Rivastigmine

Rivastigmine alleviates deficits in cognitive function due to impaired cholinergic transmission in dementia due to Alzheimer's or Parkinson's disease.

Indications Rivastigmine

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.

Release form

• 1 capsule contains rivastigmine hydrotartrate 2.4 mg, equivalent to 1.5 mg rivastigmine, or rivastigmine hydrotartrate 4.8 mg, equivalent to 3 mg rivastigmine;
• excipients: microcrystalline cellulose, hypromellose, anhydrous colloidal silicon dioxide, magnesium stearate;
• Capsule shell: gelatin, sodium lauryl sulfate, iron oxide yellow (E 172), iron oxide red (E 172) (3 mg capsules), titanium dioxide (E 171).

Dosage form. Hard capsules.

Basic physicochemical properties:

• hard capsules 1.5 mg: hard gelatin capsules with opaque body and cap of yellow color; capsule contents - powder of almost white to slightly yellow color;
• hard capsules 3 mg: hard gelatin capsules with opaque body and orange-colored cap; capsule contents - powder of almost white to slightly yellow color.

Pharmacodynamics

Rivastigmine is a carbamate-type acetyl- and butyrylcholinesterase inhibitor; it is thought to promote cholinergic transmission by slowing the degradation of acetylcholine released from cholinergic neurons with undisturbed function.

Rivastigmine interacts with target enzymes to form a covalent complex that temporarily inactivates the enzymes. In healthy young males, an oral dose of 3 mg reduces the activity of acetylcholinesterase (AChE) in cerebrospinal fluid (CSF) by approximately 40% during the first 1.5 hours. The enzyme activity returns to baseline values approximately 9 h after the maximum inhibitory effect is reached. In patients with Alzheimer's disease, the suppression of AChE activity by rivastigmine in the CSF was dose-dependent, up to the highest dose studied, 6 mg twice daily. The suppression of butyrylcholinesterase activity in the CSF of 14 Alzheimer's patients treated with rivastigmine was similar to the suppression of AChE activity.

Pharmacokinetics

Absorption: Rivastigmine is rapidly and completely absorbed. The maximum concentration (Cmax) in plasma is reached in approximately 1 hour. As a consequence of interaction of the drug with the target enzyme, one can expect about 1.5 times higher bioavailability than with increasing dose. Absolute bioavailability after dose administration

3 mg - approximately 36% ± 13%. Food administration of rivastigmine slows absorption (tmax) by 90 minutes, decreases Cmax and increases AUC by approximately 30%.

Distribution: Rivastigmine binding to proteins is about 40%. It easily passes through the blood-brain barrier; the apparent volume of distribution is 1.8 - 2.7 L/kg.

Metabolism -- Rivastigmine is rapidly and extensively converted (plasma half-life approximately 1 hour), mainly by hydrolysis, to a decarbamylated product mediated by cholinesterase. In vitro, this metabolite slightly inhibits acetylcholinesterase (< 10%).

Based on in vitro studies, no pharmacokinetic interaction is expected with drugs metabolized by the following cytochrome isoenzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19 or CYP2B6. Based on data from in vitro experiments and animal studies, the major cytochrome P450 isoenzymes are minimally involved in the metabolism of rivastigmine. The total clearance of rivastigmine from plasma after intravenous administration at a dose of 0.2 mg was approximately 130 L/hour and decreased to 70 L/hour after a dose of 2.7 mg intravenously.

Elimination: Rivastigmine is not found unchanged in the urine; the main route of excretion is renal excretion in the form of metabolites. After administration of l4C-rivastigmine, renal excretion was rapid and almost complete (> 90%) within 24 h.

Less than 1% of the administered dose is excreted in the feces. No accumulation of rivastigmine or its decarbamylated metabolite has been detected in patients with Alzheimer's disease.

Pharmacokinetic analysis showed that nicotine administration increased oral clearance of rivastigmine by 23% in patients with Alzheimer's disease after administration of rivastigmine in capsules at doses up to 12 mg/day.

Older adults -- Whereas the bioavailability of rivastigmine in the elderly is higher than in young healthy volunteers, studies in Alzheimer's disease patients aged 50 to 92 years have not shown a change in bioavailability with age.

Patients with hepatic dysfunction. In patients with mild to moderate liver dysfunction Cmax of rivastigmine was about 60% higher and AUC - more than twice as high as in healthy subjects.

Patients with impaired renal function: in patients with moderate renal impairment Cmax and AUC of rivastigmine were more than twice as high as in healthy subjects. However, no changes in Cmax and AUC of rivastigmine were found in patients with severe renal impairment.

Dosing and administration

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia or dementia due to Parkinson's disease. Diagnosis should be made in accordance with current guidelines. Rivastigmine therapy should only be initiated when caregivers are available to regularly monitor the patient's intake.

