Label: SELEGILINE HYDROCHLORIDE capsule

Rationale for the use of a 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.

Selegiline's benefit in Parkinson's disease has only been documented as an adjunct to levodopa/carbidopa. Whether or not it might be effective as a sole treatment is unknown, but past attempts to treat Parkinson's disease with non-selective MAOI monotherapy are reported to have been unsuccessful. 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.

Pharmacokinetic Information (Absorption, Distribution, Metabolism and Elimination-ADME)

The absolute bioavailability of selegiline following oral dosing is not known; however, selegiline undergoes extensive metabolism (presumably attributable to presystemic clearance in gut and liver). The major plasma metabolites are N-desmethylselegiline, L-amphetamine and L-methamphetamine. Only N-desmethylselegiline has MAO-B inhibiting activity. The peak plasma levels of these metabolites following a single oral dose of 10 mg are from 4 to almost 20 times greater than that of the maximum plasma concentration of selegiline [1 ng/mL]. The maximum concentrations of amphetamine and methamphetamine, however, are far below those ordinarily expected to produce clinically important effects.

Single oral dose studies do not predict multiple dose kinetics, however, at steady state the peak plasma level of selegiline is 4 fold that obtained following a single dose. Metabolite concentrations increase to a lesser extent, averaging 2 fold that seen after a single dose.

The bioavailability of selegiline is increased 3 to 4 fold when it is taken with food. 

The extent of systemic exposure to selegiline at a given dose varies considerably among individuals. Estimates of systemic clearance of selegiline are not available. Following a single oral dose, the mean elimination half-life of selegiline is two hours. Under steady state conditions the elimination half-life increases to ten hours.

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 (see CLINICAL PHARMACOLOGY).

Special Populations

Renal Impairment

No pharmacokinetic information is available on selegiline or its metabolites in renally impaired subjects.

Hepatic Impairment

No pharmacokinetic information is available on selegiline or its metabolites in hepatically impaired subjects.

Age

Although a general conclusion about the effects of age on the pharmacokinetics of selegiline is not warranted because of the size of the sample evaluated (12 subjects greater than 60 years of age, 12 subjects between the ages of 18 to 30), systemic exposure was about twice as great in older as compared to a younger population given a single oral dose of 10 mg.

Gender

No information is available on the effects of gender on the pharmacokinetics of selegiline.

General

Some patients given selegiline may experience an exacerbation of levodopa associated side effects, presumably due to the increased amounts of dopamine reaction with super sensitive, post-synaptic receptors. These effects may often be mitigated by reducing the dose of levodopa/carbidopa by approximately 10 to 30%.

The decision to prescribe selegiline should take into consideration that the MAO system of enzymes is complex and incompletely understood and there is only a limited amount of carefully documented clinical experience with selegiline. Consequently, the full spectrum of possible responses to selegiline may not have been observed in pre-marketing evaluation of the drug. It is advisable, therefore, to observe patients closely for atypical responses.

Melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using selegiline for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Information for Patients

Patients should be advised of the possible need to reduce levodopa dosage after the initiation of selegiline therapy.

Patients (or their families if the patient is incompetent) should be advised not to exceed the daily recommended dose of 10 mg. The risk of using higher daily doses of selegiline should be explained, and a brief description of the `cheese reaction' provided. Rare hypertensive reactions with selegiline at recommended doses associated with dietary influences have been reported.

Consequently, it may be useful to inform patients (or their families) about the signs and symptoms associated with MAOI induced hypertensive reactions. In particular, patients should be urged to report, immediately, any severe headache or other atypical or unusual symptoms not previously experienced.

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease, including selegiline. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with selegiline. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking selegiline. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking selegiline.

Laboratory Tests

No specific laboratory tests are deemed essential for the management of patients on selegiline. Periodic routine evaluation of all patients, however, is appropriate.

Drug Interactions

The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination (see CONTRAINDICATIONS). Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and selegiline and selective serotonin reuptake inhibitors and selegiline. (See WARNINGS for details.) One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine).

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Assessment of the carcinogenic potential of selegiline in mice and rats is ongoing.

Selegiline did not induce mutations or chromosomal damage when tested in the bacterial mutation assay in Salmonella typhimurium and in an in vivo chromosomal aberration assay. While these studies provide some reassurance that selegiline is not mutagenic or clastogenic, they are not definitive because of methodological limitations. No definitive in vitro chromosomal aberration or in vitro mammalian gene mutation assays have been performed.

The effect of selegiline on fertility has not been adequately assessed.

Pregnancy

Nursing Mothers

It is not known whether selegiline hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, consideration should be given to discontinuing the use of all but absolutely essential drug treatments in nursing women.

Pediatric Use

The effects of selegiline hydrochloride in children have not been evaluated.

