Rivastigmine (rivastigmine)

Dosage of rivastigmine tartrate is expressed in terms of rivastigmine.

Rivastigmine is administered orally (as capsules or oral solution) twice daily. The drug also is available as a transdermal system for topical application.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Antipsychotics; Phenothiazines; Rivastigmine/Metoclopramide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: These agents block dopamine (D2) receptors. D2 blockade can cause extrapyramidal reactions, such acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia. Neuroleptic malignant syndrome may also occur in patients receiving D2 blockers. The risk of these adverse effects may be increased by concurrent use.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of extrapyramidal reactions (e.g. acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia) and neuroleptic malignant syndrome. Tardive dyskinesia, which may be permanent, typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs.(1-3) Symptoms of neuroleptic malignant syndrome include hyperpyrexia, muscle rigidity, altered mental status, an autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias), elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.(1)

PREDISPOSING FACTORS: Patients with Parkinson's or Lewy Body Disease may be more likely to have extrapyramidal reactions or unmasking of their primary disease symptoms. The risk of extrapyramidal symptoms is also increased in patients on metoclopramide for longer than 12 weeks. Elderly patients, especially elderly women, and diabetics are at higher risk of developing tardive dyskinesia. Other extrapyramidal symptoms, like acute dystonia, have occurred more frequently in patients younger than 30 years old.(1)

PATIENT MANAGEMENT: The concurrent use of metoclopramide and agents likely to cause extrapyramidal reactions should be avoided.(1) If concurrent use is warranted, monitor patients closely for extrapyramidal reactions and neuroleptic malignant syndrome. The manufacturer of metoclopramide says to avoid treatment with metoclopramide for longer than 12 weeks, and to use the lowest possible dose.(1) Discontinue therapy if symptoms occur. Instruct patients to seek immediate medical attention if symptoms develop. Symptoms of extrapyramidal reactions, including tardive dyskinesia, include involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech, trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.(3)

DISCUSSION: Both metoclopramide and phenothiazines can cause extrapyramidal reactions, such as tardive dyskinesia, and neuroleptic malignant syndrome. The risk may be increased by concurrent use.(1,2) Extrapyramidal symptoms have been reported with concurrent metoclopramide and neuroleptics, prochlorperazine, and chlorpromazine.(4-6)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Anticholinesterases/Beta-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Anticholinesterases inhibit plasma cholinesterases and increase cholinergic activity. Use of anticholinesterases may have vagotonic effects on heart rate (e.g. bradycardia). Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1)

CLINICAL EFFECTS: Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of anticholinesterases and beta-blockers is not recommended. Additive effects may be increased with cardioselective beta-blockers (e.g. atenolol). Monitor patients closely if concurrent use is warranted.(1)

DISCUSSION: Concurrent use of anticholinesterases and beta-blockers may have additive effects on cardiac conduction and increase the risk of bradycardia.(1) A case report of a 65 year old African American female had a witnessed a presyncopal episode followed by a true syncopal episode with concurrent use of rivastigmine and atenolol. On day 2 of the hospital stay, the patient developed bradycardia with a heart rate in the 40s and sinus pauses greater than 2 seconds. Atenolol was discontinued yet bradycardia persisted. Following discontinuation of rivastigmine, sinus pauses resolved and heart rate returned to normal.(2) A population-based cohort study in Ontario, Canada reviewed the relationship between cholinesterase inhibitor use and syncope-related outcomes over a two year period. Hospital visits for syncope were more frequent in patients receiving cholinesterase inhibitors than controls (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.57-1.98). Other syncope-related events were also more common in patients receiving cholinesterase inhibitors than controls: hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR 1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(3) A population based case-time-control study of 1,009 patients hospitalized for bradycardia within 9 months of using a cholinesterase inhibitor were reviewed for outcomes. Of these patients, 11% required pacemaker insertion during hospitalization and 4% died prior to discharge. With adjustment for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor drug (adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51). Risk was similar in patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI 1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34; 95% CI 1.16-4.71).(4)

Anticholinesterases/Succinylcholine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Anticholinesterases inhibit plasma cholinesterases, delaying succinylcholine hydrolysis and prolonging its duration of action.

CLINICAL EFFECTS: May see an increase in the neuromuscular blocking effects of succinylcholine, producing profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent administration of anticholinesterases and succinylcholine in patients with depolarizing type (phase I) neuromuscular blockade. In addition, use with caution in the presence of a nondepolarizing type (phase II) blockade. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Concomitant administration of anticholinesterases and succinylcholine has been associated with prolonged respiratory depression and apnea.

Cholinergics/Quinidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The anticholinergic properties of quinidine may oppose cholinergic drug effects.

