US Pharm. 2013;38(10):18-20.
After a new drug entity enters the pharmaceutical
marketplace, it is always wise to keep abreast of the current literature
documenting postmarketing randomized clinical trials (RCTs) and
surveillance reports, in addition to case studies, so that the clinical
experience of others, including evidence-based regimens, may be
considered when making recommendations for, and monitoring patients
receiving, a particular pharmaceutical. Ongoing, lifelong continuing
education is not only helpful in practice with regard to therapeutic
outcomes and patient safety, but also imperative from a risk-management
point of view, for both the individual practitioner and the health care
focuses on postmarketing evidence and current clinical considerations
regarding rasagiline for treatment of Parkinson’s disease (PD),
particularly as compared with selegiline, another monoamine oxidase
type-B (MAO-B) inhibitor used in the treatment of PD.
In 2006, the FDA approved rasagiline (Azilect) for the treatment of PD (TABLE 1), a chronic, progressive neurodegenerative condition caused by the destruction of brain cells that produce dopamine.1
Owing to this neuronal loss, slowing of neurotransmission renders
patients incapable of initiating and controlling normal body movements, a
state characteristically manifesting as resting tremor, rigidity,
bradykinesia, and postural instability; these symptoms are often
described by patients and caregivers as shaking, stiff muscles, slow
movements, and falling. PD affects about 0.4% of people over 40 years,
1% of people 65 years or older, and 10% of people 80 years or older; the
mean age at onset is about 57 years.2
A new molecular entity when it was introduced, rasagaline
had shown the ability to block the breakdown of dopamine as an
irreversible and selective second-generation MAO-B inhibitor.1,3 Compared with selegiline (Eldepryl), the only other
inhibitor for PD, rasagiline is five times more potent; unlike
selegiline, rasagiline is not metabolized to an amphetamine-like
substance, so that insomnia is not an issue as with selegiline oral
tablet or capsule (insomnia 12%) and orally disintegrating tablets
(insomnia 7%).3-6 Further, while selegiline has demonstrated
neuroprotective properties in experimental laboratory models, the
amphetamine metabolites may interfere with or neutralize such
neuroprotective effects.7 Rasagiline was proposed to have a
neuroprotective effect similar to that of selegiline, which was
introduced in 1996 (see below, Clinical Controversy).8
Evidence Supports Safety and Efficacy
As with selegiline, PD symptoms are mildly improved with rasagiline.9-12
Early clinical studies have shown that rasagiline is associated with
improved outcomes in patients with early PD, in addition to its ability
to reduce “off” time (periods of the day when the drug is not working
optimally, causing worsening of parkinsonian symptoms) in patients with
moderate-to-advanced PD with motor fluctuations.3 Compared
with patients on placebo, PD patients on rasagiline showed significantly
less worsening of their condition on a rating scale that measures the
ability to perform mental and motor tasks as well as daily living
activities.1 Two other studies compared rasagiline effects
with placebo when taken concomitantly with levodopa in patients with
more advanced PD; patients using rasagiline and concomitant levodopa had
significantly less time per day with relatively poor function and
mobility as compared with patients on levodopa and placebo.1
Of note, the efficacy of rasagiline for the management of patients with
motor fluctuations appears similar to that of the catechol O-methyltransferase (COMT) inhibitor entacapone; both agents are considered first-line interventions for motor fluctuations.11,13 Rasagiline is FDA approved for initial monotherapy in idiopathic early PD and as an adjunct to levodopa in advanced disease. 1,3,6
Rasagiline Therapy: Early in Course of Disease
For monotherapy in idiopathic PD, rasagiline 1 mg once
daily is recommended in both geriatric and adult patients. As an adjunct
with levodopa, 0.5 mg once daily is the initial recommended dose,
increased to 1 mg once daily based on response and tolerability.5-6,14
No dosage adjustment is necessary in mild renal impairment; dosage
adjustment is not defined in moderate-to-severe renal impairment.5
In mild hepatic impairment, rasagiline is dosed 0.5 mg once daily; use
is not recommended in moderate-to-severe hepatic impairment. Owing to
the potential risk of hypertensive crisis, concomitant use of foods high
in tyramine (>150 mg) should be avoided.5,6 Rasagiline should be tapered to discontinuation to avoid abrupt withdrawal.5
As with the majority of agents for Parkinson’s disease (TABLE 2),
the potential to cause dyskinesias, hallucinations, and orthostatic
hypotension (particularly with levodopa) may occur with rasagiline as
well.1,6 Orthostasis is usually most problematic during the first 2 months of therapy. While
rasagiline appears to be well tolerated, elderly patients may be more
prone to treatment-emergent adverse cardiovascular and psychiatric
effects.3 Of note, rasagiline is considered a hazardous agent so that appropriate precautions for handling and disposal are required.6
While it is commonly inferred that MAO-B inhibitors have
disease-modifying effects, much debate and scientific interest continue
in this regard.12,14 In a large, placebo-controlled,
18-month, delayed-start clinical trial, the initiation of rasagiline
monotherapy early in idiopathic PD was associated with less functional
decline than when treatment was delayed for 9 months.15 Better long-term outcomes were attributed to a disease-modifying effect (as opposed to a symptomatic effect).14
It is not known if this is a class effect of the MAO-B inhibitors;
however, currently there are no treatments clinically proven to arrest
or delay the neuronal loss associated with PD.12
