Pharmacological properties
Pharmacodynamics. Rivastigmine is an inhibitor of acetylcholinesterase and butyrylcholinesterase of the carbamate type, which promotes cholinergic neurotransmission by slowing the degradation of acetylcholine, which is 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, temporarily inactivating target enzymes. In healthy young men, oral administration of a dose of 3 mg reduces acetylcholinesterase activity in the cerebrospinal fluid by approximately 40% during the first 1.5 hours after taking the drug. After reaching the maximum inhibitory effect, enzyme activity returns to baseline levels after approximately 9 hours. In patients with Alzheimer's disease, the suppression of acetylcholinesterase activity by rivastigmine in the cerebrospinal fluid was dose-dependent (in the studied dose range up to a dose of 6 mg 2 times a day). Suppression of BUTYRYLCHOLINESTERASE activity in the cerebrospinal fluid of patients with Alzheimer's disease treated with rivastigmine was similar to the suppression of acetylcholinesterase activity.
Pharmacokinetics
Absorption. Rivastigmine is rapidly and completely absorbed. C max in plasma is reached after approximately 1 hour. Due to the interaction of rivastigmine with the target enzyme, bioavailability increases by 1.5 times the expected value with increasing dose. The absolute bioavailability of rivastigmine after administration 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 (t max) increases by 90 min), C max decreases, and 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 body weight.
Metabolism: Rivastigmine is rapidly and extensively metabolized (T½ from plasma is approximately 1 h), mainly by hydrolysis with the participation of cholinesterase to form a decarbamylated metabolite. In vitro, this metabolite slightly inhibits acetylcholinesterase (10%).
Based on in vitro data, no pharmacokinetic interactions are expected with drugs metabolized by the following P450 isoforms (CYP): CYP 1A2, 2D6, 3A4/5, 2E1, 2C9, 2C8, 2C19 or 2B6. Animal studies indicate that the major P450 isoenzymes are minimally involved in the metabolism of rivastigmine. The total clearance of rivastigmine after intravenous administration of 0.2 mg was approximately 130 l/h, decreasing to 70 l/h after administration of 2.7 mg.
Excretion. Rivastigmine is not found unchanged in the urine; the main route of excretion is renal excretion as metabolites. After administration of l4 C-rivastigmine, renal excretion was rapid and almost complete (90%) within 24 hours. Less than 1% of the dose is excreted in the feces. 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 healthy young 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, Cmax of rivastigmine was approximately 60% higher and AUC was ≥2-fold higher compared to healthy volunteers.
Patients with renal impairment: 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, Alzheimer's disease.
Symptomatic treatment of mild to moderate dementia in patients with idiopathic Parkinson's disease.
Application
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 use of the medicinal product.
Method of administration. The drug is taken orally, during meals, 2 times a day - in the morning and in the evening. Swallow the capsule whole, without chewing.
Recommended dosage regimen
Initial dose and titration doses. Initial dose - 1.5 mg 2 times a day.
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 omitted. If adverse reactions persist, the 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, a higher dose that is well tolerated by the patient should be used. The recommended maximum dose is 6 mg twice daily.
Maintenance therapy should 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 below 3 mg twice daily. If the patient does not improve after 3 months of maintenance therapy, treatment should be discontinued. In addition, discontinuation of therapy should be considered if there is no longer evidence of therapeutic benefit.
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 effectiveness of rivastigmine.
Resuming therapy: If the break in taking the drug was 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 rivastigmine exposure in these 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 Adverse Reactions).
Contraindication
Hypersensitivity to Rivastigmine, other carbamate derivatives or 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 such patients.
Side effects
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 commonly reported in women than in men.
The following adverse reactions are classified according to frequency: very common (≥1/10), common (≥1/100 to 1/10), uncommon (≥1/1000 to 1/100), rare (≥1/10,000 to 1/1000) 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:
From the nervous system: very often - dizziness; often - headache, drowsiness, tremor; infrequently - fainting; rarely - convulsions; very rarely - extrapyramidal disorders (including worsening of concomitant Parkinson's diseases).
Mental disorders: often - nightmares, agitation, confusion, anxiety; infrequently - insomnia, depression; very rarely - hallucinations; unknown - aggression, anxiety.
On the part of the digestive system: often - nausea, vomiting, diarrhea; often - abdominal pain and dyspepsia; rarely - gastric and duodenal ulcers; very rarely - gastrointestinal bleeding, pancreatitis; unknown - some cases of severe vomiting were associated with esophageal rupture (see Features of use).
From the hepatobiliary system: rarely - increased liver function tests; unknown - hepatitis.
Metabolism: often - anorexia; often - decreased appetite; unknown - dehydration.
From the cardiovascular system: rarely - angina pectoris; very rarely - arrhythmias (including bradycardia, block, atrial fibrillation and tachycardia), hypertension.
Skin and subcutaneous tissue disorders: often - hyperhidrosis; rarely - rash, unknown - 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:
From the nervous system: very often - tremor; often - dizziness, drowsiness, headache, worsening of Parkinson's disease, bradykinesia, dyskinesia, hypokinesia, cogwheel rigidity; infrequently - dystonia.
Mental disorders: often - insomnia, anxiety, restlessness, visual hallucinations, depression; unknown - aggression.
From the hepatobiliary system: unknown - hepatitis.
From the cardiovascular system: often - bradycardia, hypertension; infrequently - atrial fibrillation, AV block; unknown - sick sinus syndrome, arterial hypotension.
Metabolic: often - decreased appetite, dehydration.
Skin and subcutaneous tissue disorders: often - hyperhidrosis; not known - allergic dermatitis (disseminated).
