Rivastigmine

Pharmacological properties

rivastigmine is an inhibitor of carbamate-type acetylcholinesterase and butyrylcholinesterase, which promotes cholinergic neurotransmission, slowing down the degradation of acetylcholine, which is released by functionally intact cholinergic neurons. thus, rivastigmine has a beneficial effect on cognitive deficit caused by impaired cholinergic neurotransmission in dementia associated with Alzheimers or Parkinsons disease.

Rivastigmine interacts with target enzymes to form covalent complexes, temporarily inactivates target enzymes. In healthy young men, an oral dose of 3 mg reduces the activity of acetylcholinesterase in CSF by about 40% during the first 1.5 hours after taking the drug. After reaching the maximum inhibitory effect, the enzyme activity returns to its initial level after about 9 hours. In patients with Alzheimers disease, the suppression of the activity of rivastigmine acetylcholinesterase in CSF was dose-dependent (in the studied dose range up to the dose of 6 mg 2 times a day). The inhibition of butyrylcholinesterase activity in the CSF of patients with Alzheimers disease who received rivastigmine was similar to the inhibition of acetylcholinesterase activity.

Pharmacokinetics

Absorption. Rivastigmine is rapidly and completely absorbed. WITH_max in plasma is reached after about 1 hour. Due to the interaction of rivastigmine with the target enzyme, with increasing doses, the bioavailability increases 1.5 times more than expected. The absolute bioavailability of rivastigmine after administration at a dose of 3 mg is about 36 ± 13%. When taking rivastigmine with food, its absorption slows down (time to reach maximum concentration (t_max) increases by 90 min), decreases_maxAUC increases by approximately 30%.

Distribution. The binding of rivastigmine to proteins is about 40%. It easily penetrates the BBB. The imaginary distribution volume is 1.8–2.7 l / kg body weight.

Metabolism. Rivastigmine is rapidly and extensively metabolized (T_½ from blood plasma - about 1 hour) mainly by hydrolysis with the participation of cholinesterase with the formation of decarbamylated metabolite. In vitro, this metabolite slightly inhibits acetylcholinesterase (10%).

According to data obtained in in vitro studies, pharmacokinetic interactions with drugs that are metabolized by the following isoforms of cytochrome P450 (CYP) are not expected: CYP 1A2, 2D6, 3A4 / 5, 2E1, 2C9, 2C8, 2C19 or 2B6. According to animal studies, the main isoenzymes of cytochrome P450 are involved in the metabolism of rivastigmine to a minimum. The total clearance of rivastigmine after i.v. administration at a dose of 0.2 mg was approximately 130 l / h, after administration at a dose of 2.7 mg it decreased to 70 l / h.

Rivastigmine unchanged in urine is not detected; the main route of excretion is by the kidneys in the form of metabolites. After introduction ^l4C-rivastigmine excretion by the kidneys was fast and almost complete (90%) within 24 hours. Less than 1% of the dose is excreted in the feces. In patients with Alzheimers disease, no accumulation of rivastigmine or its decarbamyl metabolite was detected.

According to population pharmacokinetic analysis in patients with Alzheimers disease, nicotine intake increases rivastigmine clearance 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 older people is higher than in healthy volunteers of a young age, in studies involving patients with Alzheimers disease aged 50 to 92 years did not reveal any changes in bioavailability associated with age.

Patients with impaired liver function. In patients with impaired liver function of mild or moderate severity_max rivastigmine was approximately 60% higher, and AUC ≥2 times higher than healthy volunteers.

Patients with impaired renal function. In patients with impaired renal function of moderate severity, the value of C_max and AUC of rivastigmine were higher at ≥2 times than in healthy volunteers; however, changes in C values_max and AUC of rivastigmine in patients with severe renal impairment has not been established.

Indications

Symptomatic treatment of mild to moderate dementia due to Alzheimers disease.

Symptomatic treatment of mild to moderate dementia in patients with idiopathic Parkinsons disease.

Application

Treatment should be started and carried out under the supervision of a physician experienced in the diagnosis and treatment of dementia in Alzheimers disease or dementia due to Parkinsons disease, and under the supervision of individuals who will regularly monitor the patient’s use of the drug.

Mode of application. 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

Initial dose and titration doses. The initial dose is 1.5 mg 2 times a day.

If after a minimum of 2 weeks of treatment there is a good tolerance to the initial dose, the dose can be increased to 3 mg 2 times a day. It is possible to further increase the dose to 4.5 mg 2 times a day and then to 6 mg 2 times a day with good tolerance of the previous dose with an interval of at least 2 weeks after each previous dose increase.