Rivastigmine is taken 2 times a day, morning and evening, together with food. Capsules should be swallowed whole.

The initial dose is 1.5 mg 2 times a day.

Dose titration: the initial dose is 1.5 mg twice daily. If this dose is well tolerated, after at least two weeks of treatment, it can be increased to 3 mg twice daily. Subsequent increase to 4.5 mg and then to 6 mg twice daily should be based on good tolerance of the current dose and is allowed not earlier than after two weeks of treatment with this dose.

If adverse reactions (e.g. Nausea, vomiting, abdominal pain or decreased appetite), weight loss or worsening of extrapyramidal symptoms (e.g. Tremor) occur in patients with dementia due to Parkinson's disease, you may try to skip one or more doses. If adverse reactions do not disappear, the daily dose should be temporarily reduced to the previous well-tolerated dose or treatment should be suspended.

Maintenance dose: the effective dose is 3-6 mg 2 times a day.

To achieve maximum therapeutic effect, patients should use the highest well tolerated dose. The recommended maximum dose is 6 mg 2 times a day.

Maintenance treatment can be continued as long as it is of benefit to the patient. Consequently, the clinical benefit of rivastigmine should be regularly reassessed, especially in patients receiving a dose of less than 3 mg twice daily. If the severity of dementia symptoms has not decreased after 3 months of treatment, treatment should be discontinued. In addition, discontinuation of treatment should be considered if signs of therapeutic effect are no longer observed.

Individual response to rivastigmine cannot be predicted. However, the best treatment effect was observed in patients with Parkinson's disease with moderately severe dementia and in patients with Parkinson's disease with visual hallucinations.

No clinical trials lasting more than 6 months have been conducted to study the therapeutic effect.

Resumption of therapy.

If treatment has been interrupted for more than three days, it should be resumed from a dose of 1.5 mg twice daily. The dose should then be titrated as described above.

Renal and liver dysfunction.

Due to the increased effect of the drug in mild to moderate renal and hepatic insufficiency, it is recommended to accurately adjust the dose by titration according to individual tolerance. Rivastigmine Orion capsules can be used in patients with severe hepatic impairment, provided careful monitoring is performed.

Children: Rivastigmine is not indicated for use in children.

Use Rivastigmine during pregnancy

In animals rivastigmine and/or metabolites penetrate through the placenta. There are no clinical data on the use of rivastigmine during pregnancy. During peri- and postnatal studies in animals prolongation of pregnancy was found. Rivastigmine should not be used in pregnant women unless absolutely necessary.

Breast-feeding period: Rivastigmine has been found to be excreted into milk in animals. It is not known whether rivastigmine is excreted into breast milk. Therefore, women receiving rivastigmine should not breastfeed.

Fertility: Animal studies have shown no adverse effects on fertility and development of embryos and fetuses. The effect of rivastigmine on human fertility is not known.

Contraindications

This drug is contraindicated in patients with known hypersensitivity to rivastigmine, other carbamate derivatives, or any of the excipients in the formulation.

Contact allergic dermatitis in the anamnesis, which occurred against the background of application of the drug containing rivastigmine in the form of a patch.

Side effects Rivastigmine

The most common adverse reactions include gastrointestinal disorders, including nausea (38%) and vomiting (23%), especially during dose titration. Clinical studies have shown that women are more susceptible to gastrointestinal adverse reactions and weight loss than men.

The incidence of adverse reactions is categorized as follows: very frequent (≥1/10); frequent (≥1/100, <1/10); infrequent (≥1/1000, <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); frequency unknown (cannot be determined from available data).

In patients with dementia due to Alzheimer's disease, adverse reactions have been observed during rivastigmine treatment:

Infections and Infections.

Very rare: urinary tract infections.

Mental disorders.

Frequent: agitation, confusion, nightmares, anxiety.

Infrequent: insomnia, depression.

Very rare: hallucinations.

Frequency unknown: aggression, restlessness.

Nervous system side.

Very often: dizziness.

Frequent: headache, drowsiness, tremor.

Infrequent: syncope.

Rarely: seizures.

Very rare: extrapyramidal symptoms (including worsening of Parkinson's disease).

Cardiovascular system.

Rarely: angina pectoris.

Very rare: arrhythmias (including bradycardia, atrial-ventricular node block, atrial fibrillation and tachycardia), arterial hypertension.

Frequency unknown: sinus node weakness syndrome.

Gastrointestinal tract.

Very often: nausea, vomiting, diarrhea.

Frequent: abdominal pain and dyspepsia.

Rarely: gastric and duodenal ulcers.

Extremely rare: hemorrhage from the gastrointestinal tract, pancreatitis.

Frequency unknown: some cases of severe vomiting have been associated with esophageal rupture.

