Drug Criteria & Outcomes: New drug evaluation: Rivastigmine (Exelon®)
New drug evaluation: Rivastigmine (Exelon®)
By Evelyn Senwo, PharmD Candidate, Harrison School of Pharmacy
Auburn University, Auburn, AL
Drug Name
Rivastigmine (Exelon®) transdermal patch and oral capsule
Similar Drugs
Tacrine (Cognex®), donepezil (Aricept®), and galantamine (Reminyl®)
Strengths/Dosage Forms Available
Transdermal Patch: 4.6 mg/24 hours and 9.5 mg/24 hours
Oral capsule: 1.5 mg, 3 mg, 4.5 mg, and 6 mg bid
Mechanism of Action
The primary effect of rivastigmine is the reversible inhibition of cholinesterase, which increases the level of acetylcholine available in the central nervous system.
Indication
Rivastigmine (transdermal patch and oral capsule) is approved by the FDA for the treatment of mild-to-moderate dementia of both Alzheimer's disease and Parkinson's disease.
Storage
Store both the rivastigmine transdermal patch and oral capsule at 25° C (77° F); excursions permitted to 15-30° C (59-86° F).
Keep rivastigmine transdermal patch in the individual sealed pouch until ready to use. Used systems should be folded, with the adhesive surfaces pressed together, and discarded safely.
Absorption
Transdermal patch: There is a lag time of 0.5-1 hour in the absorption after first dose. The concentrations then rises slowly reaching a maximum after 8 hours. After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period of application.
The steady-state trough levels are approximately 60-80% of peak levels. Compared to a patient with a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a body weight of 35 kg are approximately doubled. The effect of body weight on drug exposure suggests special attention to patients with very low body weight during up-titration.
Over a 24-hour period, approximately 50% of the drug load is released into the system. When the patch is applied to the upper back, chest, or upper arm, exposure to rivastigmine is high compared to the abdomen and thigh, which is 20-30% lower.
Oral capsule: Rapid, and completed within one hour.
Distribution
The distribution in both the patch and the oral capsule are equal with a Vd of 1.8-2.7 L/kg. Protein binding is 40%; rivastigmine penetrates the blood-brain barrier and reaches cerebrospinal fluid peak concentration in 1.4-2.6 hours.
Metabolism
Hepatic: cholinesterase-mediated hydrolysis, extensive; CYP450 is minimally involved in metabolism.
Metabolite: Decarbamylated metabolite shows minimal inhibition of acetylcholinesterase. The patch does bypass the first-pass effect hence providing more drug that is released into the system.
Bioavailability
Transdermal patch: 50%
Oral capsule: 36-40%
Excretion (both oral capsule and transdermal patch)
Fecal: > 1%
Renal: > 90%
Elimination Half-life
Transdermal patch: 3 hours after removal
Oral capsule: 1.5 hour
Dosage/Administration: Transdermal patch
Alzheimer's disease: Start with 4.6 mg/24 hours patch topically once daily; after 4 weeks of good tolerability, increase to 9.5 mg/24 hours patch once daily. A dose of 9.5 mg/24 hours is the recommended maintenance dose and is also the maximum dose recommended.
Parkinson's disease: Start with 4.6 mg/24 hours patch topically once daily; after 4 weeks of good tolerability, increase the dose to 9.5 mg/24 hours patch once daily.
Dosage/Administration: Oral capsule
Alzheimer's disease: Initial dose of 1.5 mg twice daily; may increase by 3 mg/day (1.5 mg/dose) every 4 weeks based on tolerability (maximum recommended dose is 6 mg twice daily).
Parkinson's disease: Initial dose of 1.5 mg twice daily; may increase by 3 mg/day (1.5 mg/dose) every 4 weeks based on tolerability (maximum recommended dose is 6 mg twice daily).
Special Populations (transdermal patch and oral capsule)
Pregnancy: Category B; no adequate or well-controlled studies in pregnant women. Should be used only if the potential benefit outweighs the potential risk to the fetus.
Nursing Mothers: Milk transfer studies in animals have not been conducted with transdermal rivastigmine.
Pediatric Use: No adequate and well-controlled trials documenting safety and efficacy of rivastigmine in children.
Geriatric Use: Age had no impact on the exposure to rivastigmine in Alzheimer's disease patients treated with rivastigmine.
Hepatic Disease: No pharmacokinetic studies were conducted
Renal Disease: No study was conducted in patients with renal impairment.
Low Body Weight: Rivastigmine exposure is higher in subjects with low body weight. Compared to a patient with a body weight of 65 kg, the steady-state concentrations in a patient with a body weight of 35 kg would be doubled.
Gender and Race: No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of rivastigmine patch, but a population pharmacokinetic analysis indicates that gender and race did not affect the clearance of rivastigmine patch.
Nicotine Use: Pharmacokinetic analysis showed that nicotine could increase the clearance of rivastigmine.
Adverse Drug Reactions (more severe in the oral dosage forms)
Serious (< 1%): Abnormal hepatic function, acute renal failure, angina, thrombocytopenia, thrombosis, sudden cardiac death, AV block, and bradycardia.
Common: Diarrhea, nausea, vomiting, anorexia, abdominal pain, dizziness, headache, insomnia, fatigue, anxiety, and rhinitis. There is increased potential of dermatological reaction with the transdermal patch due to skin irritation associated with topical application.
