatment can be continued for as long as therapeutic benefit is seen. Therefore the clinical benefit of rivastigmine should be reassessed regularly, particularly for patients treated with doses below 3 mg twice daily. If after 3 months of treatment. Treatment with maintenance dose worsening of symptoms of dementia is not positively influenced, treatment should be discontinued. Even if no therapeutic effect is found, discontinuation of treatment should be considered. Individual response to rivastigmine is unpredictable. However, a greater therapeutic effect was seen in patients with moderate dementia with Parkinson's disease. Similarly, a larger effect was observed in Parkinson's disease patients with visual hallucinations (see section 5.1).
The therapeutic effect has not been studied in placebo-controlled clinical trials lasting more than 6 months.
Reintroduction of therapy:
If treatment is interrupted for several days, therapy should be resumed starting with 1.5 mg twice daily. The dosage titration should then be performed as described above.
Renal and hepatic insufficiency:
Due to the increased exposure to the medicinal product, in case of moderate renal insufficiency or mild or moderate hepatic impairment, the posology should be carefully titrated according to individual tolerability (see section 5.2).
Patients with severe hepatic impairment have not been studied (see section 4.3).
Use in children:
The use of rivastigmine is not recommended in children.
04.3 Contraindications
The use of this medicine is contraindicated in patients with:
hypersensitivity to the active ingredient, to other carbamate derivatives or to any of the excipients used in the formulation;
severe hepatic impairment, as the medicine has not been studied in this population.
04.4 Special warnings and appropriate precautions for use
The incidence and severity of adverse reactions generally increases with higher doses. If treatment is interrupted for several days, therapy should be resumed at 1.5 mg twice daily to reduce the risk of adverse reactions (eg . He retched).
Dosage titration: Adverse reactions (eg hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, particularly tremor, in patients with dementia associated with Parkinson's disease) have been observed immediately after dose increase. may be sensitive to dose reduction. In other cases, administration of Exelon has been interrupted (see section 4.8). Gastrointestinal disturbances such as nausea and vomiting, they can occur particularly at the start of treatment and / or at dose increases. These adverse reactions occur more frequently in women. Patients with Alzheimer's disease tend to lose weight. The use of cholinesterase inhibitors, rivastigmine including, it has been associated with weight loss in these patients. Patients' body weight should be monitored during therapy.
Should severe vomiting occur in association with rivastigmine treatment, appropriate dose adjustments should be made as recommended in section 4.2. Some episodes of severe vomiting were accompanied by esophageal rupture (see section 4.8). These episodes occurred in particular after dose increases of rivastigmine or after administration of high doses.
Care should be taken when administering rivastigmine to patients with sick sinus syndrome or conduction disturbances (sino-atrial block, atrio-ventricular block) (see section 4.8).
Rivastigmine can cause increased gastric acid secretions. Particular caution is advised in the treatment of patients with active gastric or duodenal ulcer or in predisposed patients.
Cholinesterase inhibitors should be prescribed with caution to patients with a history of asthma or obstructive pulmonary disease.
Cholinomimetics can cause or aggravate urinary obstructions and seizures. Caution is recommended when treating patients predisposed to this type of disorder. The use of rivastigmine in patients with severe Alzheimer's dementia or dementia associated with Parkinson's disease, other types of dementia, or other types of memory impairment (eg, age-related cognitive decline) was not investigated. , and therefore use in these patient populations is not recommended.
Like other cholinomimetics, rivastigmine can aggravate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, abnormal gait) and "increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events may, in some cases, lead to discontinuation of treatment. rivastigmine (eg discontinuation caused by tremor in 1.7% of patients on rivastigmine versus 0% on placebo). Clinical monitoring is recommended for these adverse reactions.
04.5 Interactions with other medicinal products and other forms of interaction
Being a cholinesterase inhibitor, rivastigmine may enhance the effects of succinylcholine-type muscle relaxants during anesthesia. Caution is recommended in the choice of anesthetics. If necessary, dose adjustments or temporary discontinuation of treatment may be considered.
Due to its pharmacodynamic effects, rivastigmine should not be administered in combination with other cholinomimetic substances; it may interfere with the activity of anticholinergic medicinal products. In studies in healthy volunteers, no pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine. Coltsfoot-induced increase in prothrombin time is not affected by rivastigmine administration. . No undesirable effects on cardiac conduction were observed with concomitant administration of digoxin and rivastigmine. Based on its metabolism, metabolic drug interactions with other medicinal products appear unlikely, although rivastigmine may inhibit butyrylcholinesterase-mediated metabolism of other substances.
04.6 Pregnancy and lactation
For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryo-fetal development were observed in rats and rabbits, except at doses at which maternal toxicity occurred. In peri-postnatal studies in rats, an increase in gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.
