Exelon^® (Capsules, Solution, Transdermal system) 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

Cholinesterase inhibitor

Pharmacological Action

Cholinesterase inhibitor. Rivastigmine, being a selective carbamate-type inhibitor of brain acetyl- and butyrylcholinesterase, slows the breakdown of acetylcholine produced by functionally preserved neurons and improves synaptic transmission.

The drug selectively increases the content of acetylcholine in the cerebral cortex and hippocampus and thus contributes to the improvement of cholinergic neurotransmission.

Rivastigmine has a positive effect on the reduction of cognitive functions associated with acetylcholine deficiency, in particular, in dementia associated with Alzheimer’s disease and Parkinson’s disease.

Furthermore, there is evidence that cholinesterase inhibition may slow the formation of beta-amyloid precursor protein fragments, the accumulation of which leads to 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 men receiving rivastigmine at a dose of 3 mg, cerebrospinal fluid (CSF) acetylcholinesterase activity decreased by approximately 40% within the first 1.5 hours.

After reaching the maximum inhibitory effect, enzyme activity returned to baseline after approximately 9 hours.

Inhibition of butyrylcholinesterase in the CSF was also reversible, with enzyme activity returning to baseline after 3.6 hours.

In patients with Alzheimer’s disease, rivastigmine inhibition of acetylcholinesterase activity in the CSF was dose-dependent within the studied dose range up to 6 mg twice daily (maximum dose).

Inhibition of butyrylcholinesterase was also dose-dependent; Rivastigmine at a dose of 6 mg twice daily caused a reduction in enzyme activity of more than 60% compared to baseline.

This effect of the drug 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 consistently correlating with improved performance on tests of memory, attention, and reaction speed.

Use of the Exelon^® TTS in patients with mild to moderate dementia in Alzheimer’s disease (10-20 points on the Mini Mental State Examination, MMSE) leads to significant improvement in cognitive functions (including attention, memory, speech), functional status, and activities of daily living compared to placebo.

Pharmacokinetics

Absorption

Absorption of rivastigmine from the Exelon^® TTS occurs slowly.

After the first dose of the drug, the time to reach a quantifiable rivastigmine concentration was 0.5-1 hour.

C_max in plasma is reached after 10-16 hours.

After reaching C_max, the plasma concentration slowly decreases during the remaining 24-hour period of Exelon^® TTS application.

The C_ss of rivastigmine in blood plasma after replacing the used Exelon^® TTS with a new one slowly decreases on average for approximately 40 minutes, until the absorption of the active substance from the newly applied Exelon^® TTS begins to predominate over elimination.

After this, the plasma concentration of rivastigmine begins to slowly rise and again reaches a maximum after approximately 8 hours.

At steady state, the lowest concentration is approximately 50% of the maximum, in contrast to oral administration, where the plasma concentration is virtually zero between doses.

Similar plasma concentration time profiles of rivastigmine were observed with the use of Exelon^® TTS in the dose range from 4.6 mg/24 h to 13.3 mg/24 h.

Although the exposure (C_max and AUC) of rivastigmine is apparently less than with oral administration, its increase is directly proportional to the increase in the dose of Exelon^® TTS.

When increasing the dose from the TTS from 4.6 mg/24 h to 9.5 mg/24 h, the AUC of rivastigmine increased by 2.6 times; when increasing to 13.3 mg/24 h, it increased by 4.9 times.

The relative difference between C_max and C_min of rivastigmine (fluctuation index, FI) when using the Exelon^® TTS was within the range of 0.58 for the 4.6 mg/24 h dosage, 0.77 for the 9.5 mg/24 h dosage, and 0.72 for the 13.3 mg/24 h dosage, which is significantly less than with oral administration (FI from 3.96 for the 6 mg/day dosage and 4.15 for the 12 mg/day dosage).

The amount of rivastigmine released over 24 hours from the Exelon^® TTS (dose in mg/24 h) is not equivalent to the oral administration of the same dose of rivastigmine in capsules (assessment was based on rivastigmine exposure in blood plasma over 24 hours).

Exelon^® TTS 9.5 mg/24 h is equivalent to the oral administration of Exelon^® capsules at a dose of 6 mg twice daily (12 mg/day).

In a direct comparison of a single dose of the Exelon^® TTS drug and oral capsules, the interpopulation variability of C_max and AUC_{0-24 h} of rivastigmine was 43% and 49% for the Exelon^® TTS and 74% and 103% for the capsules, respectively.

With multiple administrations and at steady state, the interpopulation variability of C_max and AUC_{0-24 h} of rivastigmine in patients with dementia in Alzheimer’s disease was also significantly lower for the Exelon^® TTS compared to oral capsules: 45% and 43% for the TTS and 71% and 73% for the capsules, respectively.

In patients with Alzheimer’s-type dementia, a clear relationship was noted between body weight and the C_ss of rivastigmine and the metabolite NAP266-90.

In patients with Alzheimer’s-type dementia and a body weight of 35 kg, the C_ss of rivastigmine increased approximately 2-fold compared to patients with a body weight of 65 kg; while for patients with a body weight of 100 kg, a decrease in C_ss of approximately 2-fold was noted.

The influence of body weight on rivastigmine exposure is particularly important for patients with very low body weight when increasing the drug dose.

Rivastigmine was well released from the Exelon^® TTS during the 24-hour period of patch application to the skin (about 50% of the drug content).

The highest AUC_∞ of rivastigmine and the metabolite NAP266-90 was noted when the TTS was applied to the upper back, chest, or shoulder; AUC_∞ decreased by approximately 20-30% when applied to the abdomen and thigh.

No significant accumulation of rivastigmine or the metabolite NAP226-90 was observed in the blood plasma of patients with dementia in Alzheimer’s disease.

Except that the plasma concentration of rivastigmine during the second application of the Exelon^® TTS was higher than on the first day.

Distribution

Rivastigmine is weakly bound to plasma proteins (about 40%), easily penetrates the BBB.

The apparent V_d is 1.8- 2.7 L/kg.

Metabolism

Rivastigmine is rapidly and extensively metabolized with a T_1/2 from plasma of about 3.4 hours after TTS removal.

Elimination was limited by the rate of absorption of rivastigmine (flip-flop kinetics), which explains the increase in T_1/2 after application of the Exelon^® TTS (3.4 hours) compared to oral or IV administration (1.4 and 1.7 hours, respectively) of the drug.

Metabolism of rivastigmine occurs mainly through hydrolysis by cholinesterase to form a decarbamylated metabolite (NAP 226-90), which in vitro demonstrated minimal ability to inhibit acetylcholinesterase (<10%).

According to data obtained in vitro and in experimental studies, the major cytochrome P450 isoenzymes are minimally involved in the metabolism of rivastigmine.

The total plasma clearance of rivastigmine is about 130 L/h after IV administration of a 0.2 mg dose and decreases to 70 L/h after IV administration of 2.7 mg, which is consistent with the nonlinear, inversely proportional nature of rivastigmine pharmacokinetics due to its saturable elimination.

The ratio of AUC_∞ of the metabolite to the parent substance was 0.7 for the TTS versus 3.5 for oral capsules, indicating less intensive metabolism after dermal application.

The formation of a smaller amount of the metabolite NAP226-90 is due to the absence of presystemic metabolism (first-pass effect through the liver).

Based on data obtained from in vitro studies, no interaction with drugs metabolized by the following cytochrome system isoenzymes is expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19 or CYP2B6.

Excretion

Rivastigmine is excreted mainly by the kidneys in the form of metabolites; it is almost 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.

Pharmacokinetics in elderly patients

In elderly patients with Alzheimer’s disease using the Exelon^® TTS, no age-related changes in bioavailability were identified.

Pharmacokinetics in patients with impaired liver function

A study of the use of the Exelon^® TTS in patients with impaired liver function has not been conducted.

In patients with mild and moderate hepatic impairment after oral administration of rivastigmine, an increase in C_max of approximately 60% and AUC of more than 2 times compared to healthy volunteers was noted.

After a single dose of 3 mg rivastigmine or after multiple doses of the drug according to the regimen of 6 mg twice daily, the clearance of rivastigmine was approximately 60-65% lower in patients with mild to moderate hepatic impairment compared to healthy patients.

These pharmacokinetic features do not affect the frequency of occurrence and severity of adverse events.

Pharmacokinetics in patients with impaired renal function

A study of the use of the Exelon^® TTS in patients with impaired renal function has not been conducted.

Based on population analysis, no clear effect of CrCl on the steady-state concentrations of rivastigmine or its metabolite in plasma was established.

In patients with impaired renal function, dose adjustment is not required.

Indications

• Mild or moderate Alzheimer’s-type dementia;
• Severe Alzheimer’s-type dementia.

ICD codes

Dosage Regimen

Capsules, Solution

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

Transdermal system

Therapy with the drug should be carried out only under the supervision of a physician experienced in the treatment of patients with dementia and under the supervision of persons caring for the patients.

Patients and their caregivers should be instructed on the features of the drug use by competent healthcare professionals.

