Chemical formula: C₁₄H₂₂N₂O₂ Molecular mass: 250.337 g/mol PubChem compound: 77991
Rivastigmine interacts in the following cases:
Since bradycardia constitutes a risk factor in the occurrence of torsades de pointes, the combination of rivastigmine with torsades de pointes-inducing medicinal products such as antipsychotics i.e. some phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, tiapride, veralipride), pimozide, haloperidol, droperidol, cisapride, citalopram, diphemanil, erythromycin IV, halofantrin, mizolastin, methadone, pentamidine and moxifloxacine should be observed with caution and clinical monitoring (ECG) may also be required.
In view of its pharmacodynamic effects and possible additive effects, rivastigmine should not be given concomitantly with other cholinomimetic substances.
Rivastigmine might interfere with the activity of anticholinergic medicinal products (e.g oxybutynin, tolterodine).
Additive effects leading to bradycardia (which may result in syncope) have been reported with the combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta-blockers are expected to be associated with the greatest risk, but reports have also been received in patients using other beta-blockers. Therefore, caution should be exercised when rivastigmine is combined with beta-blockers.
As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed.
Caution is advised in patients at higher risk of developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial infarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant use with medicinal products known to induce QT prolongation and/or torsade de pointes.
Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases.
Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block).
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions.
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs in humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.
In animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.
No adverse effects of rivastigmine were observed on fertility or reproductive performance in rats. Effects of rivastigmine on human fertility are not known.
Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability to use machines. Furthermore, rivastigmine may induce syncope or delirium. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, in patients with dementia treated with rivastigmine, the ability to continue driving or operating complex machines should be routinely evaluated by the treating physician.
The most commonly reported adverse reactions (ADRs) are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.
Adverse reactions below are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
The following adverse reactions, listed below, have been accumulated in patients with Alzheimer’s dementia treated with rivastigmine.
Very rare: Urinary infection
Very common: Anorexia
Common: Decreased appetite
Not known: Dehydration
Common: Nightmares, Agitation, Confusion, Anxiety
Uncommon: Insomnia, Depression
Very rare: Hallucinations
Not known: Aggression, restlessness
Very common: Dizziness
Common: Headache, Somnolence, Tremor
Uncommon: Syncope
Rare: Seizures
Very rare: Extrapyramidal symptoms (including worsening of Parkinson’s disease)
Rare: Angina pectoris
Very rare: Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia)
Not known: Sick sinus syndrome
Very rare: Hypertension
Very common: Nausea, Vomiting, Diarrhoea
Common: Abdominal pain and dyspepsia
Rare: Gastric and duodenal ulcers
Very rare: Gastrointestinal haemorrhage, Pancreatitis
Not known: Some cases of severe vomiting were associated with oesophageal rupture
Uncommon: Elevated liver function tests
Not known: Hepatitis
Common: Hyperhydrosis
Rare: Rash
Not known: Pruritus, allergic dermatitis (disseminated)
Common: Fatigue and asthenia, Malaise
Uncommon: Fall
Common: Weight loss
The following list shows the adverse reactions reported during clinical studies conducted in patients with dementia associated with Parkinson’s disease treated with rivastigmine capsules.
Common: Decreased appetite, Dehydration
Common: Insomnia, Anxiety, Restlessness, Hallucination, visual, Depression
Not known: Aggression
Very common: Tremor
Common: Dizziness, Somnolence, Headache, Parkinson’s disease (worsening), Bradykinesia, Dyskinesia, Hypokinesia, Cogwheel rigidity
Uncommon: Dystonia
Common: Bradycardia
Uncommon: Atrial Fibrillation, Atrioventricular block
Not known: Sick sinus syndrome
Common: Hypertension
Uncommon: Hypotension
Very common: Nausea, Vomiting
Common: Diarrhoea, Abdominal pain and dyspepsia, Salivary hypersecretion
Not known: Hepatitis
Common: Hyperhydrosis
Not known: Allergic dermatitis (disseminated)
Very common: Fall
Common: Fatigue and asthenia, Gait disturbance, Parkinson gait
The following table lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson’s disease with pre-defined adverse events that may reflect worsening of parkinsonian symptoms.
