Alcenorm (Capsules, Solution) Instructions for Use

ATC Code

N06DA03 (Rivastigmine)

Active Substance

Rivastigmine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Selective inhibitor of acetylcholinesterase in the brain. A drug for the treatment of dementia

Pharmacotherapeutic Group

Anticholinesterase agent

Pharmacological Action

Rivastigmine is a selective inhibitor of brain acetyl- and butyrylcholinesterase, slows the breakdown of acetylcholine produced by functionally preserved neurons and improves neurotransmission.

Rivastigmine selectively increases the acetylcholine content in the cerebral cortex and hippocampus, and thus contributes to the improvement of cholinergic nerve transmission. Rivastigmine may have a positive effect on cognitive decline associated with acetylcholine deficiency, in particular, in dementia associated with Alzheimer’s disease and Parkinson’s disease.

In addition, there is evidence that cholinesterase inhibition may slow the formation of beta-amyloid precursor protein fragments involved in amyloidogenesis, and thus slow the formation of amyloid plaques, which are one of the main pathological signs of Alzheimer’s disease.

Rivastigmine interacts with the target enzyme to form a covalent bond, leading to temporary enzyme inactivation. In young healthy males, after taking the drug at a dose of 3 mg, acetylcholinesterase activity in the cerebrospinal fluid (CSF) decreases by approximately 40% within the first 1.5 hours.

After reaching the maximum inhibitory effect, the enzyme activity returns to the baseline level after about 9 hours. The activity of butyrylcholinesterase in the CSF in young healthy volunteers is reversibly inhibited and recovers to the baseline after 3.6 hours.

In patients with Alzheimer’s disease, rivastigmine inhibition of acetylcholinesterase activity in the CSF is dose-dependent in the studied dose range (namely, up to the highest dose of 6 mg twice daily). Butyrylcholinesterase inhibition is also dose-dependent; a dose of 6 mg twice daily causes a decrease in enzyme activity by more than 60% compared to baseline.

This effect of rivastigmine persisted for 12 months of therapy (the maximum studied period). A statistically significant correlation was shown between the degree of rivastigmine inhibition of both enzymes in the CSF and changes in cognitive functions in patients with Alzheimer’s disease; with inhibition of butyrylcholinesterase in the CSF significantly and stably correlating with improvements in memory, attention and reaction speed test results.

The efficacy of rivastigmine therapy for dementia in Alzheimer’s disease and for dementia associated with Parkinson’s disease has been shown in patients with mild to moderate dementia (Mini-Mental State Examination score – 10-24).

Rivastigmine leads to significant improvement in cognitive functions (attention, memory, speech), functional status and activities of daily living, as well as a reduction in the severity of the disease and the severity of mental and behavioral manifestations.

Pharmacokinetics

Rivastigmine is rapidly and completely absorbed. The maximum plasma concentration (C_max) is reached in about 1 hour.

Due to interaction with the target enzyme, when the rivastigmine dose is increased, the increase in its bioavailability is 1.5 times higher than expected (for this dose increase). After a dose of 3 mg, the absolute bioavailability is about 36%.

When taken with food, absorption is slowed (the time to reach C_max increases by 90 minutes); C_max decreases; while the area under the concentration-time curve (AUC) increases by approximately 30%.

Rivastigmine is weakly bound to plasma proteins (approximately 40%). It easily penetrates the blood-brain barrier. The apparent volume of distribution (V_d) is 1.8-2.7 L/kg.

It is rapidly and extensively metabolized (plasma T_1/2 is about 1 hour), mainly by hydrolysis by cholinesterase to form a decarbamylated metabolite.

In vitro, this metabolite has minimal ability to inhibit acetylcholinesterase (less than 10%). According to data obtained in vitro and in experimental studies, the main cytochrome P450 isoenzymes are minimally involved in the metabolism of rivastigmine.

It is excreted mainly by the kidneys as metabolites; it is not detected unchanged in the urine. More than 90% of the dose is excreted within 24 hours after administration. Less than 1% of the dose is excreted in the feces. In patients with Alzheimer’s disease, no accumulation of rivastigmine or its decarbamylated metabolite was noted.