Introduction

The number of patients who received selegiline in prospectively monitored pre-marketing studies is limited. While other sources of information about the use of selegiline are available (e.g., literature reports, foreign post-marketing reports, etc.) they do not provide the kind of information necessary to estimate the incidence of adverse events. Thus, overall incidence figures for adverse reactions associated with the use of selegiline cannot be provided. Many of the adverse reactions seen have also been reported as symptoms of dopamine excess.

Moreover, the importance and severity of various reactions reported often cannot be ascertained. One index of relative importance, however, is whether or not a reaction caused treatment discontinuation. In prospective pre-marketing studies, the following events led, in decreasing order of frequency, to discontinuation of treatment with selegiline: nausea, hallucinations, confusion, depression, loss of balance, insomnia, orthostatic hypotension, increased akinetic involuntary movements, agitation, arrhythmia, bradykinesia, chorea, delusions, hypertension, new or increased angina pectoris, and syncope. Events reported only once as a cause of discontinuation are ankle edema, anxiety, burning lips/mouth, constipation, drowsiness/lethargy, dystonia, excess perspiration, increased freezing, gastrointestinal bleeding, hair loss, increased tremor, nervousness, weakness, and weight loss.

Experience with selegiline obtained in parallel, placebo controlled, randomized studies provides only a limited basis for estimates of adverse reaction rates. The following reactions that occurred with greater frequency among the 49 patients assigned to selegiline as compared to the 50 patients assigned to placebo in the only parallel, placebo controlled trial performed in patients with Parkinson's disease are shown in the following Table. None of these adverse reactions led to a discontinuation of treatment.

In all prospectively monitored clinical investigations, enrolling approximately 920 patients, the following adverse events, classified by body system, were reported.

Central Nervous System

Autonomic Nervous System

dry mouth, blurred vision, sexual dysfunction.

Cardiovascular

orthostatic hypotension, hypertension, arrhythmia, palpitations, new or increased angina pectoris, hypotension, tachycardia, peripheral edema, sinus bradycardia, syncope.

Gastrointestinal

nausea/vomiting, constipation, weight loss, anorexia, poor appetite, dysphagia, diarrhea, heartburn, rectal bleeding, bruxism*, gastrointestinal bleeding (exacerbation of preexisting ulcer disease).

Genitourinary/Gynecologic/Endocrine

slow urination, transient anorgasmia*, nocturia, prostatic hypertrophy, urinary hesitancy, urinary retention, decreased penile sensation*, urinary frequency.

* indicates events reported only at doses greater than 10 mg/day.

Skin and Appendages

increased sweating, diaphoresis, facial hair, hair loss, hematoma, rash, photosensitivity.

Miscellaneous

asthma, diplopia, shortness of breath, speech affected.

Post-marketing Reports

The following experiences were described in spontaneous post-marketing reports. These reports do not provide sufficient information to establish a clear causal relationship with the use of selegiline.

CNS

Seizure in dialyzed chronic renal failure patient on concomitant medications.

Selegiline

No specific information is available about clinically significant overdoses with selegiline. However, experience gained during selegiline's development reveals that some individuals exposed to doses of 600 mg of d,l-selegiline suffered severe hypotension and psychomotor agitation.

Since the selective inhibition of MAO B by selegiline hydrochloride is achieved only at doses in the range recommended for the treatment of Parkinson's disease (e.g., 10 mg/day), overdoses are likely to cause significant inhibition of both MAO A and MAO B. Consequently, the signs and symptoms of overdose may resemble those observed with marketed non-selective MAO inhibitors [e.g., tranylcypromine, isocarboxazide, and phenelzine].

Overdose with Non-Selective MAO Inhibition

NOTE: This section is provided for reference; it does not describe events that have actually been observed with selegiline in overdose.

Characteristically, signs and symptoms of non‑selective MAOI overdose may not appear immediately. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur. Importantly, the peak intensity of the syndrome may not be reached for upwards of a day following the overdose. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring for a period of at least two days following the ingestion of such drugs in overdose, is strongly recommended.

The clinical picture of MAOI overdose varies considerably; its severity may be a function of the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved.

Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonus, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.

Treatment Suggestions For Overdose

NOTE: Because there is no recorded experience with selegiline overdose, the following suggestions are offered based upon the assumption that selegiline overdose may be modeled by non-selective MAOI poisoning. In any case, up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians' Desk Reference (PDR).

Treatment of overdose with non-selective MAOIs is symptomatic and supportive. Induction of emesis or gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, provided the airway has been protected against aspiration. Signs and symptoms of central nervous system stimulation, including convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated with intravenous fluids and, if necessary, blood pressure titration with an intravenous infusion of a dilute pressor agent. It should be noted that adrenergic agents may produce a markedly increased pressor response.

Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required.

Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential.