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Zelapar

CLINICAL PHARMACOLOGY

The mechanisms accounting for selegiline's beneficial adjunctive action in the treatment of Parkinson's disease are not fully understood. Inhibition of monoamine oxidase type B (MAO-B) activity is generally considered to be of primary importance; in addition, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity.

Selegiline is best known as an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. Selegiline inhibits MAO by acting as a suicide substrate for the enzyme; that is, it is converted by MAO to an active moiety which combines irreversibly with the active site and/or the enzyme's essential flavin adenine dinucleotide (FAD) cofactor. Because selegiline has greater affinity for type B rather than for type A active sites, it can serve as a selective inhibitor of MAO type B if it is administered at the recommended dose. However, even for “selective” MAO-B inhibitors, the selectivity for inhibiting MAO-B typically diminishes and is ultimately lost as the dose is increased beyond particular dose levels.

MAOs are widely distributed throughout the body; their concentration is especially high in liver, kidney, stomach, intestinal wall, and brain. MAOs are currently subclassified into two types, A and B, which differ in their substrate specificity and tissue distribution. In humans, intestinal MAO is predominantly type A (MAO-A), while most of that in brain is type B (MAO-B).

In CNS neurons, MAO plays an important role in the catabolism of catecholamines (dopamine, norepinephrine and epinephrine) and serotonin. MAOs are also important in the catabolism of various exogenous amines found in a variety of foods and drugs. MAO in the GI tract and liver (primarily type A), for example, is thought to provide vital protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a hypertensive crisis, the so-called cheese reaction. (If large amounts of certain exogenous amines gain access to the systemic circulation – e.g., from fermented cheese, red wine, herring, over-the-counter cough/cold medications, etc. – they are taken up by adrenergic neurons and displace norepinephrine from storage sites within membrane bound vesicles. Subsequent release of the displaced norepinephrine causes the rise in systemic blood pressure, etc.)

In theory, since MAO-A of the gut is not inhibited, patients treated with ZELAPAR® (selegiline hydrochloride) at the recommended dose of 2.5 mg a day should be able to take medications containing pharmacologically active amines and consume tyramine-containing foods without risk of uncontrolled hypertension.

Although rare, a few reports of hypertensive reactions have occurred in patients receiving swallowed selegiline at the recommended dose (a dose believed to be selective for MAO-B), with tyramine-containing foods. In addition, one case of hypertensive crisis has been reported in a patient taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine). The pathophysiology of the cheese reaction is complicated and, in addition to its ability to inhibit MAO-B selectively, selegiline's relative freedom from this reaction has been attributed to an ability to prevent tyramine and other indirect acting sympathomimetics from displacing norepinephrine from adrenergic neurons. However, until the pathophysiology of the cheese reaction is more completely understood, it seems prudent to assume that ZELAPAR® (selegiline hydrochloride) can ordinarily only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 2.5 mg/day). Safe use of ZELAPAR® (selegiline hydrochloride) at doses above 2.5 mg daily without dietary tyramine restrictions has not been established.

In short, attention to the dose-dependent nature of ZELAPAR® (selegiline hydrochloride) 's selectivity is critical if it is to be used without elaborate restrictions being placed on diet and concomitant drug use. Physicians and patients should be mindful that, as noted above, a few cases of hypertensive crisis have been reported with the swallowed use of selegiline, even at its recommended dose. (See WARNINGS and PRECAUTIONS.)

Because selegiline's inhibition of MAO-B is irreversible, it is impossible to predict the extent of MAO-B inhibition from steady state plasma levels. For the same reason, it is not possible to predict the rate of recovery of MAO-B activity as a function of plasma levels. The recovery of MAO-B activity is a function of de novo protein synthesis; however, information about the rate of de novo protein synthesis is not yet available. Although platelet MAO-B activity returns to the normal range within 5 to 7 days of selegiline discontinuation, the linkage between platelet and brain MAO-B inhibition is not fully understood nor is the relationship of MAO-B inhibition to the clinical effect established.

It is important to be aware that selegiline may have pharmacological effects unrelated to MAO-B inhibition. As noted above, there is some evidence that it may increase dopaminergic activity by other mechanisms, including interfering with dopamine re-uptake at the synapse. Effects resulting from swallowed selegiline may also be mediated through its metabolites. However, the extent to which these metabolites contribute to the effects of swallowed selegiline are unknown. Since ZELAPAR® (selegiline hydrochloride) is primarily absorbed across the buccal mucosa, thereby bypassing the significant first pass metabolism seen with swallowed selegiline, the concentrations of these metabolites (including amphetamine and methamphetamine) are negligible.