In animals, rivastigmine is excreted in milk. It is not known whether rivastigmine is excreted in human milk and therefore women treated with rivastigmine should not breastfeed.
04.7 Effects on ability to drive and use machines
Alzheimer's disease can cause a gradual loss of the ability to drive or impair the ability to use machines. Rivastigmine can also induce dizziness and somnolence, especially at the start of treatment or in conjunction with dose escalation. rivastigmine has mild or moderate effects on the ability to drive or use machines, so the ability of patients with dementia treated with rivastigmine to continue driving or operating complex machines should routinely be evaluated by the treating physician.
04.8 Undesirable effects
The most frequently reported adverse reactions are gastrointestinal in nature and include nausea (38%) and vomiting (23%), especially during the titration phase. In clinical studies, women were found to be more sensitive than men to gastrointestinal reactions and weight loss. The following adverse reactions, listed in Table 1, refer to patients with Alzheimer's dementia treated with Exelon.
Adverse reactions in Table 1 are listed by MedDRA system organ class and frequency class. Frequency classes are defined using the following conventional parameters: very common (≥1 / 10), common (≥1 / 100;
Table 1
The following adverse reactions have been observed with Exelon transdermal patches: anxiety, delirium, pyrexia (common).
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson's disease treated with Exelon.
Table 2
Table 3 lists the number and percentage of patients who participated in a specific 24-week clinical study conducted in patients with dementia associated with Parkinson's disease treated with Exelon, in which pre-defined adverse events occurred. which may reflect worsening of parkinsonian symptoms.
Table 3
04.9 Overdose
Symptoms:
Most incidents of accidental overdose were asymptomatic and nearly all affected patients continued rivastigmine treatment. In cases of symptomatic overdose the following have been observed: nausea, vomiting, diarrhea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, episodes of bradycardia and / or syncope may occur. There was one case of ingestion of 46 mg; after a conservative treatment the patient recovered completely in 24 hours.
Treatment:
Since rivastigmine has a plasma half-life of approximately 1 hour and the duration of acetylcholinesterase inhibition is approximately 9 hours, in the event of asymptomatic overdose it is recommended that no further doses of rivastigmine be administered for the next 24 hours. In cases of overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. In the event of other symptoms, appropriate symptomatic treatment should be provided. In cases of severe overdose, atropine can be used. It is recommended to use atropine. an initial dose of 0.03 mg / kg intravenously of atropine sulphate, with subsequent dose adjustments in accordance with clinical response. The use of scopolamine as an antidote is not recommended.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03.
Rivastigmine is a carbamide-type acetyl- and butyrylcholinesterase inhibitor, which facilitates cholinergic neurotransmission by slowing the inactivation of acetylcholine released by functionally intact cholinergic neurons. Rivastigmine may therefore exert an improvement in cholinergic mediated cognitive deficits in dementia associated with Alzheimer's disease and Parkinson's disease.
Rivastigmine interacts with its target enzymes to form a covalently bonded complex which temporarily inactivates the enzymes. In healthy young volunteers, an oral dose of 3 mg reduces acetylcholinesterase (AChE) activity in the cerebrospinal fluid by approximately 40% in the first hour and a half after administration. The activity of the enzyme returns to baseline levels approximately 9 hours after reaching the maximum inhibitory effect. In patients with Alzheimer's disease, the inhibition of AChE in the cerebrospinal fluid by rivastigmine was dose-dependent. up to 6 mg administered twice daily, which was the highest dose tested. In 14 patients with Alzheimer's disease treated with rivastigmine, inhibition of butyrylcholinesterase activity in the cerebrospinal fluid was similar to that observed for the brain. AChE.
Clinical Studies in Alzheimer's Dementia:
The efficacy of rivastigmine was assessed using three independent and domain specific assessment tools, which were verified at regular intervals during 6 month treatment periods. These tools are the ADAS-Cog (an assessment of cognitive capacity), the CIBIC-Plus (an overall assessment of the patient by the doctor considering what is also reported by the "caregiver"), and the PDS (an assessment carried out by the "caregiver" of normal daily activities such as personal hygiene, the ability to eat, dress, do housework, shop, maintain the ability to orient oneself in the surrounding environment as well as involvement in activities related to money management, etc. .). The patients studied had a Mini-Mental State Examination (MMSE) score between 10 and 24. The results of patients with clinically significant response, emerged from the combined analysis of two of the flexible-dose studies on three pivotal multicenter studies of the duration of 26 weeks, conducted in patients with mild or moderately severe Alzheimer's type dementia are shown in Table 4, below. In these studies, clinically relevant improvement was defined a priori as an improvement of at least 4 points of the ADAS-Cog, an improvement of the CIBIC-Plus or an improvement of at least 10% of the PDS.
