Zelapar

ZELAPAR- selegiline hydrochloride tablet
Valeant Pharmaceuticals International

DESCRIPTION

ZELAPAR ® Orally Disintegrating Tablets contain selegiline hydrochloride, a levorotatory acetylenic derivative of phenthylamine. Selegiline hydrochloride is described chemically as (-)-(R)-N,α-dimethyl-N-2-propynylphenethylamine hydrochloride and its structural formula is:

Chemical Structure
(click image for full-size original)

Its empirical formula is C13 H17 N• HCl, representing a molecular weight of 223.75. Selegiline hydrochloride is a white to almost white crystalline powder that is freely soluble in water, chloroform, and methanol.

ZELAPAR® Orally Disintegrating Tablets are available for oral administration (not to be swallowed) in a strength of 1.25 mg. Each lyophilized orally disintegrating tablet contains the following inactive ingredients: gelatin, mannitol, glycine, aspartame, citric acid, yellow iron oxide, and grapefruit flavor.

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, 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® 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® 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® 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® ‘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® 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® ‘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® disintegrates within seconds after placement on the tongue and is rapidly absorbed. Detectable levels of selegiline from ZELAPAR® 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® (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® 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® is greater than from the swallowed formulation.

The pre-gastric absorption from ZELAPAR® 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® were dose proportional at doses between 2.5 and 10 mg daily.

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