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PHARMACOTHERAPY OF
SMOKING CESSATION: FOCUS ON
VARENICLINE


Kathleen Mason, Pharm.D. Candidate


Smoking remains the leading cause of pre-
ventable death in the United States. Yet, an estimated
20.9 percent of all adults (44.5 million people)
smoke cigarettes in the US.1 The deleterious effects
of tobacco use incur a great cost to society. Men and
women smokers accrue $15,800 and $17,500, re-
spectively, more in lifetime medical expenses and
are absent from work more often than non-smokers.2
Smoking's harmful effects are not limited to
the individual smoker. Second-hand smoke has detri-
mental effects to the body. According to the 2006
Surgeon General's Report, second-hand smoke con-
tains toxic chemicals and carcinogens that cause dis-
ease and premature death in children and adults who
do not smoke.3 Specifically, children are at an in-
creased risk for sudden infant death syndrome, acute
respiratory infections, ear problems, and more severe
asthma.3 Second-hand smoke exposure to adults has
immediate adverse effects on the cardiovascular sys-
tem (CVS) and causes coronary heart disease (CHD)
and lung cancer.3
Nicotine plays a complex role in mediating
physical dependence and addiction that is not fully
understood. Nicotine activates nicotinic acetylcho-
line receptors (nAChRs) on dopamine (DA) neurons


in the ventral tegmental area (VTA), which projects
to the nucleus accumbens (NAc), or the brain's
"reward center."4 The a402 subtype plays a pivotal
role in reinforcement, tolerance and sensitization.5
Additionally, chronic smokers accumulate concentra-
tions of nicotine in the brain which lead to prolonged
desensitization of the nAChRs; thus DA overflow in
the NAc no longer occurs over time.6 Habitual use
may be associated with the need to maintain nicotine
concentrations at a certain level to avoid the aversive
abstinence syndrome.6
There are six medications approved as first-
line therapy for the treatment of nicotine dependence
and addiction, including several dosage forms of
nicotine replacement therapy (NRT) and the dopa-
mine (DA) and norepinephrine (NE) reuptake inhibi-
tor, bupropion SR (Zyban).7 On May 10, 2006 the
FDA approved a new class of medication, vareni-
cline (ChantixTM [chin' tiks]), for smoking cessation,
a nicotine acetylcholine receptor (nAChR) agonist.8
This article will review the current first-line pharma-
cotherapeutic agents and evaluate varenicline (var 6
nik' len) for smoking cessation.
NRT Options Available
NRTs work by providing a source of nicotine


INSIDE THIS ISSUE:
PHARMACOTHERAPY OF SMOKING CESSATION:
FOCUS ON VARENICLINE
AND
RASAGILINE (AZILECT@): A NEW MONOAMINE
OXIDASE B (MAO-B) INHIBITOR FOR THE
TREATMENT OF PARKINSON'S DISEASE.


l,^


mm


SPharmaNote


VOLUME 21, ISSUE 12 SEPTEMBER 2006
Lir


Volume 21, Issue 12, September 2006


PharmaNote







to the brain to prevent withdrawal symptoms as well
as aid the patient in weaning off nicotine depend-
ence. NRTs come in a variety of dosage forms, some
of which are available over-the-counter (OTC)
(Table 1). Side effects (SEs) of NRTs include nau-
sea, vomiting, headache, hypertension, irritability,
insomnia and others typical of tobacco use.8
Nicotine gum and patches increased quit rates
compared to placebo; however quit rates with NRTs
are slightly lower without adjunct behavioral sup-
port.9 A recent meta-analysis of eight studies con-
cluded that OTC NRT produces similar quit rates
compared with NRT obtained by prescription.10
However, quit rates even among those who use NRT
and behavioral therapy are less than desirable.
Cost is a barrier to using NRT. An 8-12
week course of NRT can cost $200-$350.10 Several
studies have shown that when cost barriers are re-
duced, NRT use increases.-13

Other Available Pharmacotherapeutic Options
Bupropion SR (Zyban)
Bupropion SR was approved for smoking
cessation in 1997. Combination therapy with the
nicotine patch was approved in 1999. It is unknown
exactly how bupropion enhances the patient's ability
to abstain from smoking; however it is likely related
to its inhibition of dopaminergic and/or noradrener-
gic neuronal uptake. Cravings may be reduced by
increased levels of DA, and increased norepinephrine
(NE) may alleviate nicotine withdrawal symptoms.8
The onset of activity for bupropion SR is approxi-
mately a week. Patients should set a target quit date
at one to two weeks after initiating therapy (usually
the eighth day of treatment).8
Doses of 150 to 300 mg per day are effective.


In Hurt et al.14 smoking cessation rates at one year
were significant for 150mg (22.9%; P=0.02) and
300mg (23.1%; P=.01) versus placebo (12.4%).
Doses as low as 100mg were not found to be statisti-
cally significant (P=0.09).
Jorenby et al.15 compared bupropion SR, a
downward titration of the nicotine patch, bupropion
plus the patch and placebo in a double-blind, pla-
cebo-controlled study enrolling 893 participants.
Treatment lasted 9 weeks, and abstinence rates were
assessed for a 12 month period. At one year, absti-
nence rates were 15.6% for placebo, 16.4% for the
patch only group, 30.3% for bupropion SR only
(P<0.001), and 35.5% for the bupropion SR and
nicotine patch group(P<0.001). The authors con-
cluded that bupropion SR alone or in combination
with the patch resulted in significantly higher long-
term quit rates than either the patch alone or placebo.
Side effects statistically significant compared
with placebo included insomnia (p<0.05) and dry
mouth (p<0.05). Other reported SEs included head-
ache, nausea, dizziness and dream abnormalities. Bu-
propion SR has been implicated in causing seizures
and thus should not be used in patients with seizure
disorder. Other contraindications include anorexia
nervosa, concomitant MAO-I use, bulimia nervosa,
and breast-feeding.