| Pre-defined adverse events that may reflect worsening of parkinsonian symptoms in patients with dementia associated with Parkinson’s disease | Rivastigmine n (%) | Placebo n (%) |
|---|---|---|
| Total patients studied | 362 (100) | 179 (100) |
| Total patients with pre-defined AE(s) | 99 (27.3) | 28 (15.6) |
| Tremor | 37 (10.2) | 7 (3.9) |
| Fall | 21 (5.8) | 11 (6.1) |
| Parkinson’s disease (worsening) | 12 (3.3) | 2 (1.1) |
| Salivary hypersecretion | 5 (1.4) | 0 |
| Dyskinesia | 5 (1.4) | 1 (0.6) |
| Parkinsonism | 8 (2.2) | 1 (0.6) |
| Hypokinesia | 1 (0.3) | 0 |
| Movement disorder | 1 (0.3) | 0 |
| Bradykinesia | 9 (2.5) | 3 (1.7) |
| Dystonia | 3 (0.8) | 1 (0.6) |
| Gait abnormality | 5 (1.4) | 0 |
| Muscle rigidity | 1 (0.3) | 0 |
| Balance disorder | 3 (0.8) | 2 (1.1) |
| Musculoskeletal stiffness | 3 (0.8) | 0 |
| Rigors | 1 (0.3) | 0 |
| Motor dysfunction | 1 (0.3) | 0 |
Application site skin reactions (usually mild to moderate application site erythema), are the most frequent adverse reactions observed with the use of rivastigmine transdermal patch. The next most common adverse reactions are gastrointestinal in nature including nausea and vomiting.
Adverse reactions below are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
The following list displays the adverse reactions reported in 1,670 patients with Alzheimer’s dementia treated in randomised, double-blind, placebo and active-controlled clinical studies with rivastigmine transdermal patches for a duration of 24-48 weeks and from post-marketing data.
Common: Urinary tract infection
Common: Anorexia, decreased appetite
Uncommon: Dehydration
Common: Anxiety, depression, delirium, agitation
Uncommon: Aggression
Not known: Hallucinations, restlessness, nightmares
Common: Headache, syncope, dizziness
Uncommon: Psychomotor hyperactivity
Very rare: Extrapyramidal symptoms
Not known: Worsening of Parkinson’s disease, seizure, tremor, somnolence
Uncommon: Bradycardia
Not known: Atrioventricular block, atrial fibrillation, tachycardia, sick sinus syndrome
Not known: Hypertension
Common: Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain
Uncommon: Gastric ulcer
Not known: Pancreatitis
Not known: Hepatitis, elevated liver function tests
Common: Rash
Not known Pruritus, erythema, urticaria, vesicles, allergic dermatitis (disseminated)
Common: Urinary incontinence
Common: Application site skin reactions (e.g. application site erythema*, application site pruritus*, application site oedema*, application site dermatitis, application site irritation), asthenic conditions (e.g. fatigue, asthenia), pyrexia, weight decreased
Rare: Fall
* In a 24-week controlled study in Japanese patients, application site erythema, application site oedema and application site pruritus were reported as “very common”.
The following additional adverse reaction has been observed in a study of patients with dementia associated with Parkinson’s disease treated with rivastigmine transdermal patches: agitation (common).
When doses higher than 13.3 mg/24 h were used in the above-mentioned placebo-controlled study, insomnia and cardiac failure were observed more frequently than with 13.3 mg/24 h or placebo, suggesting a dose effect relationship. However, these events did not occur at a higher frequency with rivastigmine 13.3 mg/24 h transdermal patches than with placebo.
In double-blind controlled clinical trials, application site reactions were mostly mild to moderate in severity. The incidence of application site skin reactions leading to discontinuation was ≤2.3% in patients treated with rivastigmine transdermal patches. The incidence of application site skin reactions leading to discontinuation was higher in the Asian population with 4.9% and 8.4% in the Chinese and Japanese population respectively.
In two 24-week double-blind, placebo-controlled clinical trials, skin reactions were measured at each visit using a skin irritation rating scale. When observed in patients treated with rivastigmine transdermal patches, skin irritation was mostly slight or mild in severity. It was rated as severe in ≤2.2% of patients treated with rivastigmine transdermal patches in a Japanese study.
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