The amount of rivastigmine contained and released depending on the dosage of the Exelon^® TTS is presented in Table 1.

Table 1.

Mild or moderate Alzheimer’s-type dementia

Initial dose and selection of the recommended effective dose

Treatment with the drug should be started with the application of Exelon^® TTS 4.6 mg/24 h once daily.

After a minimum of 4 weeks of treatment, if well tolerated, the drug dose should be increased to the recommended effective dose by applying Exelon^® TTS 9.5 mg/24 h, which can be used as long as the therapeutic effect persists.

Dose escalation

For long-term treatment in the presence of therapeutic efficacy in the patient, the use of Exelon^® TTS 9.5 mg/24 h is recommended.

If the drug is well tolerated and, at a minimum, after 6 months of treatment with Exelon^® TTS 9.5 mg/24 h, the treating physician, if necessary to achieve an additional therapeutic effect, may increase the dose to 13.3 mg/24 h in patients who, despite the use of Exelon^® TTS 9.5 mg/24 h, have significant impairment of cognitive functions (for example, worsening of MMSE results) and/or deterioration of functional status (based on the physician’s subjective assessment).

Severe Alzheimer’s-type dementia

Initial dose and selection of the recommended effective dose

Treatment with the drug should be started with the application of Exelon^® TTS 4.6 mg/24 h once daily.

The drug dose should be sequentially increased first to 9.5 mg/24 h, and then to the effective dose of 13.3 mg/24 h.

Each dose increase is possible only after a minimum of 4 weeks of treatment and with good tolerance of the previous dose.

A dose above 13.3 mg/24 h does not provide a significant advantage but increases the frequency of side effects.

Interruption of treatment

The clinical effect of therapy with Exelon^® TTS should be regularly assessed.

If there is no clinical effect from therapy when using optimal doses of Exelon^® TTS, therapy with the drug should be discontinued.

Therapy with the drug should be temporarily discontinued in case of adverse events from the digestive system and/or worsening of existing extrapyramidal symptoms (including tremor) until they resolve.

If the break in drug use was no more than 3 days, the drug can be resumed at the same dose.

In case of a longer period of discontinuation, treatment should be resumed with the initial dose (Exelon^® TTS 4.6 mg/24 h).

Patients whose rivastigmine treatment was conducted in the form of capsules or oral solution can switch to treatment with Exelon^® TTS as follows:

• In patients receiving oral rivastigmine therapy at a dose less than or equal to 6 mg/day, treatment should be started with the application of Exelon^® TTS 4.6 mg/24 h;
• In patients receiving oral rivastigmine therapy at a stable and well-tolerated dose of 9 mg/day, treatment can be started immediately with the application of Exelon^® TTS 9.5 mg/24 h. But if the oral therapy was not stable and well-tolerated, switching to the transdermal form is recommended to start with a dose of 4.6 mg/24 h;
• In patients receiving oral rivastigmine therapy at a dose of 12 mg/day, treatment can be started immediately with the application of Exelon^® TTS 9.5 mg/24 h.

After a minimum of 4 weeks of treatment, if well tolerated, the dose of the Exelon^® TTS 4.6 mg/24 h drug should be increased to the recommended effective dose by applying Exelon^® TTS 9.5 mg/24 h.

Treatment with Exelon^® TTS is recommended to start the day after the last oral dose of rivastigmine is taken.

Patients with body weight less than 50 kg

In patients with body weight less than 50 kg, more frequent development of adverse events (AEs) and discontinuation of therapy due to the occurrence of AEs was noted, therefore, when increasing the dose in this group of patients, special caution should be exercised, the dose should be carefully titrated and monitored for the development of AEs (for example, excessive nausea or vomiting), and the possibility of reducing the drug dose by applying Exelon^® TTS 4.6 mg/24 h in case of such AEs should be considered.

Particular caution should be exercised when titrating the dose above the recommended effective dose of Exelon^® TTS 9.5 mg/24 h.

Patients with impaired liver function

Correction of the dosing regimen of Exelon^® TTS is not required.

However, due to the increased exposure of rivastigmine observed with oral rivastigmine in patients with mild to moderate hepatic impairment, it is recommended to carefully titrate the rivastigmine dose according to individual tolerance in patients of this category.

A study of the use of Exelon^® TTS in patients with severe hepatic impairment has not been conducted.

Particular caution should be exercised when titrating the dose in patients of this category.

In patients with clinically significant hepatic impairment, more frequent development of dose-dependent adverse events may be noted, in connection with which, in patients of this category, the possibility of using Exelon^® TTS 4.6 mg/24 h as the initial and maximum dose should be considered.