Metabolic and nutritional disorders.

Very common: anorexia.

Frequent: decreased appetite.

Frequency unknown: dehydration.

Hepatobiliary system.

Infrequent: elevation of hepatic parameters.

Frequency unknown: hepatitis.

Skin and subcutaneous tissue.

Frequent: increased sweating.

Rarely: rashes.

Frequency unknown: pruritus, allergic dermatitis (disseminated).

General Disturbances.

Frequently: increased fatigue, asthenia, malaise.

Infrequent: accidental fall.

Research Results.

Frequent: decrease in body weight.

In patients with dementia due to Parkinson's disease, adverse reactions have been observed during rivastigmine treatment:

Mental disorders.

Frequent: insomnia, anxiety, restlessness, hallucinations, depression.

Frequency unknown: aggression.

Nervous system side.

Very common: tremor.

Frequent: dizziness, drowsiness, headache, worsening of Parkinson's disease, bradykinesia, dyskinesia, hypokinesia, cogwheel phenomenon.

Infrequent: dystonia.

Cardiovascular system.

Frequent: bradycardia, arterial hypertension.

Infrequent: atrial fibrillation, atrial ventricular node block, arterial hypotension.

Frequency unknown: sinus node weakness syndrome.

Gastrointestinal tract.

Very often: nausea, vomiting.

Frequent: diarrhea, decreased appetite, abdominal pain and dyspepsia, increased saliva secretion.

Hepatobiliary system.

Frequency unknown: hepatitis.

Skin and subcutaneous tissue.

Frequent: increased sweating.

Frequency unknown: allergic dermatitis (disseminated).

Musculoskeletal system and connective tissue:

Frequent: muscle rigidity.

Metabolic and nutritional disorders.

Frequent: anorexia, dehydration.

General Disturbances.

Very often: an accidental fall.

Frequent: increased fatigue, asthenia, gait disturbance, parkinsonian gait.

Overdose

Symptoms: most overdose cases did not present any clinical signs or symptoms, and almost all patients continued treatment with rivastigmine within 24 h.

In moderate poisonings, cholinergic toxicity with muscarinic symptoms such as miosis, flushes, digestive disorders including abdominal pain, nausea, vomiting and diarrhea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary urination and/or defecation, lacrimation, hypotension and salivary hypersecretion have been reported.

In more severe cases, nicotine effects such as muscle weakness, fasciculations, seizures and respiratory arrest with possible death may develop.

In addition, incidences of dizziness, tremor, headache, drowsiness, confusion, arterial hypertension, hallucinations and malaise have been observed in the post-marketing period.

Treatment: since the half-life 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 24 hours. In case of overdose with severe nausea and vomiting, antiemetics should be considered. In case of other adverse events, symptomatic therapy should be used.

Atropine may be administered in case of severe overdose. The recommended starting dose of atropine sulfate is 0.03 mg/kg with subsequent increases depending on clinical signs. The use of scopolamine as an antidote is not recommended.

Interactions with other drugs

As a cholinesterase inhibitor, rivastigmine may increase the effects of muscle relaxants such as succinylcholine during anesthesia. Caution is advised in the selection of anesthetic agents. If necessary, dose adjustment or temporary discontinuation of treatment may be considered.

Due to its pharmacodynamic effects, rivastigmine should not be used with other cholinomimetics; it may also interact with anticholinergic drugs such as oxybutynin, tolterodine.

Additive effects leading to bradycardia (which can lead to syncope) have been reported with the combined use of various beta-blockers (including atenolol) and rivastigmine. The greatest risk is associated with cardiovascular beta-blockers, but there have also been reports of patients who have used other beta-blockers. Thus, caution should be exercised when combining rivastigmine with beta-blockers, as well as with other drugs that cause bradycardia (e.g., class III antiarrhythmic agents, calcium channel antagonists, digitalis glycosides, pilocarpine).

Since bradycardia is a risk factor for the development of paroxysmal ventricular tachycardia (torsades de pointes), combine rivastigmine with drugs that may lead to paroxysmal ventricular tachycardia (torsades de pointes), such as antipsychotic drugs, i.e. Some phenothiazines (chlorpromazine, levomepromazine), benzamide (sulpiride, sultopride, amisulpride, thiapride, veralipride), pimozide, haloperidol, droperidol, cisapride, citalopram, diphenamyl, erythromycin IV, halofantrine, misolastine, methadone, pentamidine, and moxifloxacin should be used with caution and clinical monitoring (ECG) should be performed if necessary.

No pharmacokinetic interactions between rivastigmine and digoxin, warfarin, diazepam or fluxetine were found during studies in healthy volunteers. Rivastigmine does not affect the increase in prothrombin time under the effect of warfarin. When coadministration of digoxin and rivastigmine no undesirable effect on cardiac conduction was detected.