In elderly patients

Although the bioavailability of rivastigmine in the elderly is higher than in healthy young volunteers, no age-related changes in bioavailability were identified in clinical studies in patients with Alzheimer’s disease aged 50 to 92 years.

In patients with impaired liver function

In individuals with mild or moderate hepatic impairment compared to healthy volunteers, the C_max of rivastigmine was almost 60% higher, and the AUC value was almost twice as high.

In patients with impaired renal function

In individuals with moderate renal impairment compared to healthy volunteers, the C_max and AUC values of rivastigmine were twice as high; in individuals with severe renal impairment, the C_max and AUC values did not change.

Indications

• Mild to moderate dementia of the Alzheimer’s type;
• Mild to moderate dementia in Parkinson’s disease.

ICD codes

Dosage Regimen

Capsules

Orally, with meals, twice a day. The capsule should be swallowed whole, without breaking its integrity.

Initial dosefor adults – 1.5 mg per dose.

If well tolerated (no earlier than 2 weeks later), the dose can be increased to 3 mg and then to 4.5-6 mg twice a day.

Maintenance dose – 3-6 mg twice a day.

Maximum daily dose – 12 mg.

If the drug intake was interrupted for several days, treatment should be resumed with the initial dose of 1.5 mg twice a day, gradually increasing the dose.

In patients with impaired renal and liver function, no dose adjustment is required.

Solution

Used orally and topically. The dose, method and regimen of administration, duration of therapy are determined individually, depending on the indications, clinical situation and the dosage form used.

Adverse Reactions

Side effects are classified according to the following frequency: very common – not less than 10%; common – not less than 1%, but less than 10%; uncommon – not less than 0.1%, but less than 1%; rare – not less than 0.01%, but less than 0.1%; very rare – less than 0.01%, including isolated cases.

Infections: very rare – urinary tract infections.

Nervous system disorders: very common – dizziness; common – agitation, confusion, headache, drowsiness, tremor; uncommon – insomnia, depression, fainting; rare – seizures; very rare – hallucinations.

Cardiovascular system disorders: rare – angina pectoris; very rare – bradycardia, atrioventricular block, atrial fibrillation, tachycardia, significant increase in blood pressure.

Digestive system disorders: very common – nausea, vomiting, diarrhea, anorexia; common – dyspepsia and abdominal pain; rare – gastric and duodenal ulcers; very rare – gastrointestinal bleeding, pancreatitis (mild), isolated cases of severe vomiting associated with esophageal rupture.

Skin and subcutaneous tissue disorders: common – increased sweating; rare – rash.

Other: common – increased fatigue, asthenia, general malaise, weight loss; uncommon – accidental falls.

Contraindications

• Hypersensitivity to the active substance, other carbamate derivatives, or to any other component of the drug;
• Severe hepatic insufficiency;
• Lactation period;
• Children under 18 years of age.

With caution

Peptic ulcer of the stomach and duodenum, sick sinus syndrome, conduction disorders (sinoatrial and atrioventricular), bronchial asthma and chronic obstructive pulmonary disease (in history), urinary tract obstruction (in history), seizure syndrome (in history), simultaneous use of other cholinomimetic drugs, pregnancy.

Use in Pregnancy and Lactation

The safety of rivastigmine use during human pregnancy has not been established to date, so the drug can be prescribed during pregnancy only in cases where the expected success of treatment outweighs the potential risk to the fetus. Experimental studies have shown that Rivastigmine does not have teratogenic properties.

It is not known whether Rivastigmine is excreted in breast milk. Therefore, breastfeeding should be discontinued during the use of the drug.

Use in Hepatic Impairment

In patients with impaired liver function, no dose adjustment is required.

Use in Renal Impairment

In patients with impaired renal function, no dose adjustment is required.

Contraindicated in severe hepatic insufficiency

Pediatric Use

Contraindicated for children under 18 years of age.

Geriatric Use

In clinical studies in patients with Alzheimer’s disease aged 50 to 92 years, no age-related changes in bioavailability were identified.

Special Precautions

Cholinergic stimulation may enhance the secretion of hydrochloric acid in the stomach.