Melanoma Risk: Awaiting Study Data
During rasagiline’s development, melanoma was diagnosed in
a small number of patients treated with this drug. While the FDA has
concluded that data available to date do not establish that the drug is
the causative agent, it appears that compared to the general population,
patients with Parkinson’s disease have an increased risk for this form
of skin cancer.1,6 Data from the postmarket phase IV study (see RESOURCES)
are awaited to address this question. Product labeling recommends that
patients undergo periodic dermatologic examinations; bruising (2%),
alopecia, skin carcinoma, and vesiculobullous rash have been reported in
patients receiving rasagiline.1,6 Of note, seborrheic dermatitis is common in patients with PD.2
Beneficial Addition to the Formulary
The management of PD is likely to continue to change as
more information is obtained regarding the pathoetiology of PD and new
therapeutic interventions.12 Until then, Chen and Ly suggest
that rasagiline may be a beneficial addition to the formulary for
monotherapy for early PD or as an alternative for patients with a
history of intolerance to selegiline.3 These researchers propose rasagaline as an addition to the formulary based on the following reasons:
demonstrated clinical efficacy as monotherapy in patients in early PD
and was associated with improved quality of life.16
Rasagiline has shown
beneficial effects as an adjunct to levodopa in patients with
moderate-to-advanced disease and motor fluctuations.10,11
entacapone have both shown similar reductions in off-time hours compared
with placebo as an adjunct to levodopa with or without additional
antiparkinsonian drugs (e.g., amantadine, dopamine agonists) in patients
with moderate-to-advanced disease and motor fluctuations.11
which is metabolized to amphetamine derivatives, rasagiline is
biotransformed to the nonamphetamine compound aminoindan. Safety and
tolerability data show rasagiline appearing to be well tolerated, with
infrequent adverse cardiovascular or psychiatric effects.3
The long-term (more
than one year) data suggest that rasagiline continues to provide a
benefit (e.g., less symptom progression, slower functional decline) over
several years, although the data are limited.17
Pharmacists need to be confident in recommending one agent
over another in the management of PD. While results of a phase IV
postmarket study are pending and in the absence of head-to-head
comparator trials, no firm conclusions can be drawn regarding the
superiority of rasagiline when compared with selegiline, dopamine
agonists, carbidopa-levodopa, COMT inhibitors, or other agents used in
PD.12 Pharmacists need to consider and rely on current
clinical factors until additional data are available. Long-term clinical
trials are necessary in order to determine whether or not
neuroprotective or disease-modifying effects of rasagiline observed in
preclinical experiments will translate into clinically meaningful results.12
1. FDA approves new treatment for Parkinson’s disease.
News & Events. U.S. Food and Drug Administration. Updated April 8,
Accessed August 26, 2013.
2. Parkinson disease. Merck Manual online. Updated
Accessed September 1, 2013.
3. Chen JJ, Ly AV. Rasagiline: a second-generation monoamine oxidase Type-B inhibitor for the treatment of Parkinson’s disease. Am J Health Syst Pharm. 2006;63(10):915-928.
Clark MA, Finkel R, Rey JA, eds. Pharmacology. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2012:99,104-105.
5. Epocrates Essentials Version 13.7. www.epocrates.com. Accessed September 2, 2013.
6. Semla TP, Beizer JL, Higbee MD. Geriatric Dosage Handbook. 18th ed. Hudson, OH: Lexi-Comp, Inc; 2013:1591-1594,1995-1996.
7. Bar-Am O, Amit T, Youdim MB. Contrasting
neuroprotective and neurotoxic actions of respective metabolites of
anti-Parkinson drugs rasagiline and selegiline. Neurosci Lett. 2004;355:169-172.
8. Olanow CW, Hauser RA, Jankovic J, et al. A randomized,
double-blind, placebo-controlled, delayed start study to assess
rasagiline as a disease modifying therapy in Parkinson’s disease (the
ADAGIO study): rationale, design, and baseline characteristics. Mov Disord. 2008;23:2194-2201.
9. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. 2002;59:1937-1943.
10. Parkinson Study Group. A randomized placebo-controlled
trial of rasagiline in levodopa-treated patients with Parkinson disease
and motor fluctuations: the PRESTO study. Arch Neurol. 2005;62:241-248.
11. Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as
an adjunct to levodopa in patients with Parkinson’s disease and motor
fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline
Given Once daily, study): a randomised, double-blind, parallel-group
trial. Lancet. 2005;365:947-954.
12. Ahlskog JE, Uitti RJ. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? Neurology. 2010;74(14):1143-1148.
www.ncbi.nlm.nih.gov/pubmed/20368634. Accessed August 26, 2013.
13. Pahwa R, Factor SA, Lyons KE, et al. Quality Standards
Subcommittee of the American Academy of Neurology. Practice parameter:
treatment of Parkinson’s disease with motor fluctuations and dyskinesia
(an evidence-based review): report of the Quality Standards Subcommittee
of the American Academy of Neurology. Neurology. 2006;66:983-995.
14. Chen JJ, Nelson MV, Swope DM. Parkinson’s disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill Inc; 2011:1033-1044.
15. Olanow CW, Rascol O, Hauser R. ADAGIO Study
Investigators. A double-blind, delayed-start trial of rasagiline in
Parkinson’s disease. N Engl J Med. 2009;361:1268-1278.
16. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol. 2004; 61:561-566.
17. Hauser RA, Lew MF, Hurtig HI, et al. Early treatment
with rasagiline is more beneficial than delayed treatment start in the
long-term management of Parkinson’s disease. Mov Disord. 2005;20(suppl 10):S75.
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