Metabolic interactions appear unlikely, although rivastigmine can inhibit butyrylcholinesterase-mediated metabolism of other drugs.

Storage conditions

Store at a temperature not exceeding 25 °C out of reach of children.

Special instructions

The frequency and severity of adverse reactions usually increase with increasing dose. If treatment is interrupted for more than a few days, it should be resumed at a dose of 1.5 mg twice daily to reduce the likelihood of adverse reactions (e.g. Vomiting).

In the course of post-registration use of the drug, data on the development of allergic dermatitis (disseminated) in some patients when using rivastigmine regardless of the route of administration (oral, transdermal) were obtained. In these cases the use of the drug should be discontinued.

Patients and their caregivers should be informed of the possibility of developing relevant reactions in an appropriate manner.

Dose titration: adverse reactions (e.g. Arterial hypertension and hallucinations in patients with dementia due to Alzheimer's disease and worsening of extrapyramidal symptoms, especially tremor, in patients with dementia due to Parkinson's disease) have been observed shortly after dose increase. They may decrease after dose reduction. In other cases, the drug was discontinued.

Gastrointestinal disturbances, such as nausea and vomiting, have been observed particularly at the beginning of treatment and with dose escalation. Adverse reactions are more frequent in women.

In patients who develop signs of dehydration, as a result of prolonged diarrhea or vomiting, intravenous fluid administration and dose reduction or discontinuation of rivastigmine treatment are recommended because of the possible risk of serious complications.

In Alzheimer's disease there may be a decrease in body weight associated with the use of cholinesterase inhibitors, including rivastigmine. The patient's weight should be monitored during therapy.

In case of severe vomiting associated with rivastigmine treatment, an appropriate dose adjustment is recommended. Some cases of severe vomiting have been associated with esophageal rupture. In particular, such phenomena have been observed after dose escalation or use of high doses of rivastigmine.

Rivastigmine may lead to bradycardia, which is a risk factor for the development of paroxysmal ventricular torsades de pointes, mainly in patients with risk factors. The drug should be used with caution in patients with increased risk of developing paroxysmal ventricular torsades de pointes (torsades de pointes), e.g. Patients with uncompensated heart failure, patients who have recently undergone myocardial infarction, patients with bradyarrhythmia, tendency to hypokalemia or hypomagnesemia or in concomitant use with drugs that induce QT interval and/or with paroxysmal ventricular tachycardia (torsades de pointes).

As with other cholinomimetics, caution should be exercised when prescribing rivastigmine in patients with sinus node weakness syndrome or conduction disorders (sinus node block, atrial-ventricular node block).

Like other cholinergic substances, rivastigmine may increase gastric juice secretion. Caution should be exercised when prescribing the drug to patients with active gastric or duodenal ulcer or predisposition to these conditions.

Cholinesterase inhibitors should be administered with caution in patients with a history of asthma or obstructive pulmonary disease.

Cholinomimetics may induce or aggravate urinary tract obstruction and seizures. Caution should be exercised when treating patients predisposed to these pathologies.

The possibility of using rivastigmine in patients with severe dementia due to Alzheimer's or Parkinson's disease, other types of dementia, or other types of memory impairment (e.g., age-related decline in cognitive function) has not been investigated.

Like other cholinomimetics, rivastigmine can aggravate or induce extrapyramidal symptoms. In patients with dementia due to Parkinson's disease there have been cases of worsening (including bradykinesia, dyskinesia, gait disturbances) and increased frequency of tremor. In some cases, rivastigmine therapy had to be discontinued due to these phenomena (namely, the rate of drug withdrawal due to tremor was 1.7% in the rivastigmine group and 0% in the placebo group). Clinical monitoring of these events is recommended.

Patients with impaired liver and kidney function

A more frequent development of adverse reactions may be observed in patients with clinically significant hepatic and renal dysfunction. It is recommended to carefully titrate the dose of rivastigmine according to individual tolerability in this category of patients. The use of rivastigmine in patients with severe hepatic dysfunction has not been studied.

Patients with body weight less than 50 kg

Patients with body weight less than 50 kg are more prone to the development of adverse reactions, so there is a high probability of discontinuation of treatment with the drug in such patients.

Ability to affect reaction speed when driving motor transport or other mechanisms.

Alzheimer's disease may lead to a gradual deterioration of the ability to drive and operate machinery. In addition, rivastigmine may cause dizziness and drowsiness, especially at the beginning of treatment and with dose increase. As a result, rivastigmine has an insignificant or moderate effect on the ability to drive vehicles and operate mechanisms. Therefore, the ability of patients with dementia receiving rivastigmine to drive motor vehicles or operate complex mechanisms should be periodically assessed by the attending physician.

Shelf life

5 years.