Azilect (Rasagiline Mesylate) - Description and Clinical Pharmacology

DESCRIPTION

AZILECT^® Tablets contain rasagiline (as the mesylate), a propargylamine-based drug indicated for the treatment of idiopathic Parkinson's disease. It is designated chemically as: 1H-Inden-1-amine, 2, 3-dihydro-N-2-propynyl-, (1R)-, methanesulfonate. The empirical formula of rasagiline mesylate is (C₁₂H₁₃N)CH₄SO₃ and its molecular weight is 267.34.

Its structural formula is:

Rasagiline mesylate is a white to off-white powder, freely soluble in water or ethanol and sparingly soluble in isopropanol. Each AZILECT tablet for oral administration contains rasagiline mesylate equivalent to 0.5 mg or 1 mg of rasagiline base.

Each AZILECT tablet also contains the following inactive ingredients: mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid and talc.

CLINICAL PHARMACOLOGY

Mechanism of Action

AZILECT is an irreversible monoamine oxidase inhibitor indicated for the treatment of idiopathic Parkinson's disease. AZILECT 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. (See WARNINGS).

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, AZILECT can be administered with or without food (See DOSAGE AND ADMINISTRATION).

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. (See WARNINGS, Hepatic Insufficiency and DOSAGE AND ADMINISTRATION, Patients with Hepatic Impairment).

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

AZILECT has not been investigated in patients below 18 years of age.

Gender

The pharmacokinetic profile of rasagiline is similar in men and women.

Drug-Drug Interactions

Tyramine Effect

(See WARNINGS , PRECAUTIONS-Information for Patients , OVERDOSE , and DOSAGE AND ADMINISTRATION).

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.

Effect of Other Drugs on the Metabolism of AZILECT

In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of rasagiline.  There is the potential for inhibitors of this enzyme to alter AZILECT clearance when coadministered. (See WARNINGS, Ciprofloxacin and Other CYP1A2 Inhibitors and DOSAGE AND ADMINISTRATION, Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors).

Ciprofloxacin

When ciprofloxacin, an inhibitor of CYP1A2, was administered to healthy volunteers (n=12) at 500 mg (BID) with rasagiline at 2 mg/day, the AUC of rasagiline increased by 83% and there was no change in the elimination half life. (See WARNINGS, Ciprofloxacin and Other CYP1A2 Inhibitors and DOSAGE AND ADMINISTRATION, Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors ).

Theophylline

Coadministration of rasagiline 1 mg/day and theophylline, a substrate of CYP1A2, up to 500 mg twice daily to healthy subjects (n=24) did not affect the pharmacokinetics of either drug.

Antidepressants

Severe CNS toxicity associated with hyperpyrexia and death has been reported with the combination of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) and non-selective MAOIs or selective MAO-B inhibitors. (See WARNINGS, Coadministration with Antidepressants).

Effect of AZILECT on Other Drugs

No additional in vivo trials have investigated the effect of AZILECT on other drugs metabolized by the cytochrome P450 enzyme system.  In vitro studies showed that rasagiline at a concentration of 1 ug/ml (equivalent to a level that is 160 times the average Cmax ~ 5.9-8.5 ng/mL in Parkinson's disease patients after 1 mg rasagiline multiple dosing) did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A.  These results indicate that rasagiline is unlikely to cause any clinically significant interference with substrates of these enzymes.

CLINICAL TRIALS

The effectiveness of AZILECT (rasagiline tablets) for the treatment of Parkinson's disease was established in three 18- to 26-week, randomized, placebo-controlled trials.  In one of these trials AZILECT was given as initial monotherapy and in the other two as adjunctive therapy to levodopa.

Monotherapy Use of AZILECT

The monotherapy trial was a double-blind, randomized, fixed-dose parallel group, 26-week study in early Parkinson's disease patients not receiving any concomitant dopaminergic therapy at the start of the study. The majority of the patients were not treated with any anti-Parkinson's disease medication before receiving rasagiline treatment.