CLINICAL EFFECTS: Quinidine may antagonize the effects of cholinergic drugs in the treatment of myasthenia gravis. Cardiac slowing secondary to cholinergic drugs would tend to be prevented by quinidine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If both drugs are administered, observe the myasthenic patient for signs and symptoms of the disease.

DISCUSSION: Caution is warranted in co-administration of these drugs due to their opposing pharmacologic properties.

Known hypersensitivity to rivastigmine or any ingredient in the formulation. Although there are no reports of cross-sensitivity to date, the manufacturer states that the drug also is contraindicated in patients with known hypersensitivity to other carbamates.

History of previous application site reactions with rivastigmine transdermal system suggestive of allergic contact dermatitis, in the absence of negative allergy testing.

There are no contraindication contraindications for this drug.

• Asthma
• Bradycardia
• Cardiac arrhythmia
• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Chronic obstructive pulmonary disease
• Congenital long QT syndrome
• Disease of liver
• Extrapyramidal disease
• Gastrointestinal hemorrhage
• Gastrointestinal ulcer
• Prolonged QT interval
• Sick sinus syndrome
• Torsades de pointes
• Weight loss

• Anorexia
• Diarrhea
• Parkinsonism
• Seizure disorder
• Urinary tract obstructive uropathy
• Vomiting

In clinical trials of oral rivastigmine in patients with dementia of the Alzheimer's type, adverse effects occurring in 5% or more of patients receiving rivastigmine and more than twice as frequently as among those receiving placebo included nausea, vomiting, anorexia, dyspepsia, and asthenia. Dizziness, diarrhea, headache, abdominal pain, accidental trauma, fatigue, insomnia, confusion, urinary tract infection, depression, malaise, somnolence, constipation, and anxiety occurred in at least 5% of patients receiving rivastigmine and more frequently than in patients receiving placebo in clinical studies in patients with dementia of the Alzheimer's type.

In clinical trials of oral rivastigmine in patients with dementia associated with Parkinson's disease, adverse effects occurring in 5% or more of patients receiving rivastigmine and more than twice as frequently as among those receiving placebo included nausea, vomiting, tremor, anorexia, and dizziness.

In a clinical trial that evaluated rivastigmine transdermal therapy in patients with dementia of the Alzheimer's type, nausea, vomiting, and diarrhea occurred in at least 5% of patients receiving rivastigmine (one system delivering 9.5 mg/24 hours) and more frequently than in patients receiving placebo. Most patients experienced no, slight, or mild skin irritation.

Less Frequent

• Bradycardia
• Hypertension
• Syncope

Rare or Very Rare

• Abnormal hepatic function tests
• Acquired dystonia
• Allergic dermatitis
• Atrial fibrillation
• Atrioventricular block
• Bloody vomit
• Dehydration
• Dyskinesia
• Hepatitis
• Hyponatremia
• Pancreatitis
• Peptic ulcer
• Prolonged QT interval
• Seizure disorder
• Sick sinus syndrome
• Stevens-johnson syndrome
• Tachycardia
• Torsades de pointes

More Frequent

• Diarrhea
• Dizziness
• Dyspepsia
• Hallucinations
• Nausea
• Vomiting

Less Frequent

• Abdominal pain with cramps
• Anorexia
• Depression
• Drowsy
• Fatigue
• General weakness
• Headache disorder
• Hyperhidrosis
• Insomnia
• Symptoms of anxiety
• Urinary tract infection
• Weight loss

Rare or Very Rare

• Acute eruptions of skin
• Aggressive behavior
• Agitation
• Athetoid movements
• Blurred vision
• Chest pain
• Contact dermatitis
• Dyspnea
• Extrapyramidal disease
• Gait abnormality
• Gastroesophageal reflux disease
• Nightmares
• Pharyngitis
• Pruritus of skin
• Sialorrhea
• Skin rash
• Treatment site sequelae
• Tremor
• Urinary incontinence
• Urticaria
• Vertigo

No enhanced messaging available.

Safety and efficacy of rivastigmine in pediatric patients have not been established. The drug is not recommended for pediatric use.

There are no adequate data on the developmental risks associated with the use of rivastigmine in pregnant women. In animal reproduction studies, no adverse embryofetal effects were observed with oral dose exposures of 2-4 times the maximum recommended human dose.

It is not known whether rivastigmine is distributed into milk or if the drug has any effects on nursing infants or on milk production. The known benefits of breast-feeding should be considered along with the mother's clinical need for rivastigmine and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.

No overall differences in safety and efficacy have been observed between geriatric patients and younger adults in clinical studies of rivastigmine and in other reported clinical experiences; however, the possibility of increased sensitivity to rivastigmine in some geriatric patients cannot be ruled out.