If patients with dementia due to Parkinsons disease experience adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight loss or worsening extrapyramidal disorders (e.g. tremor), you can try to skip one or more doses. If adverse reactions do not disappear, the dose should be temporarily reduced to the previous dose, which was well tolerated, or treatment should be discontinued.

Maintenance dose and discontinuation of treatment. The recommended effective dose is from 3 to 6 mg 2 times a day. To achieve maximum benefit from treatment, a higher dose should be used, which is well tolerated by the patient. The recommended maximum dose is 6 mg 2 times a day.

Maintenance treatment can be continued as long as there is a benefit to the patient. So, you should regularly evaluate the benefits of treatment with rivastigmine, especially in individuals receiving a dose below 3 mg 2 times a day. If after 3 months of maintenance therapy there is no improvement in the patients condition, treatment should be discontinued. In addition, it is necessary to consider the possibility of discontinuing therapy if signs of a therapeutic effect are no longer observed.

An individual reaction to rivastigmine cannot be predicted. However, the best treatment effect was observed in patients with moderate dementia associated with Parkinsons disease. Also, the best effect was observed in patients with Parkinsons disease who had visual hallucinations.

Placebo-controlled studies lasting more than 6 months in order to study the effectiveness of rivastigmine were not performed.

The resumption of therapy. If the break in taking the drug was more than 3 days, treatment should be resumed with a dose of 1.5 mg 2 times a day. Then, dose titration should be performed as described above.

Patients with impaired renal / hepatic function. Patients with impaired renal / hepatic function of mild or moderate severity do not require dose adjustment of rivastigmine. However, due to the increased exposure of rivastigmine in these patients, the dose of the drug should be carefully titrated taking into account individual tolerance of treatment, since in patients with clinically pronounced impaired renal / liver function, dose-dependent adverse reactions may develop more frequently. The use of rivastigmine in patients with severe liver dysfunction has not been investigated (see CONTRAINDICATIONS).

Contraindications

Hypersensitivity to rivastigmine, other derivatives of carbamate or to any other component of the drug. During pregnancy and breastfeeding. childrens 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

Most commonly reported side effects from the digestive tract, including nausea (38%) and vomiting (23%), especially during dose titration. according to clinical studies, adverse reactions from the gastrointestinal tract and weight loss were more often observed in women than in men.

The following adverse reactions are distributed in frequency as follows: very often (≥1 / 10), often (≥1 / 100 to 1/10), infrequently (≥1 / 1000 to 1/100), rarely (≥1 / 10,000 to 1/1000) and very rarely (1/10 000), it is unknown (the frequency cannot be estimated from the available data).

In patients with dementia due to Alzheimers disease, the following adverse reactions were noted during treatment with rivastigmine:

From the nervous system: very often - dizziness; often - headache, drowsiness, tremor; infrequently - fainting; rarely - cramps; very rarely - extrapyramidal disorders (including worsening of the course of concomitant Parkinsons disease).

Mental disorders: often - nightmares, agitation, confusion, anxiety; infrequently - insomnia, depression; very rarely - hallucinations; unknown - aggression, anxiety.

From the digestive system: often - nausea, vomiting, diarrhea; often - abdominal pain and dyspepsia; rarely - stomach and duodenal ulcers; very rarely - gastrointestinal bleeding, pancreatitis; unknown - some cases of severe vomiting have been associated with rupture of the esophagus (see SPECIAL INSTRUCTIONS).

From the hepatobiliary system: rarely - an increase in laboratory parameters of liver function; unknown - hepatitis.

From the side of metabolism: often - anorexia; often - loss of appetite; unknown - dehydration.

From the cardiovascular system: rarely - angina pectoris; very rarely - arrhythmias (including bradycardia, blockade, atrial fibrillation and tachycardia), hypertension.

On the part of the skin and subcutaneous tissue: often - hyperhidrosis; rarely - rash, unknown - itching, allergic dermatitis (disseminated).

Infections and infestations: very rarely - 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 Parkinsons disease, the following adverse reactions were noted during treatment with rivastigmine:

From the nervous system: very often - tremor; often - dizziness, drowsiness, headache, worsening of the course of Parkinsons disease, bradykinesia, dyskinesia, hypokinesia, rigidity of the type of "gear"; infrequently - dystonia.

Mental disorders: often - insomnia, anxiety, anxiety, visual hallucinations, depression; unknown - aggression.

From the digestive system: very often - nausea, vomiting, often - diarrhea, abdominal pain and dyspepsia, hypersalivation.

From the hepatobiliary system: unknown - hepatitis.

From the cardiovascular system: often - bradycardia, hypertension; infrequently - atrial fibrillation, AV block; unknown - sinus node weakness syndrome, arterial hypotension.