Varenicline (ChantixTM)
Varenicline's activity is due to its selective,
partial agonist activity at the a402 neuronal nAChRs,
eliciting a moderate and sustained increase in
mesolimbic DA levels which counteracts low DA
levels associated with the absence of smoking.16 By
competitively binding to this receptor, varenicline
prevents nicotine-induced dopaminergic activation in


Table 1. FDA-approved nicotine replacement therapies (NRT)10
Nicotine Medication Strength(s) available Available OTC? Advantages Disadvantages
Gum 2 or 4 mg Yes Oral administration (PO); Low compliance; under
flavor options dosing is common
Patch 16-h patch: 15, 10, 5 Yes Once a day administration Fixed dose; slow delivery
mg; 24-h patch: 21, 14, does not satisfy cravings
7 mg
Nasal Spray 10 mg/ml, 0.5 ml per No Fast delivery Unpleasant side effects
spray
Inhaler 10 mg per cartridge No Simulates smoking habit; Low compliance; under
menthol flavor dosing is common
Lozenge 1, 2, or 4 mg Yes PO; faster delivery than Low compliance; under
gum dosing is common

PharmaNote 5^ Volume 21, Issue 12, September 2006







the event that the patient smokes.16 The smoker will
not go into withdrawal, but also will not get the same
'high' or reward from smoking tobacco. Varenicline
also binds to the 5-HT3 receptor with moderate af-
finity.8

Pharmacokinetics
Varenicline is almost entirely absorbed after
oral administration and systemic availability is high.8
Absorption is unaffected by food or time of dosing.
The majority of varenicline is excreted unchanged in
the urine.17 It is a substrate for the organic cation
transporter 2.17 Varenicline should be used with
caution in renal impairment and is removed by
hemodialysis.8 There is no significant hepatic me-
tabolism. No significant drug-drug interactions have
been elucidated.8

Clinical Trials
Two identical, randomized, double-blind, pla-
cebo- and active-treatment-controlled trials were
conducted comparing varenicline with bupropion SR
and placebo.18,19 In each study, subjects were as-
signed varenicline titrated to 1 mg twice per day, bu-
propion SR titrated to 150 mg twice per day, or pla-
cebo for 12 weeks. All patients received counseling
and were followed for 40 weeks. The primary end
point for both studies was continuous abstinence
from smoking during the last 4 weeks of treatment
(weeks 9-12), as measured by exhaled carbon mon-
oxide (CO). Continuous abstinence rates for weeks
9-24 and weeks 9-52 were secondary outcomes.
In Gonzales et al.,18 1025 participants were


included in the analysis with completion rates of
60.5% for varenicline, 56% for bupropion SR, and
54% for placebo. Discontinuations were mostly due
to loss of follow-up during the drug treatment phase
(weeks 1-12). Continuous absence rates for weeks 9-
12 were superior for varenicline (44%) versus pla-
cebo (17.7%) (OR, 3.85; 95% CI, 2.70-5.50; P<.001)
and versus bupropion SR (29.5%) (OR, 1.93; 95%
CI, 1.40-2.68; P<.001) (Figure 1). In addition, bu-
propion SR was superior to placebo (OR, 2.00; 95%
CI, 1.38-2.89; P<.001). Continuous absence rates for
varenicline were 2.5 times placebo and maintained
statistical significance through weeks 9-24 and
weeks 9-52 vs placebo. Varenicline preserved statis-
tical significance compared with bupropion SR at
weeks 9-24, but not through weeks 9-52.
Jorenby et al.19 demonstrated similar results
with higher completion rates in each group, at 70%
in the varenicline group, 65% in the bupopion SR
group, and 60% in the placebo group. Continuous
abstinence rates for the varenicline group (43.9%)
were significantly higher versus placebo (17.6%)
(OR, 3.85; 95% CI, 2.69-5.50; P<.001) and versus
bupropion SR (29.8%) (OR, 1.90; 95% CI, 1.38-
2.62; P<.001) for the last four weeks of the treatment
period (weeks 9-12) (Figure 2). For weeks 9-24,
29.7% of subjects in the varenicline group were con-
tinuously abstinent versus 13.2% in the placebo
group (OR, 2.83; 95% CI, 1.91-4.19; P<.001) and
20.2% in the bupropion SR group (OR, 1.69; 95%
CI, 1.19-2.42; P=.003). Varenicline maintained sig-
nificance through weeks 9-52, with a continuous ab-
stinent rate of 23% versus 10.3% in the placebo


Figure 1. Continuous abstinence rates for varenicline versus placebois

Continuous Abstinence Rates


E V are n ic line (n= 352)
B upropion SR (n=329)
P lacebo (n=344)


Weeks 9-12 Weeks 9-24 Weeks 9-52


* Value statistically significant vs placebo
tValue statistically significant vs bupropion SR


