Instructions Rivastigmine IS capsules 3 mg blister No. 30
Composition
active ingredient: rivastigmine;
1 capsule contains rivastigmine hydrotartrate 2.4 mg (equivalent to rivastigmine 1.5 mg), rivastigmine hydrotartrate 4.8 mg (equivalent to rivastigmine 3 mg), rivastigmine hydrotartrate 7.2 mg (equivalent to rivastigmine 4.5 mg) or rivastigmine hydrotartrate 9.6 mg (equivalent to rivastigmine 6 mg);
Excipients: hypromellose (hydroxypropylmethylcellulose), colloidal anhydrous silicon dioxide, microcrystalline cellulose, magnesium stearate, gelatin, titanium dioxide (E 171).
Dosage form
Capsules.
Main physicochemical properties: opaque hard gelatin capsules, body – white, cap – white; capsule contents – white to almost white powder.
Pharmacotherapeutic group
Psychoanaleptics. Drugs used in dementia. Cholinesterase inhibitors. Rivastigmine. ATX code N06D A03.
Pharmacological properties
Pharmacodynamics.
Rivastigmine is a carbamate-type acetylcholinesterase and butyrylcholinesterase inhibitor that promotes cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurons. Thus, rivastigmine has a beneficial effect on cognitive deficits caused by disorders of cholinergic neurotransmission in dementia associated with Alzheimer's disease or Parkinson's disease.
Rivastigmine interacts with target enzymes to form covalent complexes that temporarily inactivate the target enzymes. In healthy young men, oral administration of a 3 mg dose reduces acetylcholinesterase activity in the cerebrospinal fluid by approximately 40% within the first 1.5 hours after administration. After reaching the maximum inhibitory effect, enzyme activity returns to baseline levels approximately 9 hours later. In patients with Alzheimer's disease, inhibition of acetylcholinesterase activity in the cerebrospinal fluid by rivastigmine was dose-dependent (in the dose range studied up to the highest dose of 6 mg 2 times a day). Inhibition of butyrylcholinesterase activity in the cerebrospinal fluid of patients with Alzheimer's disease treated with rivastigmine was similar to inhibition of acetylcholinesterase activity.
Pharmacokinetics.
Absorption
Rivastigmine is rapidly and completely absorbed. The maximum concentration (Cmax) in the blood plasma is reached after approximately 1 hour. Due to the interaction of rivastigmine with the target enzyme, bioavailability increases 1.5 times more than would be expected with increasing doses. The absolute bioavailability of rivastigmine after taking it at a dose of 3 mg is about 36 ± 13%. When rivastigmine is taken with food, its absorption slows down (the time to reach maximum concentration (tmax) increases by 90 minutes), Cmax decreases, and the area under the "concentration-time" curve (AUC) increases by approximately 30%.
Distribution
Rivastigmine is approximately 40% protein bound. It readily crosses the blood-brain barrier. The apparent volume of distribution is 1.8–2.7 L/kg.
Metabolism
Rivastigmine is rapidly and extensively metabolized (plasma half-life approximately 1 hour), primarily by hydrolysis by cholinesterase to form a decarbamylated metabolite. This metabolite has a low inhibitory effect on acetylcholinesterase in vitro (<10%).
Based on in vitro data, no pharmacokinetic interactions are expected with medicinal products metabolised by the following cytochrome P450 (CYP) isoforms: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19 or CYP2B6. Animal studies suggest that the major cytochrome P450 isoenzymes are minimally involved in the metabolism of rivastigmine. The total plasma clearance of rivastigmine after intravenous administration of 0.2 mg was approximately 130 l/h, decreasing to 70 l/h after intravenous administration of 2.7 mg.
Elimination
Unchanged rivastigmine is not detected in the urine; the main route of elimination is renal excretion in the form of metabolites. After administration of 14C-rivastigmine, renal excretion was rapid and almost complete (> 90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. No accumulation of rivastigmine or its decarbamylated metabolite has been observed in patients with Alzheimer's disease.