During pregnancy, it should be used only in cases where the expected benefit of treatment outweighs the potential risk to the fetus.

The severity of nausea and vomiting, usually observed during the initial period of treatment and/or during the period of rivastigmine dose increase, may be reduced by reducing the rivastigmine dose.

In patients with Alzheimer’s disease, body weight may decrease. Body weight should be monitored during rivastigmine treatment. As with other cholinergic drugs, Rivastigmine may cause increased gastric acid secretion. The drug should be used with caution in patients with chronic gastric or duodenal ulcers, as well as in patients who are predisposed to these diseases.

Cholinesterase inhibitors should be used with caution in patients with a history of bronchial asthma or other respiratory diseases.

Cholinomimetic drugs can provoke or enhance urinary tract obstruction and seizure syndrome. The drug should be used with caution in patients predisposed to these diseases.

The use of rivastigmine in patients with severe dementia in Alzheimer’s disease and Parkinson’s disease, in other types of dementia and other types of memory impairment (for example, age-related cognitive decline) has not been studied.

Like other cholinomimetic drugs, Rivastigmine may enhance or cause impaired coordination. Increased motor fluctuations (including bradykinesia, dyskinesia, gait disturbance) and increased frequency of tremor were observed in patients with dementia in Parkinson’s disease. In severe cases, these circumstances may require discontinuation of rivastigmine treatment.

Effect on ability to drive vehicles and operate machinery

When using the drug Alcenorm, especially at the beginning of treatment and when changing the drug dose, adverse reactions from the nervous system may develop, reducing attention and the speed of psychomotor reactions. The ability of a patient with dementia taking the drug Alcenorm to drive a car and/or operate machinery should be regularly assessed by the attending physician.

Overdose

Symptoms: nausea, vomiting, diarrhea, significant increase in blood pressure, hallucinations. Given the vagotonic effect of cholinesterase inhibitors on heart rate, the occurrence of bradycardia and/or fainting cannot be ruled out. In one case, 46 mg of the drug was taken; after conservative treatment, complete recovery was observed after 24 hours.

Treatment: since the half-life of rivastigmine from plasma is about 1 hour, and the duration of acetylcholinesterase inhibition is about 9 hours, in cases of asymptomatic overdose, it is recommended not to use Rivastigmine for the next 24 hours. If the overdose is accompanied by severe nausea and vomiting, the use of antiemetics should be considered. If necessary, symptomatic therapy is carried out. In case of significant overdose, atropine sulfate can be used, the initial dose of which is 0.03 mg/kg intravenously; subsequent dosing depends on the clinical effect. The use of scopolamine as an antidote is not recommended.

Drug Interactions

Rivastigmine is metabolized mainly by hydrolysis with the participation of esterases. Metabolism of the drug with the participation of the main cytochrome P450 isoenzymes occurs to a minimal extent. Therefore, pharmacokinetic interactions with other drugs metabolized by these enzymes are not expected. In healthy volunteers, no pharmacokinetic interaction between rivastigmine and digoxin, warfarin, diazepam or fluoxetine was identified. Warfarin-induced increase in prothrombin time did not change when rivastigmine was prescribed. No adverse effect on intracardiac conduction was noted with the simultaneous use of rivastigmine and digoxin.

Concomitant use of rivastigmine with such commonly used drugs as antacids, antiemetics, hypoglycemic agents, centrally acting antihypertensive agents, beta-blockers, slow calcium channel blockers, drugs with positive inotropic effects, antianginal agents, non-steroidal anti-inflammatory drugs, estrogens, analgesics, benzodiazepines and antihistamines, was not accompanied by any changes in the kinetics of rivastigmine or an increased risk of adverse events. Rivastigmine, as a cholinesterase inhibitor, may enhance the effect of depolarizing muscle relaxants (succinylcholine-type muscle relaxants) during anesthesia.

Rivastigmine should not be used simultaneously with cholinomimetic drugs, and when prescribed simultaneously with anticholinergic drugs, the opposite direction of their action should be taken into account.

Storage Conditions

Store in a place inaccessible to children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.