PharmaNote Volume 21, Issue 12, September 2006


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PharmaNote







group (OR, 2.66; 95% CI, 1.72-4.11; P<.001) and
14.6% in the bupropion SR group (OR, 1.77; 95%
CI, 1.19-2.63; P=.004). Bupropion SR did not main-
tain significance compared with placebo at the end of
the study.
A major limitation of Gonzalez and Jorenby
is their external validity. The exclusion criteria in
both studies encapsulated a large percentage of the
population that would benefit from smoking cessa-
tion, including those with serious medical illnesses
(uncontrolled hypertension, history of cancer, diabe-
tes requiring treatment, severe chronic obstructive
pulmonary disease etc.) or current/recent depres-
sion.19 While stringent requirements are necessary
safety parameters for research in early stages, effi-
cacy data of varenicline in at risk populations is
needed.20
In a randomized, double-blinded, controlled
study, Tonstad et al.21 determined whether smokers
who were abstinent at 12 weeks of treatment would
maintain greater continuous abstinence rates with
varenicline compared with placebo during an addi-
tional 12 weeks of treatment up until the 52nd week.
After successfully completing the initial 12 weeks of
treatment, a total of 1210 subjects received either 1
mg varenicline twice daily or placebo for an addi-
tional 12 weeks. The primary end point was CO-
confirmed continuous abstinence rate for weeks 13-
24. Continuous abstinence rates for weeks 13-52
were also assessed as a secondary end point. Partici-
pants randomized to varenicline had significantly
higher continuous abstinence rates for weeks 13-24
as well as for weeks 13-52 (Table 2).


Adverse Effects
In all studies, nausea was the most
commonly reported side effect for varenicline, occur-
ring in as many as 33% of subjects.18'19'21. Nausea
was dose-dependent, mostly mild to moderate in se-
verity and rarely resulted in discontinuation19'22. Ab-
normal dreams and insomnia were also commonly
reported.

Administration
The patient should set a quit date and initiate
treatment 1 week prior to aforementioned date. To
reduce the incidence of nausea, varenicline should be
taken after eating and with a full glass of water. For
days 1-3, 0.5 mg daily is recommended. The dose is
increased to 0.5 mg twice daily for days 4-7. From
day 8, the maintenance dose of 1 mg BID is recom-
mended.22

Cost
The average retail price from 3 different
pharmacies for a 30 day supply of varenicline is
$117 (range $113-$124). A starter pack is available
containing both 0.5 mg and 1 mg strengths to titrate
the dose to 1 mg twice daily. A one month supply
(56 pills) is available for both the 0.5 mg and 1 mg
dose.

Summary
Varenicline represents a new class of drug to
treat smoking cessation. Currently there are six
FDA-approved drugs for smoking cessation, includ-


Figure 2. Continuous abstinence rates for varenicline versus placebo19

Continuous Smoking Abstinence Rates


m Varenicline (n=344)
m Bupropion SR (n=342)
a Placebo (n=341)


Weeks 9-12 Weeks 9-24 Weeks 9-52


Weeks 9-12 Weeks 9-24 Weeks 9-52


*Value statistically significant vs placebo
tValue statistically significant vs bupropion SR


PharmaNote Volume 21, Issue 12, September 2006


Volume 21, Issue 12, September 2006


PharmaNote







Table 2. Carbon monoxide-confirmed continuous abstinence rate at clinic visits21
Week No. (%) abstinent
Treatment phase Varenicline, n=603 Placebo, n=607
13 576 (95.5) 537 (88.5)
14 551 (91.4) 476 (78.4)
16 509 (84.4) 413 (68.0)
20 454 (75.3) 331 (54.5)
24 425 (70.5) 301 (49.6)
Non-treatment follow-up phase
25 408 (67.7) 293 (48.3)
28 361 (59.9) 282 (46.5)
36 306 (50.7) 257 (42.3)
44 280 (46.4) 239 (39.4)
52 263 (43.6) 224 (36.9)
*Weeks 13-24: OR, 2.48; 95% CI, 1.95-3.16; P<.001
tWeeks 13-52: OR, 1.34; 95% CI, 1.06-1.69; P .02


ing various dosage forms of NRT and bupropion SR.
Although all are significantly more effective than
placebo, one-year continuous abstinence rates are
still less than 50%. Varenicline may aid patients in
successfully quitting and remaining smoke-free up to
52 weeks..

References
1. CDC. Cigarette smoking among adults-United States,
2004. Morbidity and Mortality Weekly Report 2005;
54:1121-1124.
2. Hodgson T. Cigarette smoking and lifetime medical ex-
penditures. The Milbank Quarterly 1992;70:81-125.
3. U.S. Department of Health and Human Services. The
Health Consequences of Involuntary Exposure to Tobacco
Smoke: A Report of the Surgeon General. U.S. Depart-
ment of Health an Human Services, Centers for Disease
Control and Prevention, National Center for Chronic Dis-
ease Prevention and Health Promotion, Office on Smoking
and Health, 2006.
4. Laviolette SR, van der Kooy D. The Neurobiology of
Nicotine Addiction: Bridging the Gap from Molecules to
Behaviour. Nature Reviews Neuroscience 2004;5:55-65.
5. Foulds J. The neurobiological basis for parial agonist treat-
ment of nicotine dependence: varenicline. Int J Clin Pract,
2006;60:571-6.
6. BalfourDJ. The neurobiology of tobacco dependence: A
preclinical perspective on the role of the dopamine projec-
tions to the nucleus. Nicotine & Tobacco Research
2004;6:899-912.
7. U.S. Department of Health and Human Services. Treating
Tobacco Use and Dependence: Clinical Practice Guide-
lines. June 2000.
8. Clinical Pharmacology [database online]. Tampa, FL: Gold
Standard, Inc.; 2006. URL: http://
www.clinicalpharmacology.com. Updated June, 2006.
9. Cummings KM, Hyland A. Impact of Nicotine Replace-
ment Therapy on Smoking Behavior. Annual Review of
Public Health 2005;26:583-99.
10. Hughes JR, Shiffman S, Callas P, Zhang J. A meta-analysis