Patients with impaired renal function

Correction of the dosing regimen of Exelon^® TTS is not required.

However, due to the increased exposure of rivastigmine observed with oral rivastigmine in patients with mild to moderate renal impairment, it is recommended to carefully titrate the rivastigmine dose according to individual tolerance in patients of this category.

In patients with clinically significant renal impairment, more frequent development of dose-dependent adverse events may be noted, in connection with which, in patients of this category, the possibility of using Exelon^® TTS 4.6 mg/24 h as the initial and maximum dose should be considered.

Use in children

The use of rivastigmine in children has not been studied, therefore the drug is not recommended for use in children.

Instructions for using the Exelon^® TTS

Each subsequent Exelon^® TTS should be applied only after removing the previous one.

Only one Exelon^® TTS can be used at a time.

The Exelon^® TTS must not be cut or divided into parts, or damaged in any way.

The Exelon^® TTS should be pressed firmly with the palm at the attachment site for at least 30 seconds.

Placement of the Exelon^® TTS

The Exelon^® TTS should be applied to clean, dry, intact skin with minimal hair.

Do not use creams, lotions, oils, powders, or other skin care products in the area where the patch is applied to prevent it from detaching.

The Exelon^® TTS should not be applied to reddened, rash-covered, irritated, or damaged skin.

Apply only one Exelon^® TTS per day to only one of the following body areas

• Left or right shoulder;
• Upper left or right chest (do not apply to the breast area);
• Upper left or right back;
• Lower left or right back.

5. Every 24 hours, remove the previous Exelon^® TTS before applying one new Exelon^® TTS to one of the body areas shown below.

Fig.1.

To avoid skin irritation, each subsequent Exelon^® TTS should be applied to a different skin area (can be within the same anatomical region). For example, if you applied the Exelon^® TTS to the right lumbar area, next time place the system on the left. To minimize the risk of skin irritation, the TTS can be applied to the same skin site only after an interval of two weeks.

How to apply the Exelon^® TTS

The Exelon^® TTS is a thin, opaque, flexible patch for application to the skin. Do not remove the Exelon^® TTS from the sealed pouch and do not remove the previous Exelon^® TTS unless you plan to apply a new one.

The medication should be used immediately after removal from the sealed pouch.

Carefully remove the previous Exelon^® TTS.

If you are starting treatment with the medication for the first time or resuming treatment after a break, please follow the instructions for applying the Exelon^® TTS, starting from the next figure below.

• Remove the medication from the sealed pouch immediately before use.

• To remove the Exelon^® TTS, cut the pouch along the marked dotted line or groove.

• The adhesive side of the Exelon^® TTS is covered by a protective liner. Carefully remove the protective liner covering the adhesive side of the Exelon^® TTS without touching the adhesive surface with your fingers.

• Immediately after removing the protective liner, apply the Exelon^® TTS to the skin of the upper or lower back, shoulder, or chest.

• After applying the transdermal therapeutic system to the skin, remove the other protective layer.

• Press the Exelon^® TTS firmly onto the application site with the palm of your hand for at least 30 seconds. Ensure that the system adheres well to the skin, especially at the edges.

If necessary after application, you may write the application date (e.g., the day of the week) on the transdermal therapeutic system with a fine ballpoint pen.

The Exelon^® TTS must be worn continuously and replaced with a new one after 24 hours.

Applying the TTS to different skin areas allows you to choose the most convenient body areas where the system will not be in contact with tight-fitting clothing.

How to remove the Exelon^® TTS

Gently lift one corner and slowly and carefully remove the transdermal therapeutic system.

If adhesive residue remains on your skin, gently moisten the area with warm water and mild soapy solution or use baby oil to remove the adhesive residue. Do not use alcohol or other liquid solvents (nail polish remover or other solvents).

Wash your hands thoroughly with soap and water after applying or removing the Exelon^® TTS. In case of contact with eyes or if eye redness occurs after applying or removing the TTS, immediately rinse the eyes with plenty of water and, if symptoms persist, seek medical attention.

How to dispose of the used Exelon^® TTS

Fold the used TTS in half and stick the adhesive parts together.

Place the used Exelon^® TTS into a bag. The bag with the used transdermal therapeutic system should be disposed of in a place inaccessible to children. After disposing of the medication, wash your hands with soap.

Conditions for wearing the Exelon^® TTS (water procedures, prolonged exposure to heat sources)

The Exelon^® TTS does not detach during water procedures (shower, bath, swimming pool).

During water procedures, ensure that the system adheres well to the skin, especially at the edges.