According to a population pharmacokinetic analysis in patients with Alzheimer's disease, nicotine intake increases the clearance of rivastigmine when administered orally at a dose of up to 12 mg/day by 23%.
Special patient groups
Elderly patients
Although the bioavailability of rivastigmine in elderly subjects is higher than in young healthy volunteers, studies in Alzheimer's disease patients aged 50 to 92 years did not reveal any age-related changes in bioavailability.
Patients with hepatic impairment
In patients with mild to moderate hepatic impairment, the maximum concentration (Cmax) of rivastigmine was approximately 60% higher and the area under the concentration-time curve (AUC) was ≥2-fold higher compared to healthy volunteers.
In patients with moderate renal impairment, Cmax and AUC of rivastigmine were ≥ 2-fold higher than in healthy volunteers; however, no changes in Cmax and AUC of rivastigmine were observed in patients with severe renal impairment.
Indication
Symptomatic treatment of mild to moderate dementia due to Alzheimer's disease.
Symptomatic treatment of mild to moderate dementia in patients with idiopathic Parkinson's disease.
Contraindication
Hypersensitivity to rivastigmine, other carbamate derivatives or to any other component of the drug. Pregnancy and breastfeeding. Children's age (up to 18 years).
The drug is contraindicated in patients with severe liver dysfunction due to the lack of data on the efficacy and safety of rivastigmine in this group of patients.
Interaction with other medicinal products and other types of interactions
As a cholinesterase inhibitor, rivastigmine may potentiate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution should be exercised in the choice of anaesthetic. Dose adjustment or temporary discontinuation of treatment may be considered if necessary.
Due to the pharmacodynamic effects of rivastigmine and possible additive effects, rivastigmine should not be used concomitantly with other cholinomimetics. Rivastigmine may reduce the therapeutic effect of anticholinergic medicinal products (e.g. oxybutynin, tolterodine).
Additive effects leading to bradycardia (with risk of syncope) have been reported with the combined use of rivastigmine and various β-blockers (including atenolol). Although the use of rivastigmine with cardioselective β-blockers is associated with the highest risk of developing such effects, these undesirable effects have also been observed in patients receiving other β-blocking medicinal products. Therefore, caution should be exercised when rivastigmine is used in combination with β-blockers and other medicinal products that may cause bradycardia (e.g. class III antiarrhythmics, calcium channel antagonists, digitalis glycosides, pilocarpine).
Since bradycardia is a risk factor for the development of torsades de pointes, caution should be exercised and close monitoring of the patient's condition (ECG) is necessary when using rivastigmine in combination with medicinal products that can provoke torsades de pointes, such as antipsychotics, e.g. some phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, tiapride, veralipride), pimozide, haloperidol, droperidol; cisapride; citalopram; diphemanil; erythromycin (intravenous), moxifloxacin; halofantrine, pentamidine; mizolastine; methadone.
In healthy volunteers, no pharmacokinetic interactions were observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine. Rivastigmine does not affect the increase in prothrombin time caused by warfarin. No adverse effects on the cardiac conduction system were observed when digoxin and rivastigmine were co-administered.
Given that rivastigmine is minimally metabolised by the major cytochrome P450 (CYP) isoenzymes, pharmacokinetic interactions of rivastigmine with other medicinal products metabolised by CYP are unlikely. Although rivastigmine may inhibit the metabolism of medicinal products metabolised by butyrylcholinesterase.
Application features
The incidence and severity of adverse reactions usually increase with increasing dose of rivastigmine. If the break in the use of the drug was more than 3 days, treatment should be resumed at a dose of 1.5 mg 2 times a day to reduce the risk of adverse reactions (e.g. vomiting) (see section "Method of administration and dosage").
Dose titration
After a short time after dose increase, adverse reactions such as hypertension and hallucinations were observed in patients with dementia due to Alzheimer's disease, and extrapyramidal disorders, especially tremor, were observed in patients with dementia due to Parkinson's disease. If the severity of adverse reactions did not decrease with dose reduction, rivastigmine treatment was discontinued (see section "Adverse reactions").