PharmaNote "W


of the efficacy of over-the-counter nicotine replacement.
Tob. Control 2003;12:21-7.
11. Bansal M, Cummings KM, Hyland A, Giovino G. Stop
smoking medications: Who uses them? Who misuses
them? Who is misinformed? Nicotine Tob Res 2004 In
press.
12. Curry SJ, Grothaus LC, McAfee T, Pabiniak C. Use and
cost effectiveness smoking-cessation services under four
insurance plans in health maintenance organization. N Engl
J Med 1998;339:673-9.
13. Giardina TD, Hyland A, Bauer UE, Higbee C, Cummings
KM. Which population-based interventions would motivate
smokers to think seriously about stopping smoking? Am J
Health Prom 2004;18:405-8.
14. Hurt, et al. A Comparison of sustained-release bupropion
and placebo for smoking cessation. N Engl J Med
1997;337:1195-1202.
15. Jorenby, et al. A controlled trial of sustained-release bu-
propion, a nicotine patch, or both for smoking cessation. N
Engl J Med 1999;340:685-91.
16. Coe JW, et al. Varenicline: an 4P2 nicotinic receptor par-
tial agonist for smoking cessation. J Med Chem 2005;
48:3474-7.
17. Obach RS, et al. Metabolism and disposition ofvareni-
cline, a selective c4P2 acetylcholine receptor partial agonist,
in vivo and in vitro. Drug Metabolism and Disposition
2005;34:121-30.
18. Gonzales D, et al. Varenicline: an c4P2 nicotinic acetylcho-
line receptor partial agonist vs sustained-release bupropion
and placebo for smoking cessation. JAMA 2006;296:47-
55.
19. Jorenby D, et al. Efficacy of varenicline, an c4P2 nicotinic
acetylcholine receptor partial agonist, vs sustained-release
bupropion and placebo for smoking cessation. JAMA
2006;296:56-63.
20. Klesges RC, Johnson KC, and Somes G. Varenicline for
smoking cessation. JAMA 2006;296:94-5.
21. Tonstad S, et al. Effect of maintenance therapy with
varenicline on smoking cessation. JAMA 2006;296:64-71.
22. Chantix [package insert] NY, NY. Pfizer Labs. May 2006.



Volume 21, Issue 12, September 2006







RASAGILINE (AZILECT):
A NEW MONOAMINE OXIDASE B
(MAO-B) INHIBITOR FOR THE
TREATMENT OF PARKINSON'S
DISEASE.


Chau Huynh, Pharm.D. Candidate


Parkinson's disease (PD) is the second most
prevalent neurodegenerative disorder, after Alz-
heimer's disease, and affects one in 100 among the
elderly population (>65 years of age).1'2 PD is char-
acterized by rigidity, bradykinesia, resting tremor
and postural instability.3'4 Other non-motor traits as-
sociated with Parkinson's disease include autonomic
dysfunction (urinary dysfunction, erectile dysfunc-
tion, orthostatic dizziness), anxiety, depression, sleep
disturbance and cognitive dysfunction.4 Over 60,000
Americans are diagnosed each year with this chronic
degenerative disease with no known regenerative
treatment. Options are aimed mostly at symptom
improvement, enhancing patients' quality of life, and
slowing disease progression.
Parkinsonian syndrome is characterized by
degeneration of dopaminergic neurons in the sub-
stantia nigra pars compact (SNc) along with intracy-
toplasmic proteinaceous inclusions or Lewy bodies.5
These dopaminergic neurons modulate the thalamus
and its connections with the motor cortex. Degenera-
tion of these neurons results in reduced striatal dopa-
mine content and reduced thalamic excitation of the
motor cortex which lead to the aforementioned cardi-
nal symptoms of PD.2 Oxidative stress, mitochon-
drial dysfunction, inflammation, excitotoxicity, and
protein aggregation have all been implicated in the
pathogenesis of neuronal death in PD.5 Therapy is
focused on enhancement of dopaminergic activity by
replacing deficient dopamine, increasing dopamine
storage, decreasing dopamine metabolism, and
stimulating dopamine receptors. 2 Current pharma-
cologic treatments for motor symptoms of PD in-
clude: drugs that increase dopamine levodopaa) and a
decarboxylase inhibitor (carbidopa); drugs that
stimulate dopamine receptors, such as dopamine ago-
nists (pramipexole, ropinirole, pergolide, and bro-
mocriptine); and drugs that inhibit dopamine me-
tabolism, such as catechol O-methyltransferase
(COMT) inhibitors (tolcapone and entacapone) and