Rationale for the Use of Selective Monoamine Oxidase Type B Inhibitor in Parkinson's Disease: Many of the prominent symptoms of Parkinson's disease are due to a deficiency of striatal dopamine that is the consequence of a progressive degeneration and loss of a population of dopaminergic neurons which originate in the substantia nigra of the midbrain and project to the basal ganglia or striatum. Early in the course of Parkinson's disease, the deficit in the capacity of these neurons to synthesize dopamine can be overcome by administration of exogenous levodopa, usually given in combination with a peripheral decarboxylase inhibitor (carbidopa).

With the passage of time, due to the progression of the disease and/or the effect of sustained treatment, the efficacy and quality of the therapeutic response to levodopa diminishes. Thus, after several years of levodopa treatment, the response, for a given dose of levodopa, is shorter, has less predictable onset and offset (i.e., there is wearing “OFF”), and is often accompanied by side effects (e.g., dyskinesia, akinesias, “ON”-“OFF” phenomena, freezing, etc.).

This deteriorating response is currently interpreted as a manifestation of the inability of the ever-decreasing population of intact nigrostriatal neurons to synthesize and release adequate amounts of dopamine.

MAO-B inhibition may be useful in this setting because, by blocking the catabolism of dopamine, it would increase the net amount of dopamine available (i.e., it would increase the pool of dopamine). Whether or not this mechanism or an alternative one actually accounts for the observed beneficial effects of adjunctive selegiline is unknown.

ZELAPAR® (selegiline hydrochloride) 's benefit in Parkinson's disease has only been documented as an adjunct to levodopa/carbidopa in patients with significant “OFF” periods. It is important to note that attempts to treat Parkinsonian patients with combinations of levodopa and currently marketed non-selective MAO inhibitors were abandoned because of multiple side effects including hypertension, increase in involuntary movement, and toxic delirium.

Pharmacokinetics

Absorption

ZELAPAR® (selegiline hydrochloride) disintegrates within seconds after placement on the tongue and is rapidly absorbed. Detectable levels of selegiline from ZELAPAR® (selegiline hydrochloride) have been measured at 5 minutes after administration, the earliest time point examined.

Selegiline is more rapidly absorbed from the 1.25 or 2.5 mg dose of ZELAPAR® (selegiline hydrochloride) (Tmax range: 10-15 minutes) than from the swallowed 5 mg selegiline tablet (Tmax range: 40-90 minutes). Mean (SD) maximum plasma concentrations of 3.34 (1.68) and 4.47 (2.56) ng/mL are reached after single dose of 1.25 and 2.5 mg ZELAPAR® (selegiline hydrochloride) compared to 1.12 ng/mL (1.48) for the swallowed 5 mg selegiline tablets (given as 5 mg bid). On a dose-normalized basis, the relative bioavailability of selegiline from ZELAPAR® (selegiline hydrochloride) is greater than from the swallowed formulation.

The pre-gastric absorption from ZELAPAR® (selegiline hydrochloride) and the avoidance of first-pass metabolism results in higher concentrations of selegiline and lower concentrations of the metabolites compared to the 5 mg swallowed selegiline tablet.

Plasma Cmax and AUC of ZELAPAR® (selegiline hydrochloride) were dose proportional at doses between 2.5 and 10 mg daily.

Food effects

When ZELAPAR® (selegiline hydrochloride) is taken with food, the Cmax and AUC of selegiline are about 60% of those seen when ZELAPAR® (selegiline hydrochloride) is taken in the fasted state. Since ZELAPAR® (selegiline hydrochloride) is placed on the tongue and absorbed through the oral mucosa (see DOSAGE AND ADMINISTRATION section), the intake of food and liquid should be avoided 5 minutes before and after ZELAPAR® (selegiline hydrochloride) administration.

Distribution

Up to 85% of plasma selegiline is reversibly bound to proteins.

Metabolism

Following a single dose, the median elimination half-life of selegiline was 1.3 hours at the 1.25 mg dose. Under steady-state conditions, the median elimination half-life increases to 10 hours. Upon repeat dosing, accumulation in the plasma concentration of selegiline is observed both with ZELAPAR® (selegiline hydrochloride) and the swallowed 5 mg tablet. Steady state is achieved after 8 days.

Selegiline is metabolized in vivo to 1-methamphetamine and desmethylselegiline and subsequently to 1-amphetamine; which in turn are further metabolized to their hydroxymetabolites.

ZELAPAR® (selegiline hydrochloride) also produces a smaller fraction of the administered dose recoverable as the metabolites than the conventional, swallowed formulation of selegiline.

In vitro metabolism studies indicate that CYP2B6 and CYP3A4 are involved in the metabolism of selegiline. CYP2A6 may play a minor role in the metabolism.