Patients using the Exelon^® TTS should not be exposed for prolonged periods near any external heat sources (excessive solar radiation, saunas, tanning beds).

What to do if the Exelon^® TTS detaches

If the Exelon^® TTS detaches, it must be replaced with a new TTS by the end of the day. The next day, apply a new Exelon^® TTS as usual.

When and for how long to use the Exelon^® TTS

For maximum treatment effectiveness, apply a new TTS every day, preferably at the same time.

If more than one Exelon^® TTS is applied simultaneously

Immediately remove all TTS from your skin and inform your treating physician about the incident. You may require medical attention. In some cases of overdose, nausea, vomiting, diarrhea, increased blood pressure, hallucinations have been noted. Bradycardia and/or fainting may also occur.

If you forget to apply the next TTS at the usual time, apply it immediately. The next TTS can be applied the next day at the usual time. Do not apply two TTS to compensate for a missed dose.

Adverse Reactions

The overall incidence of adverse events during therapy with the Exelon^® TTS 9.5/24 h (50.5%) was lower compared to oral therapy with capsules at a daily dose of 3-12 mg (63.3%) (for comparison, this figure was 46% in the placebo group).

The incidence and severity of adverse events generally increase with dose escalation, especially immediately after a dose change. If the interruption in the use of the medication lasted more than 3 days, treatment should be resumed with the initial dose (Exelon^® TTS 4.6 mg/24 h).

The most frequent adverse events were skin reactions at the application site (usually mild to moderate erythema). The next most frequent were gastrointestinal system adverse events: nausea (7.2%) and vomiting (6.2%) were significantly less frequent with the Exelon^® TTS 9.5 mg/24 h compared to oral capsules, 23.1% and 17.0%, respectively (in the placebo group, the same figures were 5.0% and 3.3%).

The incidence of adverse reactions in patients (854 persons) with Alzheimer’s-type dementia receiving therapy with Exelon^® TTS (all dosages) was assessed as follows: very common (≥ 1/10), common ( >1/100, <1/10), uncommon ( ≥ 1/1000, <1/100), rare (≥ 1/10000, <1/1000), very rare (<1/10000), adverse reactions with unknown frequency are presented separately.

In patients with Alzheimer’s-type dementia receiving therapy with Exelon^® TTS, the following adverse events were noted.

Infections and infestations: common – urinary tract infections.

Metabolism and nutrition disorders: common – anorexia, decreased appetite; uncommon – dehydration.

Psychiatric disorders common – anxiety, depression, delirium, agitation, insomnia; uncommon – aggression; frequency unknown – restlessness, hallucinations, nightmares.

Nervous system disorders: common – headache, syncope, dizziness; uncommon – cerebrovascular accident, psychomotor hyperactivity, somnolence; very rare – extrapyramidal disorders; frequency unknown – worsening of Parkinson’s disease symptoms, seizures, tremor.

Cardiac disorders uncommon – bradycardia; frequency unknown – tachycardia, AV block, atrial fibrillation, sick sinus syndrome.

Vascular disorders frequency unknown – increased blood pressure.

Gastrointestinal disorders: common – nausea, vomiting, diarrhea, dyspepsia, abdominal pain; uncommon – gastric ulcer; frequency unknown – pancreatitis.

Hepatobiliary disorders frequency unknown – hepatitis, increased liver function biochemical parameters.

Skin and subcutaneous tissue disorders common – rash; uncommon – hyperhidrosis; frequency unknown – pruritus, erythema, urticaria, blistering, allergic dermatitis, generalized allergic dermatitis.

Renal and urinary disorders common – urinary incontinence.

General disorders and administration site conditions common – skin reactions at the application site (including erythema, pruritus, edema, dermatitis, irritation), increased fatigue, asthenia, pyrexia, weight decreased; rare – accidental falls.

In patients with severe Alzheimer’s-type dementia receiving therapy with Exelon^® TTS 13.3 mg/24 h, the following adverse events with a frequency of ≥ 5% were noted.

Infections and infestations common – urinary tract infections.

Metabolism and nutrition disorders common – decreased appetite.

Psychiatric disorders very common – agitation; common – insomnia, anxiety, depression, hallucinations.

Gastrointestinal disorders common – nausea, vomiting, diarrhea.

General disorders and administration site conditions very common – application site erythema; common – accidental falls, weight decreased.

In a clinical study with doses higher than 13.3 mg/24 h, the following adverse events occurred more frequently than in the Exelon^® TTS 13.3 mg/24 h and placebo groups: insomnia, heart failure (possibly dose-related). The frequency of these adverse events during therapy with Exelon^® TTS 13.3 mg/24 h was similar to that in the placebo group.