PharmaNote


monoamine oxidase type B (MAO-B) inhibitor
(selegiline). Other pharmacologic approaches be-
lieved to improve parkinsonian symptoms and have
antiparkinsonian activity include anticholinergics
(trihexiphenidyl, benztropine, biperiden, orphena-
drine, and procyclidine) and amantadine.
Selegiline (Eldepryl) is a propargylamine
MAO-B inhibitor that has traditionally been used in
the treatment of PD. However, selegiline undergoes
extensive first-pass metabolism to 1-
methamphetamine and 1-amphetamine. Long-term
exposure to these metabolites have been associated
with oxygen-glucose deprivation-induced cell death
and reduced neuroprotective effect of the parent
drug.6-
Rasagiline (Azilect[az' 1i Ekt]) is a new selec-
tive and irreversible monoamine oxidase type B in-
hibitor approved by the FDA in May 2006. It is
manufactured by Teva Pharmaceutical and is ap-
proved for use as initial drug therapy in early stages
of Parkinson's disease and as an addition to levodopa
in more advanced cases. In contrast to selegiline,
rasagiline (rd sdj' a len) and its aminoindan metabo-
lite have nonamphetamine features.6-9 This article
will examine the efficacy, safety, and tolerability of
rasagiline.

Pharmacology and Pharmacokinetics
Dopamine is oxidized by monoamine oxidase
(MAO) to generate hydrogen peroxide (H202).
H202 is normally detoxified by glutathione but has
the potential to react with ferrous iron to produce a
highly cytotoxic hydroxyl radical. This cytotoxic free
radical has been implicated in the pathogenesis of
PD.3 The MAO enzyme consists of two forms, type
A and B. MAO-A is mainly found in the gastrointes-
tinal tract and deactivates circulating catecholamines
and dietary vasopressors. MAO-B is more abundant
in the glial cells within the brain and is responsible
for the metabolism of dopamine as well as endoge-
nous amine that stimulates the release and inhibits
neuronal reuptake of dopamine.7'8 MAO-B converts
1-methyl,-4-phenyl- 1,2,3,6-tetrahydropyridine
(MPTP) to MPP+, a neurotoxin, which selectively
2
destroys the dopaminergic nigrostriatal neurons.2
Selective inhibition of MAO-B results in elevations
of synaptosomal dopamine concentrations.
Propargylamine MAO inhibitors (selegiline and
rasagiline) are neuroprotective by inhibiting apop-
tosis (programmed cell death) through inhibition of


Volume 21, Issue 12, September 2006







GAPDH translocation (an enzyme involved in apop-
tosis).5 Rasagiline increases superoxide dismutase
(SOD) and catalase. SOD and catalase are anti-
oxidative enzymes that reduce oxidative stress,
which is associated with neuronal death thought to
be implicated in neurodegenerative diseases such as
PD.10 Rasagiline inhibits MAO-B 93 times more
potently than it inhibits MAO-A. Youdim et al.11
showed that rasagiline was three to 15 times more
potent than selegiline for inhibition of MAO-B in rat
brain and liver in vivo.7-8'11
Rasagiline is rapidly absorbed by the gastroin-
testinal tract and readily crosses the blood brain bar-
rier. The absolute bioavailability of a single 1 mg
dose is approximately 36%. Rasagiline can be ad-
ministered without regard to food since food does
not significantly affect rasagiline's AUC. Rasagiline
is primarily metabolized by hepatic CYP1A2-
mediated N-dealkylation to form its main metabolite,
1-R-aminoindan, which has shown neuroprotective
actions in vitro. Following oral administration of ra-
diolabeled drug, 62% and 7% of the total dose was
excreted in the urine and feces, respectively, over
seven days. AUC and Cmax are increased by 80%
and 38%, respectively, in patients with mild hepatic
impairment, and by 586% and 83%, respectively, in
patients with moderate hepatic impairment. Less than
1% of rasagiline is excreted unchanged in the urine,
hence there is no need for dosage adjustment in pa-
tients with renal impairment. The pharmacokinetic
profile of rasagiline does not differ between men and
women.7-8'12 Pharmacokinetic values of rasagiline in
patients with PD are listed in Table 1.

Clinical Trials
Three main studies have investigated the safety,


tolerability, and efficacy of rasagiline as monother-
apy and as an adjunct to levodopa. These include: a
multicenter, double-blind, placebo-controlled trial of
rasagiline as monotherapy in early PD (TEMPO),
and two studies that evaluated the efficacy of
rasagiline as adjunctive therapy in more advanced
PD (PRESTO and LARGO).

Efficacy of rasagiline as monotherapy
The TEMPO trial (Rasagiline Mesylate (TVP-
1012) as Early Monotherapy in PD Outpatient),
evaluated the safety and efficacy of rasagiline at
doses of 1 mg and 2 mg per day in untreated patients
with early PD who had not developed sufficient dis-
ability to require dopaminergic therapy. Four hun-
dred and four eligible patients were randomly as-
signed to one of three groups: rasagiline mesylate, 1
mg/d; rasagiline mesylate, 2 mg/d; or matching pla-
cebo. Treatment began with a 1-week titration pe-
riod during which all subjects on active treatment
received 1 mg/d of rasagiline. After one week, sub-
jects assigned to 2 mg/d of rasagiline took the main-
tenance dosage for the remaining 25-week period.
No changes in anticholinergic therapy were allowed
during the study. The primary efficacy measure in
the trial was the change in total Unified Parkinson's
Disease Rating Scale (UPDRS) score between base-
line and the week 26 visit. Secondary endpoints in-
cluded changes in mental, ADL and motor subscales
of the UPDRS, symptom-based subscores, changes
in the Hoehn and Yarh stage, the Schwab-England
ADL scale, Beck Depression Inventory score, timed
motor tests, and the Parkinson's Disease Quality of
Life (PDQUALIF) scale. Safety, tolerability, fre-
quency and severity of adverse effects were also as-
sessed. Rasagiline at dosages of 1 mg and 2 mg per