Elimination

Following metabolism in the liver, selegiline is excreted primarily in the urine as metabolites (mainly as L-methamphetamine) and as a small amount in the feces.

Special Populations

Age: The effect of age on the pharmacokinetics of selegiline following ZELAPAR® (selegiline hydrochloride) administration has not been adequately characterized.

Gender: There are no differences between male and female subjects in overall (AUC), time to maximum exposure (Tmax), and elimination half-life (t½) after administration of ZELAPAR® (selegiline hydrochloride) . Female subjects have an approximate 25% decrease in Cmax compared to male subjects. However, since the overall exposure (AUC) is not different between the genders, this pharmacokinetic difference is not likely to be clinically relevant.

Race: No studies have been conducted to evaluate the effects of race on the pharmacokinetics of ZELAPAR® (selegiline hydrochloride) .

Hepatic/Renal Impairment: No studies have been conducted to evaluate the pharmacokinetics of ZELAPAR® (selegiline hydrochloride) in hepatically- or renally-impaired patients. ZELAPAR® (selegiline hydrochloride) should be used with caution in patients with a history of or suspected renal or hepatic disease. (See PRECAUTIONS.)

Drug Interactions

No studies have been conducted to evaluate drug interactions on the pharmacokinetics of ZELAPAR® (selegiline hydrochloride) .

Effect of CYP3A inhibitor itraconazole: Itraconazole (200 mg QD) did not affect the pharmacokinetics of selegiline (single 10 mg oral, swallowed dose).

Although adequate studies have not been done investigating the effect of CYP3A4-inducers on selegiline, drugs that induce CYP3A4 (e.g. phenytoin, carbamazepine, nafcillin, phenobarbital, and rifampin) should be used with caution.

In vitro studies have demonstrated that selegiline is not an inhibitor of CYP450 enzymes. The induction potential of selegiline has not been adequately characterized. (See PRECAUTIONS: DRUG INTERACTIONS.)

Clinical Studies

The effectiveness of ZELAPAR® (selegiline hydrochloride) as an adjunct to levodopa/carbidopa in the treatment of Parkinson's disease was established in a multicenter randomized placebo-controlled trial (n=140; 94 received ZELAPAR® (selegiline hydrochloride) , 46 received placebo) of three months' duration. Patients randomized to ZELAPAR® (selegiline hydrochloride) received a daily dose of 1.25 mg for the first 6 weeks and a daily dose of 2.5 mg for the last 6 weeks. Patients were all treated with concomitant levodopa products and could additionally have been on concomitant dopamine agonists, anticholinergics, amantadine, or any combination of these during the trial. COMT (catechol-O-methyl-transferase) inhibitors were not allowed.

Patients with idiopathic Parkinson's disease receiving levodopa were enrolled if they demonstrated an average of at least 3 hours of “OFF” time per day on weekly diaries collected during a 2-week screening period. The patients enrolled had a mean duration of Parkinson's disease of 7 years, with a range from 0.3 years to 22 years.

At selected times during the 12 week study, patients were asked to record the amount of “OFF,” “ON,” “ON with dyskinesia,” or “sleep” time per day for two separate days during the week prior to each scheduled visit. The primary efficacy outcome was the reduction in average percentage daily “OFF” time during waking hours from baseline to the end of the trial (averaging results at Weeks 10 and 12). Both treatment groups had an average of 7 hours per day of “OFF” time at baseline. The absolute mean percent reduction of “OFF” time was 13.1% for ZELAPAR® (selegiline hydrochloride) and 5.1% for placebo. ZELAPAR® (selegiline hydrochloride) -treated patients had an average of 2.2 hours per day less “OFF” time compared to baseline. Placebo-treated patients had 0.6 hours per day less “OFF” time compared to baseline. These differences were statistically significant (p < 0.001). Figure 1 shows the mean daily % “OFF” time during treatment over the whole study period for patients treated with ZELAPAR® (selegiline hydrochloride) vs. patients treated with placebo.

Figure 1

Mean Daily % Off Time During Treatment - Illustration

Dosage reduction of levodopa was allowed during this study if dopaminergic side effects, including dyskinesia and hallucinations, emerged. Levodopa dosage reduction occurred in 17% of patients in the ZELAPAR® (selegiline hydrochloride) group and in 19% in the placebo group. In those patients who had levodopa dosage reduced, the dose was reduced on average by 24% in the ZELAPAR® (selegiline hydrochloride) group and by 21% in the placebo group.

No difference in effectiveness based on age (patients > 66 years old vs. < 66 years) was detected. The treatment effect size in males was twice that in females, but, given the size of this single trial, this finding is of doubtful significance.

Last reviewed on RxList: 2/19/2009
This monograph has been modified to include the generic and brand name in many instances.

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