General disorders: very often - accidental fall; often - increased fatigue and asthenia, gait disturbance, parkinsonian gait.
Special instructions
The incidence and severity of adverse reactions usually increase with increasing dose of rivastigmine. If the break in taking 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 use).
Dose titration. After a short time after increasing the dose, adverse reactions such as hypertension and hallucinations were observed in patients with dementia due to Alzheimer's disease, and in those with dementia due to Parkinson's disease, extrapyramidal disorders, especially tremor, were observed. If the severity of adverse reactions did not decrease with dose reduction, rivastigmine treatment was discontinued (see 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. Isolated cases of allergic dermatitis (disseminated) have been reported with rivastigmine, regardless of the route of administration (oral or transdermal). In these cases, rivastigmine treatment should be discontinued (see Adverse Reactions). Patients and caregivers should be informed of the possibility of skin reactions with rivastigmine.
Gastrointestinal disorders. Gastrointestinal adverse reactions such as nausea, vomiting and diarrhoea are dose-dependent and may occur particularly at the start of treatment and/or with dose increases (see Adverse Reactions). These adverse reactions are more common in women. In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustment is recommended (see Dosage and Administration). Some cases of severe vomiting have been associated with oesophageal rupture (see Adverse Reactions). Such cases have been reported particularly after dose increases or high doses of rivastigmine. Patients who develop signs of dehydration due to prolonged vomiting or diarrhoea are recommended to receive intravenous fluids and reduce the dose or discontinue rivastigmine therapy. 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 those predisposed to these conditions.
Cardiovascular 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 those with decompensated heart failure, recent myocardial infarction, bradyarrhythmias, those prone to hypokalemia or hypomagnesemia, and those receiving concomitant medications known to prolong the QT interval and/or torsades de pointes (see Interactions, Adverse Reactions).
Caution should be exercised when using rivastigmine in patients with sick sinus syndrome or conduction disorders (sinoauricular block, block) (see Side effects).
Other adverse events. Cholinesterase inhibitors should be used with caution in 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 with these conditions.
The use of rivastigmine in patients with severe dementia due to Alzheimer's disease or Parkinson's disease, with other types of dementia or with other types of memory impairment (e.g. age-related cognitive decline) has not been studied, therefore the use of the drug in these groups of patients is not recommended.
As with other cholinomimetics, the use of rivastigmine may cause or worsen extrapyramidal disorders.
In patients with dementia associated with Parkinson's disease, movement disorders (including bradykinesia, dyskinesia, gait disturbance) and increased tremor have been reported (see Adverse Reactions). 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.
Patients with clinically significant renal/hepatic impairment may experience a higher incidence of dose-related adverse reactions (see Pharmacological properties, Use and Interactions). It is recommended that the dose be carefully titrated based on the individual tolerability of treatment in this group of patients. The use of rivastigmine in patients with severe hepatic impairment has not been studied (see Adverse Reactions).
Patients weighing 50 kg may experience more frequent adverse reactions, which may lead to discontinuation of treatment.
Use during pregnancy and 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 human data on the use of rivastigmine during pregnancy. In studies of pre- and postnatal development in rats, prolongation of the gestation period was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.
Breastfeeding. 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: In a study conducted in rats, there was no effect of rivastigmine on fertility or reproductive function in animals. There are no data on the effect of rivastigmine on fertility in humans.
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.
Ability to drive or use machines. Alzheimer's disease may lead to a gradual deterioration in the ability to drive or use machines. In addition, rivastigmine may cause dizziness and drowsiness, especially at the beginning of treatment and when the dose is increased. Therefore, rivastigmine has minor or moderate influence on the ability to drive or use machines. The ability of patients with dementia taking rivastigmine to continue driving or using machines should be regularly assessed by a doctor.
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 its possible additive effects, rivastigmine should not be used with other cholinomimetics. Rivastigmine may reduce the therapeutic effect of anticholinergic drugs (e.g. oxybutynin, tolterodine).
Additive effects leading to bradycardia (with a risk of syncope) have been reported with the combined use of rivastigmine and various β-adrenergic blockers (including atenolol). Although the use of rivastigmine with cardioselective β-adrenergic blockers is associated with a high risk of developing such effects, these side effects have also been observed in patients receiving other β-adrenergic blockers. Therefore, caution should be exercised when rivastigmine is used in combination with β-adrenergic blockers and other drugs that can 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 the patient's health status (ECG) should be closely monitored when using rivastigmine in combination with drugs that can provoke torsades de pointes, such as antipsychotics, for example, some phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, tiapride, veralipride), pimozide, haloperidol, droperidol; cisapride; citalopram; diphemanil; erythromycin (iv), moxifloxacin; halofantrine, pentamidine; mizolastine; methadone.
In healthy volunteers, no pharmacokinetic interaction between rivastigmine and digoxin, warfarin, diazepam or fluoxetine was observed. Rivastigmine did 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.
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 noted. In more severe poisonings with cholinesterase inhibitors, nicotinic effects such as muscle weakness, muscle twitching, convulsions, respiratory arrest with possible fatal outcome may develop.
Cases of dizziness, tremor, headache, drowsiness, psychosis, hypertension, hallucinations and malaise have also been reported.
Treatment. Since the T½ of rivastigmine from blood plasma 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 the next 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. In the event of other undesirable effects, appropriate symptomatic therapy should be used if necessary.
In severe overdose, atropine may be used. An initial dose of atropine sulfate of 0.03 mg/kg is recommended, with subsequent increases depending on clinical response. The use of scopolamine as an antidote is not recommended.
Storage conditions
In the original packaging at a temperature not exceeding 25 °C.