Table 1. Pharmacokinetics of rasagiline in healthy volunteers and patients with PD 78
Dose (mg) Cmax (mg/mL) AUCO-24h (ng/h/mL) Tmax (h) ttM (h) Vd (L) Cl (L/h)
Healthy Volunteersa
2 17.55 (3.51) 20.02 (4.81) 0.4 (0.2) 2.06 (1.14) NR 0.56 (0.13)b
5 45.78 (19.26) 55.25 (12.23) 0.49 (0.15) 3.04 (0.94) NR 0.15 (0.07)b
10 86.54 (27.47) 116.27 (19.83) 0.51(0.29) 3.5 (1.5) NR 0.32 (0.28)b

PD patients
0.5 4.2(2.6) 6.4(3.1) 0.5-0.7 NR NR NR
1 8.5 (2.2) 12.4 (3.5) 0.5-0.7 NR NR NR
2 14.9 (10.5) 23.5 (10.5) 0.5-0.7 NR NR NR
4d NR NR 0.5e 1.34 182 94.3'


NR= not reported; "age range, 18 to 40 years. Values obtained after daily dosing for 10 days; renal clearance; Cage range, 40 to 70 years. Values obtained after daily
dosing for 12 weeks; values obtained between land 13 weeks of daily dosing; median value; hepatic clearance.

PharmaNote Volume 21, Issue 12, September 2006







day resulted in better overall UPDRS performance
compared with placebo. Total UPDRS score was im-
proved by 4.2 points (P<.001; 95% CI -5.66 to -2.73)
for the 1 mg group and by 3.56 points (P<.001; 95%
CI -5.04 to -2.08) for the 2 mg group compared to
placebo. There were no advantages in efficacy for 2
mg/d of rasagiline compared with the 1 mg/d dosage.
Both active treatment groups showed significant im-
provements in PDQUALIF scores, motor and ADL
subscales of the UPDRS compared with the placebo
group. Mean changes in primary and secondary end-
points from baseline between placebo and treatment
groups are summarized in Table 2. Adverse events
were no more frequent in the active treatment groups
than in the placebo group. The most commonly ob-
served adverse events were infection (16%) and
headache (12%). 13-15
The TEMPO trial was extended for one year to
evaluate the long-term effects of rasagiline on PD.
Patients were randomized into: an immediate-
treatment group where patients received 1 mg/day or
2 mg/day of rasagiline for the entire trial period, and
a delayed-start group where patients received pla-
cebo for the first 6 months then 2 mg/day for the last
half of the trial. Assessment of changes in total
UPDRS score from baseline indicated that the pa-
tients who took 1mg/day and 2 mg/day of rasagiline
throughout the trial had less functional decline than
that of the placebo group.16

Efficacy of rasagiline as adjunctive therapy to
levodopa
The PRESTO study (Parkinson's Rasagiline: Ef-
ficacy and Safety in the Treatment of Off), a multi-
center, randomized, double-blind, placebo-controlled

Table 2. TEMPO trial: primary analysis of changes between


trial, and the LARGO study ( Lasting effect in Ad-
junct therapy with RasaGiline), a randomized, pla-
cebo-controlled, double-blind, double-dummy, paral-
lel-group trial, both evaluated the efficacy of
rasagiline as adjunctive therapy to levodopa in pa-
tients with more advanced PD and motor fluctua-
tions. Primary outcome measure of efficacy for both
studies was the change from baseline in mean total
daily off time, as measured by 24 hour diaries. In
these diaries, patients recorded their status: on-time
with troublesome dyskinesia, on-time without dyski-
nesia or with non-troublesome dyskinesia, off-time,
or sleep. Off-time was defined as a period of poor
overall function with worsening tremor, rigidity, bal-
ance, or bradykinesia. Secondary measures of effi-
cacy include clinical global impression of patient im-
provement during the study by examiners from base-
line, UPDRS activities of daily living subscale dur-
ing off periods and motor examination scores during
the on period. 15-18
Patients in the PRESTO study were randomized
to 0.5 mg/day rasagiline, 1.0 mg/day rasagiline, or
matching placebo. Results of this 26-week trial
showed that patients treated with 1.0 mg/day of
rasagiline had 0.94 hour (95% CI, 0.51-1.36 hours;
P<0.001) less off time per day compared with pla-
cebo. Patients in the 0.5 mg/day treatment had 0.49
hour (95% CI, 0.08-0.91 hour; P=0.02) less off time
compared with placebo. Patients treated with 1.0 mg/
day of rasagiline showed greater benefits compared
with 0.5 mg/day of rasagiline, but differences be-
tween the two doses were not significant for most
end points. PRESTO's efficacy end points are sum-
marized in Table 3. Adverse events that were signifi-
cantly more common in both doses of rasagiline
baseline and 26 weeks14
Effect Size (95% Confidence Interval)