Weight loss
Since weight loss may occur in patients with Alzheimer's disease treated with cholinesterase inhibitors, including rivastigmine, the weight of patients should be monitored during treatment with rivastigmine.
Skin reactions
Rare cases of allergic dermatitis (disseminated) have been reported with rivastigmine, regardless of the route of administration (internal or transdermal). In these cases, rivastigmine treatment should be discontinued (see section 4.3). Patients and caregivers should be informed of the possibility of skin reactions with rivastigmine.
Gastrointestinal adverse reactions such as nausea, vomiting and diarrhoea are dose-related and may occur particularly at the start of treatment and/or with dose increases (see section 4.8). These adverse reactions are more common in women. In the event of severe vomiting associated with rivastigmine treatment, appropriate dose adjustment is recommended (see section 4.2). Some cases of severe vomiting have been associated with oesophageal rupture (see section 4.8). Such cases have been observed particularly after dose increases or high doses of rivastigmine. In patients who develop signs of dehydration due to prolonged vomiting or diarrhoea, intravenous fluids and dose reduction or discontinuation of rivastigmine are recommended. Dehydration may be associated with serious consequences.
Rivastigmine may increase gastric acid secretion. Rivastigmine should be used with caution in patients with active gastric or duodenal ulcers or in patients predisposed to these conditions.
Cardiovascular system disorders
Rivastigmine may cause bradycardia, which is a risk factor for torsades de pointes, particularly in patients with risk factors. Rivastigmine should be used with caution in patients at high risk of torsades de pointes, including patients with decompensated heart failure, recent myocardial infarction, bradyarrhythmias, a tendency to hypokalaemia or hypomagnesaemia, and patients receiving concomitant medicinal products known to prolong the QT interval and/or torsades de pointes (see sections 4.5 and 4.8).
Rivastigmine should be used with caution in patients with sick sinus syndrome or conduction disorders (sinoauricular block, atrioventricular block) (see section 4.8).
Other adverse events
Cholinesterase inhibitors should be prescribed with caution to patients with a history of asthma or obstructive pulmonary disease.
Cholinomimetics may induce or exacerbate urinary tract obstruction and convulsions. Caution should be exercised when treating patients predisposed to these conditions.
The use of rivastigmine in patients with severe dementia due to Alzheimer's disease or Parkinson's disease, other types of dementia, or other types of memory impairment (e.g. age-related cognitive decline) has not been studied, and therefore its use in these groups of patients is not recommended.
As with other cholinomimetics, the use of rivastigmine may cause or exacerbate extrapyramidal disorders.
In patients with dementia associated with Parkinson's disease, movement disorders (including bradykinesia, dyskinesia, gait disturbance) and increased tremor have been observed (see section 4.8). In some cases, these events led to discontinuation of rivastigmine therapy (i.e., the incidence of discontinuation due to tremor was 1.7% in the rivastigmine group versus 0% in the placebo group). Clinical monitoring for these adverse reactions is recommended.
Special patient groups
Patients with clinically significant renal/hepatic impairment may experience a higher incidence of dose-related adverse reactions (see sections 5.1 and 5.2). Careful dose titration is recommended, taking into account the individual tolerability of the treatment in this group of patients. Rivastigmine has not been studied in patients with severe hepatic impairment (see section 4.3).
Patients with a body weight below 50 kg may experience a higher incidence of adverse reactions, which may lead to discontinuation of treatment.
Use during pregnancy or breastfeeding
Pregnancy
Studies in pregnant animals have shown that rivastigmine and its metabolites cross the placental barrier. The potential risk to humans is unknown. There are no data on the use of rivastigmine in pregnant women. In studies of peri- and postnatal development in rats, prolongation of gestation was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.