An a posteriori definition of the answer is also provided in the same table. The secondary definition of response required a 4-point or greater improvement in ADAS-Cog, with no worsening of CIBIC-Plus and PDS. The mean dose in responders in the 6-12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary, and direct comparison of results for different therapeutic agents is not valid.
Table 4
* p
Clinical studies in dementia associated with Parkinson's disease:
The efficacy of rivastigmine in dementia associated with Parkinson's disease was demonstrated in the double-blind phase of a 24-week, multicenter, placebo-controlled study and in its open label extension of 24 weeks. Patients enrolled. in this study they had a MMSE (Mini-Mental State Examination) score between 10 and 24. The evaluation of efficacy was performed through the use of two independent scales, evaluated at regular intervals during the treatment period of duration of 6 months, as reported in Table 5 below: the ADAS-Cog (a scale of assessment of cognitive ability), and the general assessment of the ADCS-CGIC (a scale of the physician's global assessment of the patient).
Table 5
1 Based on ANCOVA with treatment and country as factors and baseline assessment of ADASCog as covariate. Positive change indicates improvement.
2 Mean values presented for convenience, category analysis performed with van Elteren ITT test: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward
Although the treatment effect was demonstrated in the overall population studied, the data suggest that a larger effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson's disease. a more prominent effect of treatment in those patients with visual hallucinations (see Table 6).
Table 6
1 Based on ANCOVA with treatment and country as factors and baseline assessment of ADASCog as covariate. Positive change indicates improvement.
ITT: Intent-To-Treat: RDO: Retrieved Drop Outs
05.2 Pharmacokinetic properties
Absorption:
Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached within approximately 1 hour. As a consequence of the interaction between rivastigmine and its target enzyme, the increase in bioavailability is approximately 1.5 times greater than that expected with dose increase. At the 3 mg dose, absolute bioavailability is 36% ± Approximately 13%. Taking rivastigmine with food delays absorption (tmax) by 90 ", reduces Cmax values and increases AUC by approximately 30%.
Distribution:
Approximately 40% of rivastigmine is bound to plasma proteins. It rapidly crosses the blood brain barrier and has an apparent volume of distribution between 1.8 and 2.7 l / kg.
Metabolism:
Rivastigmine is rapidly and extensively metabolised (plasma half-life approximately 1 hour) to the decarbamylated metabolite, primarily by cholinesterase hydrolysis. In vitro, this metabolite exhibits a negligible inhibitory effect of acetylcholinesterase (cytochrome P450 is negligibly involved in the metabolism of rivastigmine. After intravenous administration of 0.2 mg the total plasma clearance of rivastigmine is approximately 130 l / h and decreases. at 70 l / h after intravenous administration of 2.7 mg.
Excretion:
Unchanged rivastigmine is not found in urine; renal excretion of metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and virtually complete (> 90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease.
Elderly subjects:
Although the bioavailability of rivastigmine is higher in elderly subjects than in young healthy volunteers, studies in Alzheimer's patients aged 50 to 92 years have not reported any changes in bioavailability with age.
Subjects with impaired liver function:
Rivastigmine Cmax and AUC values are approximately 60% respectively and more than two-fold higher in subjects with mild to moderate hepatic impairment than in healthy subjects.
Subjects with renal insufficiency:
Rivastigmine Cmax and AUC values are more than twice as high in subjects with moderate renal impairment compared to healthy subjects; however, rivastigmine Cmax and AUC values in subjects with severe renal impairment are not modified.
05.3 Preclinical safety data
Repeated dose toxicity studies conducted in rats, mice, dogs have shown effects attributable only to an "excessive pharmacological action. No toxicity for target organs was observed. Due to the sensitivity of the animal models used, no margins were reached. safety related to human exposure.
Rivastigmine was found to be devoid of mutagenic activity in a standard battery of tests in vitro And in vivo, with the exception of a chromosomal aberration test in human peripheral lymphocytes at a dose of 104 times the maximum dose administered in the clinic. The micronucleus test in vivo tested negative. There was no evidence of carcinogenicity in studies in mice, rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When compared to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human daily dose of 12 mg; however, compared to the maximum human dose, an approximately 6-fold multiple value was achieved in animals.
In animals, rivastigmine crosses the placenta and is excreted in milk. Oral studies in pregnant rats and rabbits did not provide information on the teratogenic potential of rivastigmine.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Gelatin, magnesium stearate, hypromellose, microcrystalline cellulose, precipitated silica, yellow iron oxide (E172), red iron oxide (E172), titanium dioxide (E171).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years
06.4 Special precautions for storage
Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Blister pack consisting of a transparent PVC tray with a blue cover sheet containing 14 capsules. Each box contains 2, 4 or 8 blisters.
High density polyethylene bottle with plastic closure and internal induction gasket.
Each bottle contains 250 capsules.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/98/066 / 004-6
EU / 1/98/066/015
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 12.05.1998
Date of last renewal: 12.05.2008