Rasagiline 1 mg/d vs Placebo Rasagiline 2 mg/d vs Placebo
Total UPDRS score -4.20 (-5.66 to -2.73) -3.56 (-5.04 to -2.08) *
UPDRS motor subscale -2.71 (-3.86 to -1.55) -1.68 (-2.84 to -0.51) *
ADL subscale -1.04 (-1.60 to -0.48) -1.22 (-1.78 to -0.65) *
Mental subscale -0.14 (-0.44 to 0.15) -0.26 (-0.56 to 0.04)
PIGD subscale -0.15 (-0.41 to 0.11) -0.20 (-0.46 to 0.06)
Rigidity -0.38 (-0.80 to 0.03) -0.39 (-0.81 to 0.03)
Tremor -0.63 (-1.03 to -0.23) -0.38 (-0.78 to 0.02)
Bradykinesia -1.51 (-2.19 to -0.82) -0.77 (-1.47 to -0.08) *
Schwab & England ADL scale 0.77 (-0.42 to 1.96) 0.39 (-0.81 to 1.58)
Hoehn & Yahr stage -0.04 (-0.13 to 0.04) -0.04 (-0.13 to 0.04)
PDQUALIF scale* -2.91 (-5.19 to -0.64)* -2.74 (-5.02 to -0.45) *
Beck Depression Inventory -0.35 (-0.86 to 0.16) -0.21 (-0.72 to 0.30)
Timed motor score -0.55 (-1.19 to 0.08) -0.36 (-1.00 to 0.28)
UPDRS indicates Unified Parkinson;s Disease Rating Scale; ADL, activities of daily living; PIGD, postural instability/gait disorder; PDQUALIF, Parkinson's Disease
Quality of Life. Statistically significant.
__________________________________________Alf-._______________________


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Volume 21, Issue 12, September 2006


PharmaNote






Table 3. PRESTO trial: efficacy end points17
Mean (95% CI)
Changes From Baseline Rasagiline, 0.5 mg/d vs Placebo Rasagiline, 1.0 mg/d vs Placebo
Primary end point of off time -0.49 (-0.91 to -0.08) -0.94 (-1.36 to -0.51) *
Clinical global impression -0.39 (-0.64 to -0.13) -0.68 (-0.94 to -0.42) *
ADL during off time -1.20 (-2.08 to -0.32) -1.34 (-2.24 to -0.43) *
Motor performance during on time -2.91 (-4.59 to -1.23) -2.87 (-4.58 to -1.16) *
PDQUALIF summary score -2.18 (-4.49 to 0.14) -1.48 (-3.86 to 0.90)
Daily on time w/o dyskinesias 0.51 (0.00 to 1.03) 0.78 (0.26 to 1.31) *
Daily on time with dyskinesiasa -0.05 (-0.41 to 0.31) 0.37 (0.00 to 0.74)
ADL, activities of daily living; PDQUALIF, Parkinson's Disease Quality of Life
aAnalysis includes the treatment center interaction. bPotential ranges are 0 to 12 for dyskinesia, 0 to 20 for postural instability and gait, 0 to 20 for rigidity, 0 to 36 for
bradykinesia, and 0 to 32 for tremor. Statistically significant


mostly involved the gastrointestinal system and ap-
peared to be dose related. The most common serious
adverse events were related to accidental injury, ar-
thritis, worsening PD, melanoma, stroke and urinary
tract infection and were not significantly different
between treatment groups and placebo. 15-17
In LARGO, patients were randomized
to, as adjunct treatment, 1 mg/day rasagiline, 200 mg
entacapone with every levodopa/carbidopa dose, or
placebo. The results of this 18-week trial showed that
both rasagiline and entacapone reduced the mean to-
tal daily off-time from baseline to treatment by more
than 1 hour, about three times more than the reduc-
tion with placebo (p=0.0001 and p<0.0001, respec-
tively). Results suggest the addition of rasagiline to
levodopa therapy significantly reduces off time with
comparable efficacy to that of entacapone and
levodopa. The mean change from baseline to treat-
ment for all endpoints are summarized in Table 4.
The frequency of adverse events, laboratory test val-
ues, physical examinations, electrocardiography, and
vital signs (heart rate and blood pressure) were simi-
lar between treatment groups and placebo.7'18

Dosing and Administration
Rasagiline is available as 0.5 mg and 1.0 mg tab-
lets to be taken orally, once daily without regard to
food. The recommended rasagiline dose for the treat-


ment of early PD as monotherapy is 1 mg adminis-
tered once daily. Adjunctive therapy in patients with
moderate to advanced disease should be initiated at a
dose of 0.5 mg once daily and titrated upwards to 1
mg/day if the desired clinical response is not
achieved.12 Rasagiline can be administered at the rec-
ommended doses in the elderly since age has little
effect on rasagiline's pharmacokinetics.18'20
Rasagiline should be used with caution in patients
with hepatic impairment due to decreased metabo-
lism.8