From the side of metabolism: often - loss of appetite, dehydration.

On the part of the skin and subcutaneous tissue: often - hyperhidrosis; unknown - allergic dermatitis (disseminated).

General violations: very often - an accidental fall; often - increased fatigue and asthenia, impaired gait, parkinsonian gait.

special instructions

The incidence and severity of adverse reactions usually increase with increasing doses of rivastigmine.if the break in taking the drug was more than 3 days, treatment should be resumed with a dose of 1.5 mg 2 times a day to reduce the risk of adverse reactions (e.g. vomiting) (see application).

Dose titration. In a short time after increasing the dose in patients with dementia in Alzheimers disease, adverse reactions such as hypertension and hallucinations were noted, in individuals with dementia in Parkinsons disease - extrapyramidal disorders, especially tremor. If the severity of adverse reactions did not decrease with a dose reduction, treatment with rivastigmine was discontinued (see ADVERSE EFFECTS).

Weight loss. Since in patients with Alzheimers disease during therapy with cholinesterase inhibitors, including rivastigmine, a decrease in body weight is possible, the body weight of patients should be monitored during treatment with rivastigmine.

Skin reactions. Rare cases of the development of allergic dermatitis (disseminated) have been reported with the use of rivastigmine, regardless of the method of application (inside or transdermally). In these cases, treatment with rivastigmine should be discontinued (see CONTRAINDICATIONS). Patients and caregivers should be informed of the possibility of skin reactions with rivastigmine.

Disorders of the digestive system. Adverse reactions from the gastrointestinal tract, such as nausea, vomiting, and diarrhea, are dose-dependent and can occur especially at the beginning of treatment and / or with an increase in dose (see ADVERSE EFFECTS). These adverse reactions are more often noted in women. In severe vomiting associated with rivastigmine treatment, appropriate dose adjustment is recommended (see APPLICATION). Some cases of severe vomiting have been associated with rupture of the esophagus (see ADVERSE EFFECTS). Such cases were noted especially after increasing the dose or using rivastigmine in high doses. Patients who have developed manifestations of dehydration due to prolonged vomiting or diarrhea are recommended in / in the introduction of fluid and dose reduction or discontinuation of rivastigmine therapy. Dehydration can be associated with serious consequences.

Rivastigmine can enhance the secretion of hydrochloric acid in the stomach. Caution must be exercised when using rivastigmine in patients with an ulcer of the stomach or duodenum in the acute stage or in persons prone to these conditions.

Violations of the cardiovascular system. Mostly in patients with risk factors, rivastigmine can cause bradycardia, which is a risk factor for ventricular tachycardia of the pirouette type (torsades de pointes). Caution should be exercised when using rivastigmine in patients at high risk of developing pirouette tachycardia, in particular those with decompensated heart failure, recent myocardial infarction, with bradyarrhythmias, a tendency to hypokalemia or hypomagnesemia, and patients who use drugs that cause Q-T prolongation interval and / or torsades de pointes (see INTERACTIONS, SIDE EFFECTS).

Caution should be exercised when using rivastigmine in patients with sinus node weakness syndrome or conduction disturbances (sinoauricular block, block) (see ADVERSE EFFECTS).

Other adverse events. Cholinesterase inhibitors should be prescribed with caution to patients with AD or a history of obstructive pulmonary disease. Cholinomimetics can induce or exacerbate urinary obstruction and convulsions. When treating patients with these pathologies, care must be taken.

The use of rivastigmine in patients with severe dementia in Alzheimers or Parkinsons disease, with other types of dementia or other types of memory impairment (for example, with an age-related decrease in cognitive function) has not been investigated, therefore, the use of the drug in patients of these groups is not recommended.

As in the case of other cholinomimetics, the use of rivastigmine may cause or increase the severity of extrapyramidal disorders.

In patients with dementia associated with Parkinsons disease, motor impairment (including bradykinesia, dyskinesia, impaired gait) and an increase in the severity of tremor were noted (seeSIDE EFFECTS). In some cases, due to these phenomena, it was necessary to discontinue rivastigmine therapy (namely: the frequency of drug withdrawal due to tremor was 1.7% in the rivastigmine group versus 0% in the placebo group). Clinical monitoring of these adverse reactions is recommended.

Special patient groups

In patients with clinically pronounced impaired renal / hepatic function, dose-dependent adverse reactions are more likely to develop (see PHARMACOLOGICAL PROPERTIES, APPLICATION). It is recommended that the dose be carefully titrated taking into account the individual tolerance of treatment by patients of this group. The use of rivastigmine in patients with severe liver dysfunction has not been investigated (see CONTRAINDICATIONS).