The following adverse reactions were observed only during treatment of dementia with Exelon^® capsules or oral solution and were not recorded in clinical studies with Exelon^® TTS

Common – somnolence, malaise, tremor, confusion, increased sweating;

Rare – duodenal ulcer, angina pectoris;

Very rare – gastrointestinal hemorrhage, hallucinations.

Frequency not known – severe vomiting leading to esophageal rupture.

Reactions at the Exelon^® TTS application site (skin irritation)

In clinical studies with Exelon^® TTS, reactions at the TTS application site were mostly mild or moderate in severity. Discontinuation of treatment due to development of a reaction at the Exelon^® TTS application site was noted in ≤ 2.3% of cases, with the frequency of treatment discontinuation in patients of Chinese and Japanese ethnicity being 4.9% and 8.4%, respectively.

The severity of skin reactions was assessed by the treating physician using a specific scale. In most cases, skin irritation was mild or moderate. In clinical studies of Exelon^® TTS, severe skin irritation was noted in ≤ 2.2% of cases, while in the study of Exelon^® TTS in Japanese patients, the frequency of severe skin irritation was ≤ 3.7%.

Contraindications

• Hypersensitivity to rivastigmine, other carbamate derivatives, or other ingredients of the medication;
• History of contact allergic dermatitis that occurred during the use of Exelon^® TTS;
• Age under 18 years.

Caution should be exercised when using Rivastigmine in patients with sick sinus syndrome or conduction disorders (sinoatrial block, AV block).

Cholinergic stimulation may lead

• To increased gastric acid secretion, therefore caution should be exercised when using rivastigmine in patients with active gastric or duodenal ulcer or in patients predisposed to these conditions;
• To the development or exacerbation of urinary tract obstruction and seizure syndrome, therefore caution should be exercised when prescribing rivastigmine to patients predisposed to these conditions.

Caution should be exercised when using Rivastigmine in patients with a history of bronchial asthma or obstructive airway diseases.

Use in Pregnancy and Lactation

Pregnancy

In animal studies, Rivastigmine crossed the placental barrier. There are no data on the ability of rivastigmine to cross the human placental barrier.

Experimental data have shown that Rivastigmine does not have teratogenic properties. Animal studies noted an increase in the duration of the gestational period. The safety of Exelon^® use during human pregnancy has not been established to date, so the medication should be used during pregnancy only if the expected benefit of treatment outweighs the potential risk to the fetus.

Breastfeeding

In studies, Rivastigmine and its metabolites were excreted in the milk of lactating animals. It is unknown whether Rivastigmine is excreted in human breast milk, therefore breastfeeding should be discontinued during use of the medication.

Fertility

There are no data on the effect of rivastigmine on women of reproductive age.

There are no data on the effect of rivastigmine on human fertility. In animal studies, no negative effects on fertility of male and female parents or offspring were observed.

Use in Hepatic Impairment

Dose titration should be conducted with caution in patients with severe hepatic impairment (as adverse reactions may occur more frequently). In patients with clinically significant hepatic impairment, adverse events may occur more frequently, therefore in this category of patients, the use of Exelon^® TTS 4.6 mg/24 h is recommended as the initial and maximum dose.

Use in Renal Impairment

No dose adjustment of Exelon^® TTS is required in patients with renal impairment.

Pediatric Use

The use of rivastigmine in children has not been studied, therefore the medication is not recommended for children and adolescents under 18 years of age.

Geriatric Use

Individual higher sensitivity to the effects of the medication in older patients cannot be excluded.

Special Precautions

Patients should avoid contact of hands with eyes immediately after applying or removing the TTS. Wash hands thoroughly with soap and water after applying or removing the TTS. In case of contact with eyes or if eye redness occurs after applying or removing the TTS, immediately rinse the eyes with plenty of water and, if symptoms persist, seek medical attention.

Gastrointestinal disorders

The frequency and severity of side effects usually increase with increasing rivastigmine dose, especially during dose titration. If the interruption in the use of Exelon^® TTS lasted more than 3 days, treatment should be resumed with the initial dose (Exelon^® TTS 4.6 mg/24 h).

The severity of such dose-dependent gastrointestinal adverse events as nausea, vomiting, and diarrhea, observed at the start of treatment or during dose increase, may decrease with a reduction in the rivastigmine dose; if there is no effect, therapy with Exelon^® TTS should be interrupted. These adverse events are more common in women. Patients who develop signs of dehydration due to prolonged diarrhea or vomiting are recommended intravenous fluid administration and dose reduction or discontinuation of rivastigmine therapy, due to the possible risk of serious complications.