In this trial, 404 patients were randomly assigned to receive placebo (138 patients), rasagiline 1 mg/day (134 patients) or rasagiline 2 mg/day (132 patients).  Patients were not allowed to take levodopa, dopamine agonists, selegiline or amantadine, but if necessary, could take stable doses of anticholinergic medication.  The average Parkinson's disease duration was approximately 1 year (range 0 to 11 years).

The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS), [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)].  The UPDRS is a multi-item rating scale that measures the ability of a patient to perform mental and motor tasks as well as activities of daily living. A reduction in the score represents improvement and a beneficial change from baseline appears as a negative number.

Rasagiline (1 or 2 mg once daily) had a significant beneficial effect relative to placebo on the primary measure of effectiveness in patients receiving six months of treatment and not on dopaminergic therapy.  Patients who received rasagiline had significantly less worsening in the UPDRS score, compared to those who received placebo.  The effectiveness of rasagiline 1 mg and 2 mg was comparable. Table 1 displays the results of the monotherapy trial.

Table 1. Parkinson's Disease Patients not on Dopaminergic Therapy

Primary Measure of Effectiveness:  Change in total UPDRS score
		Change from
	Baseline score	baseline to	p-value vs.
		termination score	placebo
Placebo	24.5	3.9	---
1.0 mg/day	24.7	0.1	0.0001
2.0 mg/day	25.9	0.7	0.0001

For the comparison between rasagiline 1 mg/day and placebo, no differences in effectiveness based on age or gender were detected.

Adjunctive Use of AZILECT

Two multicenter, randomized, multinational trials were conducted in more advanced Parkinson's disease patients treated chronically with levodopa and experiencing motor fluctuations (including but not limited to, end of dose "wearing off," sudden or random "off," etc.).  The first (Study 1) was conducted in North America (U.S. and Canada) and compared two doses (0.5 mg and 1 mg daily) of rasagiline and placebo while the second (Study 2) was conducted outside of North America (several European countries, Argentina, Israel) and studied only a single dose (1 mg daily) of rasagiline and placebo.  Patients had had Parkinson's disease for an average of 9 years (range 5 months to 33 years), had been taking levodopa for an average of 8 years (range 5 months to 32 years), and had been experiencing motor fluctuations for approximately 3 to 4 years (range 1 month to 23 years).  Patients kept home diaries just prior to baseline and at specified intervals during the trial.  Diaries recorded one of the following four conditions for each half-hour interval over a 24-hour period: "ON" (period of relatively good function and mobility) as either "ON" with no dyskinesia or without troublesome dyskinesia, or "ON" with troublesome dyskinesia, "OFF" (period of relatively poor function and mobility) or asleep. "Troublesome" dyskinesia is defined as that which interferes with the patient's daily activity.  All patients had been inadequately controlled and were experiencing motor fluctuations typical of advanced stage disease despite receiving levodopa/decarboxylase inhibitor.  The average dose of levodopa/decarboxylase inhibitor was approximately 700 to 800 mg (range 150 to 3000 mg/day).  Patients were also allowed to take stable doses of additional anti-PD medications at entry into the trials. In both trials, approximately 65% of patients were on dopamine agonists and in the North American study (Study 1) approximately 35% were on entacapone. The majority of patients taking entacapone were taking a dopamine agonist as well.

In both trials the primary measure of effectiveness was the change in the mean number of hours that were spent in the "OFF" state at baseline compared to the mean number of hours that were spent in the "OFF" state during the treatment period.

The first adjunct study (Study 1) was a double-blind, randomized, fixed-dose, parallel group trial conducted in 472 levodopa-treated Parkinson's disease patients who were experiencing motor fluctuations.  Patients were randomly assigned to receive placebo (159 patients), rasagiline 0.5 mg/day (164 patients), or rasagiline 1 mg/day (149 patients), and were treated for 26 weeks.  Patients averaged approximately 6 hours daily in the "OFF" state at baseline, as confirmed by home diaries.