In patients with a body weight of 50 kg, a more frequent development of adverse reactions is possible, which can lead to discontinuation of treatment.

Use during pregnancy and lactation

Pregnancy. According to the results of studies involving pregnant animals, rivastigmine and its metabolites crossed the placental barrier. The potential risk to humans is unknown. There are no data on the use of rivastigmine in people during pregnancy. In studies on rats of pre- and postnatal development of offspring, an extension of the gestation period was noted. Rivastigmine should not be used during pregnancy unless absolutely necessary.

Lactation. According to studies, rivastigmine penetrated into the breast milk of animals during lactation. There is no data on the penetration of rivastigmine into breast milk in humans. Women using rivastigmine should not breast-feed.

Fertility. According to a study in rats, the effect of rivastigmine on fertility or reproductive function of animals was not observed. There are no data on the effect of rivastigmine on fertility in humans.

Children. The drug is not used in children (under the age of 18 years) due to the lack of data on the use of rivastigmine in patients of this age group.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Alzheimers disease can lead to a gradual deterioration in the ability to drive vehicles or jeopardize the ability to control mechanisms. In addition, rivastigmine can cause dizziness and drowsiness, especially at the beginning of treatment and with an increase in dose. So, rivastigmine has a slight or moderate effect on the ability to drive vehicles or work with other mechanisms. The ability of patients with dementia using rivastigmine to continue to drive vehicles or operate machinery should be regularly evaluated by a physician.

Interactions

As a cholinesterase inhibitor, rivastigmine may enhance the effects of succinylcholine-type muscle relaxants during anesthesia. caution should be exercised when choosing an anesthetic. if necessary, you can consider dose adjustment or temporary cessation of treatment.

Given the pharmacodynamic effects of rivastigmine and its possible additive effects, rivastigmine should not be used in conjunction with other cholinomimetics. Rivastigmine may decrease the therapeutic effect of anticholinergic drugs (e.g. oxybutynin, tolterodine).

The additive effects that led to bradycardia (with a risk of developing syncope) have been reported with the combined use of rivastigmine and various β-adrenoreceptor blockers (including atenolol). Despite the fact that the use of rivastigmine with cardioselective β-adrenergic receptor blockers is associated with a high risk of developing such effects, these side effects were also noted in patients using other drugs of the β-adrenergic receptor blocker group.Therefore, caution should be exercised when using rivastigmine in combination with β-adrenergic receptor blockers and other drugs that can cause bradycardia (for example, class III antiarrhythmic drugs, calcium channel antagonists, digitalis glycosides, digitalis pilocarpine).

Since bradycardia is a risk factor for ventricular tachycardia of the pirouette type (torsades de pointes), care should be taken to carefully monitor the patient’s health status (ECG) when using rivastigmine in combination with drugs that can trigger pirouette type tachycardia, 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; misolastine; methadone.

In healthy volunteers, the pharmacokinetic interaction between rivastigmine and digoxin, warfarin, diazepam or fluoxetine was not detected. The use of rivastigmine does not affect the increase in prothrombin time caused by warfarin. With the simultaneous use of digoxin and rivastigmine, an undesirable effect on the conduction system of the heart was not detected.

Given that the metabolism of rivastigmine with the participation of the main isoenzymes of cytochrome P450 (CYP) is carried out to a minimum, pharmacokinetic interactions of rivastigmine with other drugs that are metabolized with the participation of CYP are unlikely. Although rivastigmine can inhibit the metabolism of drugs that are biotransformed with the participation of butyrylcholinesterase.

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 overdose.

In cases of moderate severity poisoning, cholinesterase inhibitors noted 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 urination lacrimation, arterial hypotension, hypersalivation. In the case of more severe poisoning with cholinesterase inhibitors, the development of such nicotinic effects as muscle weakness, fasciculations, cramps, respiratory arrest with a possible fatal outcome is possible.

Cases of dizziness, tremor, headache, drowsiness, psychosis, hypertension, hallucinations, and malaise have also been reported.

Treatment. Since T_½ rivastigmine from blood plasma is approximately 1 hour, and the duration of inhibition of acetylcholinesterase is about 9 hours, in cases of asymptomatic overdose, the next dose of rivastigmine is not recommended for the next 24 hours. If overdose is accompanied by severe nausea and vomiting, it is necessary to consider the use of antiemetics. In the event of other adverse events, appropriate symptomatic therapy should be used if necessary.

With a pronounced overdose, atropine can be used. An initial dose of atropine sulfate 0.03 mg / kg is recommended, followed by an increase depending on the 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.