Weight loss

Since weight loss may occur in patients with Alzheimer’s disease during therapy with cholinesterase inhibitors, including Rivastigmine, body weight should be monitored during therapy with Exelon^® TTS.

Other adverse events associated with increased cholinergic activity

As with other cholinomimetics, caution should be exercised when using Exelon^® TTS in patients with sick sinus syndrome or conduction disorders (sinoatrial block, AV block); in patients with a history of bronchial asthma or obstructive airway diseases.

Cholinergic stimulation may lead

• To increased gastric acid secretion, therefore caution should be exercised when using Exelon^® TTS in patients with active gastric or duodenal ulcer or in patients predisposed to these conditions;
• To the development or exacerbation of urinary tract obstruction and seizure syndrome, therefore caution should be exercised when prescribing rivastigmine to patients predisposed to these conditions.

Similar to other cholinomimetics, rivastigmine may cause increased severity of extrapyramidal symptoms.

QT interval prolongation and torsades de pointes

On the ECG of patients receiving therapy with cholinesterase inhibitors, including Rivastigmine, QT interval prolongation may be observed. Rivastigmine may cause bradycardia, which is a risk factor for the occurrence of torsades de pointes, mainly in patients with risk factors.

Caution should be exercised in patients at increased risk of developing torsades de pointes; for example, in decompensated heart failure, recent myocardial infarction, bradyarrhythmia, hypokalemia or hypomagnesemia, personal or family history of QT interval prolongation, or when used concomitantly with medications that cause QT interval prolongation and/or torsades de pointes. Clinical monitoring may also be required (see section “Drug Interactions”).

Reactions at the Exelon^® TTS application site and skin reactions

Skin reactions occurring during the use of Exelon^® TTS are generally mild or moderate in severity. These reactions are not an indicator of patient sensitization to rivastigmine. Nevertheless, allergic contact dermatitis may occur during the use of Exelon^® TTS.

Allergic contact dermatitis should be suspected if a skin reaction at the TTS application site spreads beyond the size of the TTS, or if skin reactions at the application site reach marked intensity (e.g., increasing erythema, edema, appearance of papules, vesicles), and also if the severity of skin reactions does not significantly decrease within 48 hours after TTS removal. In these cases, treatment with the medication should be discontinued (see section “Contraindications”).

If patients develop a reaction at the site of TTS attachment resembling contact allergic dermatitis while using Exelon^® TTS, and if continuation of rivastigmine therapy is necessary, it is recommended to switch the patient to oral dosage forms of rivastigmine under the supervision of medical personnel and after obtaining a negative result from allergy testing.

Some patients sensitized to rivastigmine due to the use of Exelon^® TTS may not be able to use Rivastigmine in other dosage forms.

During post-registration use of the drug, data were received on the development of widespread allergic dermatitis in some patients using rivastigmine, regardless of the route of administration (oral or transdermal). In these cases, the drug should be completely discontinued (see section “Contraindications”).

Patients and their caregivers should be informed about the possibility of developing corresponding skin reactions while using rivastigmine.

Use in Special Patient Groups

Use in elderly patients. In clinical studies of Exelon^® TTS, the age of 88% of patients was 65 years and older, and the age of 55% of patients was over 75 years. Overall, no differences in safety and efficacy depending on age were identified. However, individual greater sensitivity to the drug’s effects in older patients cannot be ruled out.

Patients with impaired liver function. When rivastigmine was taken orally by patients with mild to moderate hepatic impairment, an increase in rivastigmine exposure was observed, which may require a dose reduction based on individual tolerance in this patient category. The use of rivastigmine in patients with severe hepatic impairment has not been studied.

Patients with impaired renal function. When rivastigmine was taken orally by patients with mild to moderate renal impairment, an increase in rivastigmine exposure was observed, which may require a dose reduction based on individual tolerance in this patient category.

Patients with low or high body weight. Due to the relationship between body weight and rivastigmine exposure, the dose should be carefully titrated and the condition of patients with low or high body weight should be monitored.

Effect on the ability to drive vehicles and operate machinery

Dementia of the Alzheimer’s type can cause a gradual deterioration in the ability to drive vehicles or compromise their use. Patients receiving rivastigmine therapy may experience dizziness and drowsiness, especially at the beginning of treatment or when the dose is changed. Rivastigmine may cause fainting or delirium. The ability of a patient with dementia receiving the drug to drive vehicles and/or operate machinery should be regularly assessed by the treating physician.