Interactions
No specific studies have been conducted on drug interaction with rivastigmine. Rivastigmine is metabolized primarily through hydrolysis by esterases. Minimal metabolism occurs through the cytochrome P450 isoenzymes for both the oral capsule and the transdermal patch. No food interactions have been observed with the oral capsule or the transdermal patch.
Precaution and Warnings (transdermal patch and oral capsule)
• Rivastigmine use is associated with significant gastrointestinal adverse reactions, including nausea and vomiting. Nausea and vomiting may be severe, particularly at doses higher than recommended. For this reason patients should always be started at a lower dose and then titrated to the recommended maintenance dose. If treatment is interrupted for longer than several days then treatment should be reinitiated with the lowest daily dose. These effects are less common and severe with the transdermal patch.
• Rivastigmine may be expected to increase gastric acid secretion due to increased cholinergic activity. Patients should be monitored for symptoms of active or occult gastrointestinal bleeding, especially those with an increase risk of developing ulcers.
• Rivastigmine should be used with caution in patients with a history of asthma or obstructive pulmonary disease.
• Rivastigmine might also induce or exacerbate extrapyramidal symptoms.
• Because of its cholinergic activity, rivastigmine may induce significant bradycardia. Caution should be used in patients with sick sinus syndrome and pre-existing cardiac conduction abnormalities.
• Drugs like rivastigmine that increase the cholinergic activity may cause seizure.
• Differences in skin texture can influence the permeability of transdermal systems. Even though the differences in skin permeability were not evaluated during the clinical trial for the rivastigmine transdermal patch, it is worth noting that different populations and ethic groups have different skin textures. Neonates and the elderly have much thinner skin and African Americans have a much thicker and less permeable skin compared to Caucasians. Skin condition may also affect permeability. Warm, hydrated, broken, and irritated skin will absorb more drug, leading to an excess drug in the system and increased risk of adverse drug events. The rivastigmine transdermal patch should not be cut as it loses it delivery integrity.
Contraindications
Rivastigmine is contraindicated in patients with known hypersensitivity to rivastigmine, and other carbamate derivatives.
Potential for Medication Error
The following look-alike and sound-alike drugs could be a potential for medication error: Rasagiline, Ex-lax, ExeCof-XP, ExeFen-PD, and Exelderm.
Overdose
In cases of asymptomatic overdose the patch should be removed immediately and no further patch should be applied for the next 24 hours. In case of accidental overdose with the oral capsule, general supportive measures should be utilized.
Special Monitoring
Rivastigmine may affect the patient's appetite and/or weight. Any loss of appetite or weight should be monitored.
Patient Education
Any missed dose should be applied immediately; and the next transdermal patch should applied at the usual time. Two patches should not be applied at the same time. Patients should apply the rivastigmine patch on clean, dry, and hairless of the upper or lower back, upper arm, or the chest. The patch should not be applied to skin irritated in any way.
Any missed oral capsule should be taken immediately; patients should not double the doses.
Clinical Trial Summary
• The rivastigmine transdermal patch was found to show statistically significant superiority over placebo in both primary and the secondary outcomes such as ability to perform activities of daily living, cognitive performance, attention, visual tracking, and motor processing speed.
• The rivastigmine 10 cm2 (9.5 mg)/24 hours transdermal patch was found to be similar in efficacy to the capsule 12 mg/day. The adverse effect profile such as nausea, vomiting, dizziness, headache, and asthenia were found to be much improved in the 10 cm2 transdermal patch compared to the capsule 12 mg/day.
• There was a low level of skin irritation and adhesion was good. The rivastigmine transdermal patch may offer some benefits and may be an optimal way to deliver this drug as there are fewer fluctuations of plasma drug levels and more continuous drug delivery over 24 hours. These properties have the potential to improve both compliance and treatment effects.
Cost Comparisons
Rivastigmine transdermal patch (for both 5 cm2 and 10 cm2): $5.63/day; $168.90/30-day supply
Rivastigmine oral capsule (for all strengths: 1.5 mg, 3 mg, 4.5 mg, 6 mg bid): $5.56/day; $166.80/30-day supply.
Formulary Recommendation
The 10 cm2 rivastigmine transdermal patch delivered equivalent efficacy with flexible titration compared to the 6 mg bid capsule, with much improved tolerability. The rivastigmine transdermal patch caused fewer adverse effects and symptoms such as nausea, vomiting, dizziness, headache, and asthenia, compared to the oral capsule. There appears to be a low level of skin irritation and good adhesion.
The rivastigmine transdermal patch may offer some benefits and may be an optimal way to deliver this drug in specific patients as it provides more continuous drug delivery over a 24-hour period with less fluctuation of plasma drug levels. These properties have the potential to improve compliance and treatment effects.
It is recommended that the rivastigmine transdermal patch be added to both inpatient and outpatient formulary programs.
References
- Winblad B, Cummings J, Andreasen N, et al. A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease—rivastigmine patch versus capsule. Int J Geriatr Psychiatry 2007;22:456-467.
- Lefevre G, Sedek G, Jhee S, et al. Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients. Clin Pharmacol Ther 2008;83:106-114. Epub ahead of print 2007 May 23.
- Rivastigmine transdermal patch prescribing information. Available at: www.pharma.us.novartis.com. Accessed March 28, 2008.
- Rivastigmine oral capsule prescribing information. Available at: www.pharma.us.novartis.com. Accessed March 28, 2008.
- Lexi-Drugs online. Hudson, OH: Lexi-Comp; 2007. Accessed: Aug. 10, 2007.
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