Exelon

General information

The drug is used to treat Alzheimer's disease, helping to improve cognitive function by increasing the level of certain substances in the brain. It is used both in the form of capsules and solution, and in the form of transdermal systems for long-term therapeutic effect.

Trade name

Exelon

International Nonproprietary Name (INN)

Rivastigmine

Dosage form

Exelon is available in several dosage forms for easy administration to patients with different needs. Oral capsules are available in dosages of 1.5 mg, 3 mg, 4.5 mg and 6 mg, each color-coded for easy identification. Oral solution is available at a concentration of 2 mg/mL and comes in vials with a dispensing device for accurate volume measurement. Transdermal Therapeutic Systems (TTS) provide a gradual release of the active ingredient over 24 hours and are available in dosages of 4.6 mg/24 hr, 9.5 mg/24 hr and 13.3 mg/24 hr. Each dosage form is tailored to patients, including those who have difficulty swallowing or who prefer a steady supply of the drug without the need for frequent dosing.

Composition

The active substance is rivastigmine (in the form of rivastigmine hydrotartate), the content of which varies depending on the form of release.

• Capsules: in addition to the active ingredient contain microcrystalline cellulose as an excipient, hypromellose to form the structure, magnesium stearate and colloidal silicon dioxide as stabilizers. Capsule shell consists of gelatin with the addition of colorants (iron oxide yellow, iron oxide red, titanium dioxide), which gives them a characteristic shade.
• Solution: includes citric acid and sodium citrate for pH adjustment, sodium benzoate as a preservative and purified water as a base.
• TTS: consists of a multilayer structure with acrylic adhesive for skin fixation, polyethylene film as a protective layer, silicone coating for release control and a small amount of vitamin E to stabilize the system.

Pharmacologic properties

Pharmacodynamics

Rivastigmine, the underlying compound of Exelon, acts as a reversible inhibitor of two key enzymes, acetylcholinesterase and butyrylcholinesterase, which are involved in the breakdown of acetylcholine in the nervous system. Acetylcholine is a neurotransmitter critical for maintaining memory, learning ability, attention and other cognitive processes that are impaired in Alzheimer's disease and dementia associated with Parkinson's disease. By blocking the activity of these enzymes, the drug increases the concentration of acetylcholine in synapses, improving inter-neuronal communication in areas of the brain, such as the hippocampus and cortex, that are most susceptible to degenerative changes. A distinctive feature of rivastigmine is its dual action: it inhibits both acetylcholinesterase, predominant in the brain, and butyrylcholinesterase, the activity of which increases with the progression of neurodegenerative processes. This provides a wider range of effects compared to other cholinesterase inhibitors.

In addition, the drug demonstrates a certain selectivity to the central nervous system, which reduces the likelihood of peripheral side effects such as excessive salivation or bowel disturbances. Studies also suggest that rivastigmine may have additional effects on pathologic processes, including reducing the formation of amyloid plaques and tau-protein aggregates, although these findings have not yet been fully confirmed and require further clinical trials. Exelon's efficacy is demonstrated by slowing the loss of cognitive function, improving patients' activities of daily living and temporarily relieving symptoms of dementia. The therapeutic effect depends on the stage of the disease: in the early stages it is more pronounced, while at later stages the drug helps to stabilize the condition.

Pharmacokinetics

• Absorption: When taking capsules or solution rivastigmine quickly enters the bloodstream from the gastrointestinal tract, reaching maximum concentration in 1-1.5 hours. Bioavailability is about 36-40%, which is due to significant metabolism during the first passage through the liver. Food slows the rate of absorption but does not affect total absorption, making administration with meals preferable to reduce gastric irritation. The transdermal system provides a slow and uniform absorption of the substance through the skin, with peak concentration 8-16 hours after application, which reduces fluctuations in blood levels of the drug and improves tolerability.
• Distribution: Rivastigmine is highly lipophilic, which allows it to easily penetrate the blood-brain barrier and accumulate in brain tissue, where it has a major effect. The volume of distribution is about 1.8-2.7 L/kg, indicating good penetration into various tissues of the body. Binding to plasma proteins is low (about 40%), minimizing the likelihood of interaction with other drugs at this level.
• Metabolism: The major route of metabolism of rivastigmine is hydrolysis by cholinesterases to the inactive metabolite NAP226-90, which has no pharmacologic activity. This process occurs predominantly in tissues and blood rather than in the liver, which distinguishes the drug from many other drugs that depend on the cytochrome P450 system. The involvement of CYP450 enzymes is minimal (mainly CYP2D6 and CYP3A4 to a minor extent), which reduces the risk of drug interactions associated with hepatic metabolism.
• Extraction: The elimination half-life with oral administration is approximately 1.4-1.7 hours, reflecting rapid excretion of the active ingredient. With the use of TTS this indicator increases to 3-4 hours after removal of the patch due to deposition in the skin. The main route of excretion is the kidneys, where 97% of the dose is excreted as metabolites through urine, the rest (about 3%) leaves the body with feces. Clearance of the drug does not depend on age, but may decrease in severe renal dysfunction.