Overdose

Symptoms: Accidental overdose of the oral formulation was not accompanied by any clinical manifestations in most cases; almost all patients continued rivastigmine treatment. Overdose symptoms included nausea, vomiting, diarrhea, abdominal pain, dizziness, tremor, headache, drowsiness, bradycardia, confusion, increased sweating, elevated blood pressure, hallucinations, and general malaise. Overdose with cholinesterase inhibitors can lead to a cholinergic crisis with symptoms such as severe nausea, vomiting, increased salivation, increased sweating, bradycardia, decreased blood pressure, respiratory depression, and seizures. Muscle weakness may develop, which can be fatal if the respiratory muscles are involved. Given the vagotonic effect of cholinesterase inhibitors on heart rate, the occurrence of bradycardia and/or fainting cannot be ruled out.

During post-registration use of the drug, as well as in rare cases during clinical trials, reports of application/dosing errors with Exelon^® TTS have been received, due to the application of several Exelon^® TTS simultaneously (a new TTS was applied without removing the previous one). Patients and their caregivers should be instructed on the specifics of drug application.

Rare cases of fatal outcomes have been reported with drug overdose, but the connection with the drug use remains unclear. Symptoms and outcomes varied among different patients. No clear relationship between the dose taken and the severity of the outcome was observed.

Treatment: Since the T_1/2 of rivastigmine from plasma is about 3.4 hours, and the duration of acetylcholinesterase inhibition is about 9 hours, in cases of asymptomatic overdose, immediate removal of all TTS is recommended. Exelon^® TTS should not be applied for the next 24 hours. If overdose is accompanied by severe nausea and vomiting, the use of antiemetics should be considered. If other adverse events occur, appropriate symptomatic treatment should be provided as needed.

In cases of significant overdose, atropine can be used, with an initial dose of 0.03 mg/kg IV; subsequent dosing depends on the clinical effect. The use of scopolamine as an antidote is not recommended.

Drug Interactions

No specific studies on the interaction of Exelon^® TTS with other medicinal products have been conducted.

Rivastigmine is metabolized primarily by hydrolysis via esterases. Metabolism of rivastigmine involving the main cytochrome P450 isoenzymes is minimal. Therefore, pharmacokinetic interaction of rivastigmine with other drugs metabolized by these enzymes seems unlikely.

However, Rivastigmine may exert an inhibitory effect on the butyrylcholinesterase activity-mediated metabolism of other substances.

Not recommended interactions

Metoclopramide

Given the potential for combined effects on the extrapyramidal system, concomitant use of metoclopramide and rivastigmine is not recommended.

Drugs affecting the cholinergic system

Given the pharmacodynamic characteristics of rivastigmine, concomitant use with other cholinomimetics should be avoided due to the potential for additive effects. Rivastigmine may affect the action of anticholinergics (e.g., oxybutynin, tolterodine).

Suxamethonium salts. During anesthesia, Rivastigmine, being a cholinesterase inhibitor, may enhance the effects of depolarizing muscle relaxants (e.g., suxamethonium salts).

Expected interactions to be considered

Drugs that prolong the QT interval

Caution should be exercised when using rivastigmine in combination with other drugs known to prolong the QT interval (including, but not limited to, quinidine, amiodarone, pimozide, halofantrine, cisapride, citalopram, mizolastine, moxifloxacin, erythromycin). Clinical monitoring may also be required (see section “Special Instructions”).

Interactions to be considered

Beta-blockers

Concomitant use of rivastigmine with various beta-blockers (including atenolol) has been noted to have a synergistic interaction leading to bradycardia, which in turn can cause syncope. Although concomitant use with cardioselective beta-blockers is associated with the highest risk of such effects, these adverse events have also been observed in patients receiving other drugs in this group.

Interaction with nicotine

A 23% increase in rivastigmine absorption was noted with oral administration (in capsule form at doses up to 12 mg/day) in patients taking nicotine.

Interaction with most frequently co-administered drugs

In healthy volunteers, no pharmacokinetic interaction was found between oral rivastigmine and digoxin, warfarin, diazepam, or fluoxetine. The warfarin-induced increase in prothrombin time was not altered by oral rivastigmine. Concomitant use of oral rivastigmine and digoxin showed no adverse effect on intracardiac conduction.

Concomitant use of rivastigmine with commonly used drugs such as antacids, antiemetics, hypoglycemic drugs, centrally acting antihypertensive agents, slow calcium channel blockers, positive inotropic agents, antianginal drugs, estrogens, analgesics including NSAIDs, benzodiazepines, and antihistamines was not associated with any changes in rivastigmine kinetics or an increased risk of clinically significant adverse events.

Storage Conditions

The drug should be stored out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed 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.