The second adjunct study (Study 2) was a double-blind, randomized, parallel group trial conducted in 687 levodopa-treated Parkinson's disease patients who were experiencing motor fluctuations.  Patients were randomly assigned to receive placebo (229 patients), rasagiline 1 mg/day (231 patients) or an active comparator, a COMT inhibitor taken along with scheduled doses of levodopa/decarboxylase inhibitor (227 patients).  Patients were treated for 18 weeks.  Patients averaged approximately 5.6 hours daily in the "OFF" state at baseline as confirmed by home diaries.

In both studies rasagiline 1 mg once daily reduced "OFF" time compared to placebo when added to levodopa in patients experiencing motor fluctuations (Tables 2 and 3).  The lower dose (0.5 mg) of rasagiline also significantly reduced "OFF" time (Table 2), but had a numerically smaller effect than the 1 mg dose of rasagiline.  In Study 2, the active comparator also reduced "OFF" time when compared to placebo.

Table 2. Parkinson's Disease Patients Receiving AZILECT as Adjunct Therapy (Study 1)

Primary Measure of Effectiveness:  Change in mean total daily "OFF" time
		Change from	p-value vs.
	Baseline	baseline to treatment	placebo
	(hours)	period (hours)
Placebo	6.0	-0.9	---
0.5 mg/day	6.0	-1.4	0.0199
1.0 mg/day	6.3	-1.9	< 0.0001

Table 3. Parkinson's Disease Patients Receiving AZILECT as Adjunct Therapy (Study 2)

Primary Measure of Effectiveness:  Change in mean total daily "OFF" time
		Change from baseline	p-value vs.
	Baseline	to treatment period	placebo
	(hours)	(hours)
Placebo	5.5	- 0.40	---
1.0 mg/day	5.6	-1.2	0.0001

In both studies, dosage reduction of levodopa was allowed within the first 6 weeks if dopaminergic side effects, including dyskinesia and hallucinations, emerged.  In Study 1, levodopa dosage reduction occurred in 8% of patients in the placebo group and in 16% and 17% of patients in the 0.5 mg/day and 1 mg/day rasagiline groups, respectively.  In those patients who had levodopa dosage reduced, the dose was reduced on average by about 7%, 9%, and 13% in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively.  In Study 2, levodopa dosage reduction occurred in 6% of patients in the placebo group and in 9% in the rasagiline 1 mg/day group.  In patients who had their levodopa dosage reduced, the dose was reduced on average by about 13% and 11% in the placebo and the rasagiline groups, respectively.

For the comparison between rasagiline 1 mg/day and placebo in both studies, no differences in effectiveness based on age or gender were detected.

Several secondary outcome assessments in the two studies showed statistically significant improvements with rasagiline. These included effects on the activities of daily living (ADL) subscale of the UPDRS performed during an "OFF" period and the motor subscale of the UPDRS performed during an "ON" period. In both scales, a negative response represents improvement. Tables 4 and 5 show these results for Studies 1 and 2.

Table 4. Secondary Measures of Effectiveness (Study 1)

	Baseline	Change from baseline to last
	(score)	value
UPDRS ADL (Activities of Daily Living) subscale score while "OFF"
Placebo	15.5	0.68
0.5 mg/day	15.8	-0.60
1.0 mg/day	15.5	-0.68
UPDRS Motor subscale score while "ON"
Placebo	20.8	1.21
0.5 mg/day	21.5	-1.43
1.0 mg/day	20.9	-1.30

Table 5. Secondary Measures of Effectiveness (Study 2)

	Baseline	Change from baseline
	(score)	to last value
UPDRS ADL (Activities of Daily Living) subscale score while "OFF"
Placebo	18.7	-0.89
1.0 mg/day	19.0	-2.61
UPDRS Motor subscale score while "ON"
Placebo	23.5	-0.82
1.0 mg/day	23.8	-3.87