Breast-feeding
Studies have shown that rivastigmine is excreted in breast milk in lactating animals. There are no data on the excretion of rivastigmine in human breast milk. Women taking rivastigmine should not breastfeed.
Fertility
A study in rats showed no effect of rivastigmine on fertility or reproductive function in animals. There are no data on the effect of rivastigmine on human fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
Alzheimer's disease may lead to a gradual deterioration in the ability to drive or operate machinery. In addition, rivastigmine may cause dizziness and drowsiness, especially at the beginning of treatment and when the dose is increased. Therefore, rivastigmine has minor to moderate influence on the ability to drive or operate machinery. The ability of patients with dementia receiving rivastigmine to continue driving or operating complex machinery should be regularly assessed by a physician.
Method of administration and doses
Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of dementia due to Alzheimer's disease or dementia due to Parkinson's disease, and by persons who will regularly monitor the patient's medication intake.
Method of application
The drug should be taken orally, during meals, 2 times a day - in the morning and in the evening. The capsule should be swallowed whole, without chewing.
Recommended dosage regimen
Starting dose and dose titration
The initial dose is 1.5 mg 2 times a day.
If the initial dose is well tolerated after at least 2 weeks of treatment, the dose may be increased to 3 mg twice daily. The dose may be further increased to 4.5 mg twice daily and then to 6 mg twice daily if the previous dose is well tolerated with an interval of at least 2 weeks between each previous dose increase.
If patients with dementia due to Parkinson's disease experience adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight loss or worsening of extrapyramidal disorders (e.g. tremor), one or more doses may be attempted to be omitted. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or treatment should be discontinued.
Maintenance dose and discontinuation of treatment
The recommended effective dose is 3 to 6 mg twice daily. To achieve maximum benefit from treatment, the highest dose that is well tolerated by the patient should be used. The recommended maximum dose is 6 mg twice daily.
Maintenance treatment can be continued as long as the patient continues to benefit from treatment. Therefore, the benefit of rivastigmine treatment should be reassessed regularly, especially in patients receiving doses less than 3 mg twice daily. If the patient does not improve after 3 months of maintenance treatment, treatment should be discontinued. In addition, discontinuation of treatment should be considered if there is no longer evidence of a therapeutic effect.
Individual response to rivastigmine cannot be predicted. However, the best effect of treatment was observed in patients with moderate dementia associated with Parkinson's disease. The best effect was also observed in patients with Parkinson's disease who had visual hallucinations.
Placebo-controlled studies lasting more than 6 months have not been conducted to study the efficacy of rivastigmine.
Resumption of therapy
If the break in use of the drug is more than 3 days, treatment should be resumed at a dose of 1.5 mg 2 times a day. Then the dose should be titrated as described above.
Patients with renal/hepatic impairment
No dose adjustment of rivastigmine is required in patients with mild to moderate renal/hepatic impairment. However, due to increased exposure to rivastigmine in this group of patients, the dose of the drug should be carefully titrated based on individual tolerability, as patients with clinically significant renal/hepatic impairment may experience a higher incidence of dose-related adverse reactions. Rivastigmine has not been studied in patients with severe hepatic impairment (see section 4.3).
Children.
The drug is not used in children (under 18 years of age) due to the lack of data on the use of rivastigmine in patients of this age group.
Overdose
Symptoms
Accidental overdose in most cases was not accompanied by any clinical manifestations and almost all patients continued treatment with rivastigmine 24 hours after the overdose.
In moderate poisonings with cholinesterase inhibitors, muscarinic effects such as miosis, facial flushing, digestive disorders (including abdominal pain, nausea, vomiting and diarrhea), bradycardia, bronchospasm and increased bronchial secretion, hyperhidrosis, involuntary urination and/or defecation, lacrimation, hypotension, hypersalivation have been observed. In more severe poisonings with cholinesterase inhibitors, nicotinic effects such as muscle weakness, fasciculations, convulsions, respiratory arrest with possible fatal outcome may develop.
