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Generic Name:
Rasagiline (as the mesylate) 0.5 and 1 mg
Active Ingredient(s):
Rasagiline (as the mesylate) 0.5 and 1 mg
How Supplied : Oral
Tablets
0.5 mg (of rasagiline) 1 mg (of rasagiline)
DESCRIPTION:
Tablets contain rasagiline (as the mesylate), this
drug is indicated for the treatment of idiopathic
Parkinson's disease. Rasagiline mesylate is a white
to off-white powder, freely soluble in water or
ethanol and sparingly soluble in isopropanol. Each
tablet for oral administration contains rasagiline
mesylate equivalent to 0.5 mg or 1 mg of rasagiline
base.
CLINICAL PHARMACOLOGY:
Mechanism of Action:
is an irreversible monoamine oxidase inhibitor
indicated for the treatment of idiopathic
Parkinson's disease. It inhibits MAO type B, but
adequate studies to establish whether rasagiline is
selective for MAO type B (MAO-B) in humans have not
yet been conducted.
MAO, a flavin-containing enzyme, is classified into
two major molecular species, A and B, and is
localized in mitochondrial membranes throughout the
body in nerve terminals, brain, liver and intestinal
mucosa. MAO regulates the metabolic degradation of
catecholamines and serotonin in the CNS and
peripheral tissues. MAO-B is the major form in the
human brain. In ex vivo animal studies in brain,
liver and intestinal tissues, rasagiline was shown
to be a potent, irreversible monoamine oxidase type
B (MAO-B) selective inhibitor. Rasagiline at the
recommended therapeutic dose was also shown to be a
potent and irreversible inhibitor of MAO-B in
platelets. The selectivity of rasagiline for
inhibiting only MAO-B (and not MAO-A) in humans and
the sensitivity to tyramine during rasagiline
treatment at any dose has not been sufficiently
characterized to avoid restriction of dietary
tyramine and amines contained in medications.
The precise mechanisms of action of rasagiline are
unknown. One mechanism is believed to be related to
its MAO-B inhibitory activity, which causes an
increase in extracellular levels of dopamine in the
striatum. The elevated dopamine level and subsequent
increased dopaminergic activity are likely to
mediate rasagiline's beneficial effects seen in
models of dopaminergic motor dysfunction.
Pharmacodynamics:
Platelet MAO Activity in Clinical Studies:
Studies in healthy subjects and in Parkinson's
disease patients have shown that rasagiline inhibits
platelet MAO-B irreversibly. The inhibition lasts at
least 1 week after last dose. Almost 25-35% MAO-B
inhibition was achieved after a single rasagiline
dose of 1 mg/day and more than 55% of MAO-B
inhibition was achieved after a single rasagiline
dose of 2 mg/day. Over 90% inhibition was achieved 3
days after rasagiline daily dosing at 2 mg/day and
this inhibition level was maintained 3 days
post-dose. Multiple doses of rasagiline of 0.5, 1
and 2 mg per day resulted in complete MAO-B
inhibition.
Pharmacokinetics:
Rasagiline's pharmacokinetics are linear with doses
over the range of 1-10 mg. Its mean steady-state
half life is 3 hours but there is no correlation of
pharmacokinetics with its pharmacological effect
because of its irreversible inhibition of MAO-B.
Absorption:
Rasagiline is rapidly absorbed, reaching peak plasma
concentration (Cmax) in approximately 1 hour. The
absolute bioavailability of rasagiline is about 36%.
Food does not affect the Tmax of rasagiline,
although Cmax and exposure (AUC) are decreased by
approximately 60% and 20%, respectively, when the
drug is taken with a high fat meal. Because AUC is
not significantly affected it can be administered
with or without food
Distribution:
The mean volume of distribution at steady-state is
87 L, indicating that the tissue binding of
rasagiline is in excess of plasma protein binding.
Plasma protein binding ranges from 88-94% with mean
extent of binding of 61-63% to human albumin over
the concentration range of 1-100 ng/mL.
Metabolism and Elimination:
Rasagiline undergoes almost complete
biotransformation in the liver prior to excretion.
The metabolism of rasagiline proceeds through two
main pathways: N-dealkylation and/or hydroxylation
to yield 1-aminoindan (AI), 3-hydroxy-N-propargyl-1
aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan
(3-OH-AI). In vitro experiments indicate that both
routes of rasagiline metabolism are dependent on the
cytochrome P450 (CYP) system, with CYP1A2 being the
major isoenzyme involved in rasagiline metabolism.
Glucuronide conjugation of rasagiline and its
metabolites, with subsequent urinary excretion, is
the major elimination pathway.
After oral administration of 14C-labeled rasagiline,
elimination occurred primarily via urine and
secondarily via feces (62% of total dose in urine
and 7% of total dose in feces over 7 days), with a
total calculated recovery of 84% of the dose over a
period of 38 days. Less than 1% of rasagiline was
excreted as unchanged drug in urine.
Special Populations:
Hepatic Insufficiency:
Following repeat dose administration (7 days) of
rasagiline (1 mg/day) in subjects with mild hepatic
impairment (Child-Pugh score 5-6), AUC and Cmax were
increased by 2 fold and 1.4 fold, respectively,
compared to healthy subjects. In subjects with
moderate hepatic impairment (Child-Pugh score 7-9),
AUC and Cmax were increased by 7 fold and 2 fold,
respectively, compared to healthy subjects.
Renal Insufficiency:
Conclusive data are not available for renally
impaired patients. As unconjugated rasagiline is not
excreted by the kidney, rasagiline can be given at
usual doses in patients with mild renal impairment.
Geriatric:
Since age has little influence on rasagiline
pharmacokinetics, it can be administered at the
recommended dose in the elderly.
Pediatric:
Has not been investigated in patients below 18 years
of age.
Gender:
The pharmacokinetic profile of rasagiline is similar
in men and women.
Adverse effects:
Adverse events that occured commonly in patients
treated with rasagiline as monotherapy were
headache, nausea, pain and dizziness. In the trials
of rasagiline as adjunctive therapy to levodopa,
common adverse events were dyskinesia,
hallucinations, sleep disorder, dizziness, and
nausea. Depression, wieght loss and anorexia were
also reported in the SPC.
Storage:
Store Tablets at 25°C (may be exposed to 15-30°C).
Drug-Drug Interactions:
Levodopa:
Data from population pharmacokinetic studies
comparing rasagiline clearance in the presence and
absence of levodopa have given conflicting results.
Although there may be some increase in rasagiline
blood levels in the presence of levodopa, the effect
is modest and rasagiline dosing need not be modified
in the presence of levodopa.
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Notice
The products discussed herein may have different
product labeling in different countries. The product
information provided in this site is intended only
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