Toxicity and Safety
Rasagiline's selectivity for MAO-B in humans
has not yielded sufficient data to omit diet restric-
tions of amine containing drugs or tyramine contain-
ing foods (aged cheeses, meats, and fish). Selectivity
for inhibiting MAO-B is usually diminished as the
dose is increased. Ingestion of rasagiline and
tyramine or amine-rich foods or medications can re-
sult in hypertensive crisis, otherwise known as the
"cheese effect". Signs and symptoms of elevated
blood pressure (BP) include blurred vision, head-
ache, nausea/vomiting, or chest pains. Therefore,
tyramine and amine containing products should be
avoided in patients receiving rasagiline.12 Clinical
studies show that rates of adverse events such as con-
fusion, hallucinations, postural hypotension and som-


Table 4. LARGO trial: primary and associated efficacy assessments18
Adjusted mean change from baseline
Rasagiline Entacapone Placebo Rasagiline vs placebo Entacapone vs pla-
(95% CI) cebo (95% CI)
Daily off-time (h) -1.18 (0.15) -1.20 (0.15) -0.40 (0.15) -0.78 (-1.18 to -0.39) -0.80 (-1.20 to -0.41) *
Daily on-time w/o dyskinesia (h) 0.85 (0.17) 0.85 (0.17) 0.03 (0.17) 0.82 (0.36 to 1.27) 0.82 (0.36 to 1.27)
Daily on-time with dyskinesia (h) 0.23 (0.13) 0.18 (0.13) 0.14 (0.13) 0.09 (-0.28 to 0.46) 0.04 (-0.32 to 0.41)
Responder rate (number [%])a 113 (51%) 99(45%) 70 (32%) 2.5b (1.62 to 3.85)* 2.0b(1.29 to 3.06)*
Assessments measured in 24-h diaries. Off-time= period of poor overall function (increasing signs of PD). On-time= period of good overall function and mobility.
aResponders were defined as patients showing an improvement of lh or more in the change from baseline in mean total daily off-time. bOdds ratio.
* Statistically significant

P h ar m a___teV olu m e 2 1,_Iss ue_1 2,_S e pte m b er42 0 0 6


Volume 21, Issue 12, September 2006


PharmaNote






Table 5. Adverse events in monotherapy and adjunctive therapy studies in patients with PD7
Percentage of patients
Monotherapy Rasagiline 1 mg Placebo
Infection 14.9 15.9
Headache 10.1 14.2
Accidental injury 10.1 7.5
Dizziness 10.9 6.7
Asthenia 10.9 4.5
Nausea 7.2 5.2
Arthralgia 4.3 3.7
Back pain 5.1 5.2
Pain 5.8 6.0
Combination therapy Rasagiline 0.5 mg Rasagiline 1 mg Placebo
Dyskinesia 18 10
Weight Loss 2.4 9.4* 2.5
Vomitting 3.7 6.7** 1.3
Anorexia 1.8 5.4*** 0.6
Balance difficulty 5.5** 3.4 0.6
Nausea NR 3 4
Sleep disorder NR 3 2
Dizziness NR 3 2
Hallucinations NR 2 1
Peripheral edema NR 2 1
Postural hypotension NR 2 0
Somnolence NR 1 1
NR = not reported. Between-group differences were not statistically significant, unless otherwise noted.
* P= .02 (compared to placebo); ** P= .03 (compared to placebo); *** P= .04 (compared to placebo)


nolence related to rasagiline were not different from
placebo.18 In PRESTO, malignant melanoma was
discovered through dermatologic examinations in
three patients treated with rasagiline, one in the 0.5
mg/day group and two in the 1 mg/day group. One
patient had already been diagnosed with melanoma
before the study.15'18 Adverse events associated with
rasagiline compared with placebo are summarized in
Table 5.

Drug Interactions
Treatment-emergent dyskinesias were seen with
concomitant treatment of rasagiline and levodopa in
the PRESTO study by potentiation of levodopa-
induced motor activity. A reduction in levodopa can
decrease such symptoms. Selegiline, the original
MAO-B inhibitor, has been reported to interact with
meperidine to produce serotonin-like syndrome, con-
current use of rasagiline with meperidine should be
avoided. Selective serotonin reuptake inhibitors
(SSRIs), tricyclic antidepressants (TCAs), serotonin-
norepinephrine reuptake inhibitors (SNRIs), and
other MAOIs should also be avoided in patients tak-
ing rasagiline due to increased risk of developing
serotonin-like syndrome.
Dextromethorphan should be avoided in patients
taking rasagiline since psychosis has been associated


with concurrent administration.
CYP1A2 inhibitors should be used with caution
since ciprofloxacin, a CYP1A2 inhibitor, increases
the AUC of rasagiline by 83%.7-8,12

Cost
The average retail price from 3 different pharma-
cies for a 30 day supply of rasagiline is $272 (range
$242-$315). Cost is the same for 0.5 and 1 mg
strengths.

Summary
Rasagiline is a novel agent that irreversibly and
selectively inhibits MAO type B. It is indicated for
the treatment of PD as monotherapy in the early
stages of the disease and as adjunct therapy to
levodopa in the late stages of the disease. Clinical
trials demonstrate its efficacy and safety in patients
varying in ages and comorbidities. Rasagiline has an
advantage over selegiline in that it does not have
methamphetamine metabolites that have been associ-
ated with neurotoxicity and decreased effect of the
parent drug. Rasagiline's once daily dosing may im-
prove compliance. Long-term trials are needed,
however, to examine the longitudinal effects of
rasagiline on PD.


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Volume 21, Issue 12, September 2006


PharmaNote







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The PharmaNote is Published by:
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Group, Departments of Community
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Pharm.D.

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