Indications for use

• Mild to moderate dementia due to Alzheimer's disease. The drug is prescribed to improve memory, attention and ability to perform everyday tasks in patients with a confirmed diagnosis.
• Dementia associated with Parkinson's disease in the presence of marked cognitive impairment. Exelon helps to manage the impairment of thinking and orientation characteristic of this condition.

The use of the drug is appropriate at stages when the patient still retains basic self-care skills but already has difficulty remembering, planning, or concentrating. Exelon is not a treatment for severe dementia when cognitive function is almost completely lost.

Contraindications

• Excessive sensitivity to rivastigmine, other carbamate derivatives or any of the excipients of the drug, manifested as allergic reactions.
• Severe hepatic insufficiency (Child-Pugh class C), since the safety of use in such conditions has not been studied and metabolism may be impaired.
• Acute or chronic obstructive airway disease (bronchial asthma, COPD) in the acute stage, due to the risk of bronchospasm or worsening of respiratory function.
• Active peptic ulcer disease of the stomach or duodenum, because the drug may increase gastric juice secretion and provoke complications.
• Cardiovascular disorders, including marked bradycardia, sinoatrial block or atrioventricular block of II-III degree, because of the risk of aggravation of conduction.
• Pregnancy and breastfeeding period, as data on fetal effects and milk penetration are not available.
• Age under 18 years of age, as clinical studies in this group have not been conducted and indications for use in children have not been defined.

Additional consideration should be given to the presence of a history of seizures, as the drug may lower the threshold of seizure activity in predisposed patients.

Method of administration and dosage

How to take

Exelon capsules and solution are taken orally with meals, which reduces the likelihood of irritation of the gastric mucosa and reduces the severity of nausea. The drug is washed down with enough water (approximately 100-150 ml) to facilitate swallowing and absorption. The solution is measured using the syringe or measuring cup provided to ensure accurate dosage and can be mixed with a small amount of liquid (e.g. juice) if the patient has difficulty taking it. The transdermal systems are applied to clean, dry, intact skin on the upper back, chest, or upper arm, avoiding areas of sweating or hair. The patch is changed every 24 hours, not using the same area of skin repeatedly for 14 days to prevent irritation.

Dosages for adults and children

• Adults (capsules/solution): The starting dose is 1.5 mg twice daily (morning and evening) for the first 2-4 weeks. In the absence of significant side effects, the dose is increased to 3 mg twice a day, then every 2-4 weeks - up to 4.5 mg and, if necessary, up to a maximum of 6 mg twice a day (12 mg / day). The increase is carried out gradually so that the body adapts to the effect of the drug.
• Adults (TTC): Therapy is started with a patch of 4.6 mg/24 h, which is applied for 4 weeks. If well tolerated, it is switched to 9.5 mg/24 h, and after 6 months (if insufficient effect) - to 13.3 mg/24 h. The maximum dose is selected individually.
• Children: Use in persons under 18 years of age is not provided, as safety and efficacy in this age group have not been studied.

If treatment is interrupted for more than 3 days, therapy is resumed from the initial dose to avoid an abrupt increase in side effects.