Cases of dizziness, tremor, headache, drowsiness, psychosis, hypertension, hallucinations and malaise have also been reported.
Since the plasma half-life of rivastigmine is approximately 1 hour and the duration of acetylcholinesterase inhibition is approximately 9 hours, in cases of asymptomatic overdose, it is not recommended to take a further dose of rivastigmine within the next 24 hours. If the overdose is accompanied by severe nausea and vomiting, the use of antiemetics should be considered. If other adverse reactions occur, appropriate symptomatic therapy should be used as necessary.
In severe overdose, atropine may be used. An initial dose of atropine sulfate 0.03 mg/kg intravenously is recommended, with subsequent increases depending on clinical response. The use of scopolamine as an antidote is not recommended.
Adverse reactions
The most frequently reported adverse reactions were gastrointestinal, including nausea (38%) and vomiting (23%), particularly during the dose titration period. In clinical trials, gastrointestinal adverse reactions and weight loss were more frequently observed in women than in men.
The adverse reactions listed below are ranked by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000), not known (frequency cannot be estimated from the available data).
In patients with dementia due to Alzheimer's disease, the following adverse reactions have been observed during treatment with rivastigmine:
Nervous system disorders: very common - dizziness; common - headache, drowsiness, tremor; uncommon - syncope; rare - convulsions; very rare - extrapyramidal disorders (including worsening of concomitant Parkinson's disease).
Mental disorders: often - nightmares, agitation, confusion, anxiety; infrequently - insomnia, depression; very rarely - hallucinations; unknown - aggression, anxiety.
From the gastrointestinal tract:
very common - nausea, vomiting, diarrhea; common - abdominal pain and dyspepsia; rare - gastric and duodenal ulcers; very rare - gastrointestinal bleeding, pancreatitis; unknown - some cases of severe vomiting have been associated with esophageal rupture (see section "Special warnings and precautions for use").
Hepatobiliary system: infrequently - increased laboratory values of liver function; unknown - hepatitis.
Metabolic disorders: very common - anorexia; common - decreased appetite; unknown - dehydration.
Cardiovascular system: rarely - angina pectoris; very rarely - arrhythmias (including bradycardia, atrioventricular block, atrial fibrillation and tachycardia), arterial hypertension.
Skin and subcutaneous tissue disorders: often - hyperhidrosis; rarely - rash; not known - itching, allergic dermatitis (disseminated).
Infections and infestations: very rare – urinary tract infections.
General disorders: often - increased fatigue and asthenia, malaise; infrequently - accidental fall.
Research results: often - weight loss.
In patients with dementia due to Parkinson's disease, the following adverse reactions have been observed during treatment with rivastigmine:
Nervous system disorders: very common - tremor; common - dizziness, drowsiness, headache, worsening of Parkinson's disease, bradykinesia, dyskinesia, hypokinesia, cogwheel rigidity; uncommon - dystonia.
Psychiatric disorders: often - insomnia, anxiety, restlessness, visual hallucinations, depression; unknown - aggression.
Gastrointestinal: very often - nausea, vomiting; often - diarrhea, abdominal pain and dyspepsia, hypersalivation.
Hepatobiliary system: unknown - hepatitis.
From the cardiovascular system: often - bradycardia, arterial hypertension; infrequently - atrial fibrillation, atrioventricular block; unknown - sick sinus syndrome, arterial hypotension.
Metabolic disorders: often - decreased appetite, dehydration.
Skin and subcutaneous tissue disorders: often - hyperhidrosis; not known - allergic dermatitis (disseminated).
General disorders: very common - accidental fall; common - increased fatigue and asthenia, gait disturbance, parkinsonian gait.
Expiration date
2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 ºС.
Keep out of reach of children.
Packaging
10 capsules in blisters; 3 blisters in a pack.
Vacation category
According to the recipe.
Producer
Additional Liability Company "INTERCHEM".
Location of the manufacturer and address of its place of business
Ukraine, 65080, Odesa region, Odessa, Lustdorfska road, building 86.