Dose adjustment for certain conditions

In mild to moderate renal insufficiency (creatinine clearance greater than 10 ml/min), standard dosages are maintained, but the drug is not recommended in severe insufficiency (less than 10 ml/min) due to insufficient data. In mild hepatic insufficiency (Child-Pugh class A) no correction is required, in moderate hepatic insufficiency (class B) start with the minimum dose (1.5 mg twice daily or TTC 4.6 mg/24 h) with slow increase if necessary. Severe hepatic impairment (class C) is a contraindication. Patients with low body weight (less than 50 kg) are more likely to have side effects, so the dose should be selected with particular caution, starting with the lowest dose.

Side effects

• Gastrointestinal disorders: nausea (especially at the beginning of treatment), vomiting, diarrhea, decreased appetite, pain in the upper abdomen, rarely - gastritis or exacerbation of ulcer.
• Nervous system: dizziness, headache, increased drowsiness, tremor, confusion, sometimes - convulsions or fainting.
• Cardiovascular system: bradycardia, increased or decreased blood pressure, rarely - arrhythmias or orthostatic hypotension.
• Skin reactions: itching, redness, rashes, when using TTS - local irritation, erythema or peeling at the site of application.
• Mental disorders: anxiety, insomnia, depression, hallucinations or delusions, especially in elderly patients.
• General reactions: increased fatigue, sweating, weight loss, weakness, feeling of fever.

Most side effects are temporary and diminish with adaptation to the drug or dose reduction. However, if they persist or intensify, specialist consultation is required.

Overdose

Symptoms of overdose

Exceeding the therapeutic dose (more than 12 mg/day in oral administration or use of two TCAs simultaneously) may lead to pronounced symptoms: severe nausea with indomitable vomiting, profuse diarrhea, decreased blood pressure, bradycardia, confusion, convulsions, respiratory depression. In severe cases, unconsciousness, coma or collapse due to excessive cholinergic stimulation may occur.

First aid measures

In case of overdose it is necessary to immediately discontinue use of the drug. In oral administration, gastric lavage is performed within 1-2 hours after use and activated charcoal (20-30 g) is given to reduce absorption. When using TTS, the patch is removed from the skin. The patient should be placed in a horizontal position, provide access to air and call an ambulance. In hospital conditions atropine (0.5-1 mg intravenously) is used to eliminate bradycardia and other cholinergic effects, as well as monitor vital functions (ECG, blood pressure, respiration).

Interaction with other drugs

Influence on the effect of other drugs

• Anticholinergic agents (atropine, scopolamine, trihexyphenidyl): decrease in their efficacy due to opposite action on the cholinergic system.
• Cholinomimetics (betanechol, pilocarpine): increased effects, which may lead to overstimulation (salivation, bronchospasm).
• Beta-blockers (atenolol, metoprolol): increased risk of bradycardia or hypotension when co-administered.
• Depolarizing myorelaxants (suxamethonium): strengthening and prolongation of their effect during general anesthesia, which requires caution in surgery.

Since the metabolism of rivastigmine is independent of the cytochrome P450 system, it does not affect the pharmacokinetics of drugs metabolized by the liver, such as statins or antibiotics.

Compatibility with alcohol and food

Meal intake does not alter the overall absorption of Exelon, but slows the rate of absorption, which is useful in reducing nausea. Alcohol increases side effects including dizziness, drowsiness and confusion, so its use during treatment is not recommended.

Special Instructions

Use in pregnancy and breastfeeding

Clinical data on the use of Exelon in pregnant women are not available, and its effect on fetal development has not been studied, which makes the drug contraindicated during this period. Rivastigmine may be excreted with breast milk, so women during lactation should refuse treatment or stop feeding.

Effects on driving and mechanisms

Exelon is capable of causing somnolence, dizziness, tremor, or impaired coordination, especially at the beginning of therapy, with dose escalation, or in patients with severe dementia. These effects may significantly limit the ability to drive a car or operate machinery. Patients should avoid such activities until their individual reaction to the drug is established.

Particularities of use in the elderly and children

• Elderly: This is the primary patient group for Exelon, and standard dosages are applicable. However, those over 75 years of age are more likely to experience side effects (nausea, bradycardia, hallucinations), requiring more careful dose selection and monitoring.
• Children: Use in persons under 18 years of age is not envisaged, as dementia is not characteristic of this age group, and the safety of the drug in children has not been studied.

In elderly patients with comorbidities (e.g., heart failure or diabetes), the possible increase in side effects should be taken into account and treatment should be adjusted to the general condition.