MohanKumar PS, MohanKumar SM, Quadri SK.
Life Sci. 1997;61(18):1783-8.

"Deprenyl stimulates the release of luteinizing hormone from the pituitary in vitro."

Toxicology 1995 Mar 31;97(1-3):173-82

"Effect of chronic L-dopa administration on serum luteinizing hormone levels in male rats."

Yamada T, Nakamura J, Murakami M, Okuno Y, Hosokawa S, Matsuo M, Yamada H

Selegiline Hydrochloride (002218)

CATEGORIES:

Indications: Parkinson's disease
Pregnancy Category C
Orphan Drugs
FDA Approved 1989 Jun
DRUG CLASS: Extrapyramidal Movement Disorders

BRAND NAMES: Alzene (US); Carbex (US); Deprenyl (US); Eldeprine *; Eldepryl (US); Jumex *; Movergan *; Plurimen *;
(International brand names outside U.S. in italics)
* Indicates foreign drugs without region specification at time of publication.

COST OF THERAPY: $ 1971.00 (Parkinsonism; Eldepryl Tablet; 5 mg; 2/day; 365 days)

DESCRIPTION:

Selegiline hydrochloride is a levorotatory acetylenic derivative of phenethylamine. It is commonly referred to in the clinical and pharmacological literature as L-deprenyl.

The chemical name is: (R)-(-)-N,2-dimethyl-N-2- propynylphenethylamine hydrochloride. It is a white to near white crystalline powder, freely soluble in water, chloroform, and methanol. The molecular formula is C13H17N�HCland has a molecular weight of 223.75.

Each Eldepryl white, shield shaped, unscored tablet, debossed on one side with "S" and "5" on the other side, contains 5 mg selegiline hydrochloride. Inactive ingredients are citric acid, lactose, magnesium stearate, and microcrystalline cellulose.

Each Carbex tablet for oral administration contains 5 mg selegiline hydrochloride and the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, povidone, and talc.

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, 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 FAD cofactor. Because selegiline has greater affinity for type B 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.

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, while most of that in brain is type 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, therefore, because MAO A of the gut is not inhibited, patients treated with selegiline at a dose of 10 mg a day can take medications containing pharmacologically active amines and consume tyramine-containing foods without risk of uncontrolled hypertension. However, one case of hypertensive crisis has been reported in a patient taking the recommended dose of 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 sympathomimetrics from displacing norepinephrine from adrenergic neurons.

However, until the pathophysiology of the cheese reaction is more completely understood, it seems prudent to assume that selegiline can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO B (e.g., 10 mg/day). In short, attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet and concomitant drug use although, as noted above, a case of hypertensive crisis has been reported at the recommended dose. (See WARNINGS and PRECAUTIONS.)

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 selegiline administration may also be mediated through its metabolites. Two of its three principal metabolites, amphetamine and methamphetamine, have pharmacological actions of their own; they interfere with neuronal uptake and enhance release of several neurotransmitters (e.g., norepinephrine, dopamine, serotonin). However, the extent to which these metabolites contribute to the effects of selegiline are unknown.

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, 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): Only preliminary information about the details of the pharmacokinetics of selegiline and its metabolites is available.

Data obtained in a study of 12 healthy subjects that was intended to examine the effects of selegiline on the ADME of an oral hypoglycemic agent, however, provides some information. Following the oral administration of a single dose of 10 mg of selegiline hydrochloride to these subjects, serum levels of intact selegiline were below the limit of detection (less than 10 ng/ml). Three metabolites, N-desmethyldeprenyl, the major metabolite (mean half-life 2.0 hours), amphetamine (mean half- life 17.7 hours), and methamphetamine (mean half-life 20.5 hours), were found in serum and urine. Over a period of 48 hours, 45% of the dose administered appeared in the urine as these 3 metabolites.

In an extension of this study intended to examine the effects of steady state conditions, the same subjects were given a 10 mg dose of selegiline hydrochloride for seven consecutive days. Under these conditions, the mean trough serum levels for amphetamine were 3.5 ng/ml and 8.0 ng/ml for methamphetamine; trough levels of N-desmethyldeprenyl were below the levels of detection.

The rate of MAO B regeneration following discontinuation of treatment has not been quantitated. It is this rate, dependent upon de novo protein synthesis, which seems likely to determine how fast normal MAO B activity can be restored.

INDICATIONS AND USAGE:
Selegiline hydrochloride is indicated as an adjunct in the management of Parkinsonian patients being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy. There is no evidence from controlled clinical studies that selegiline has any beneficial effect in the absence of concurrent levodopa therapy.

Evidence supporting this claim was obtained in randomized controlled clinical investigations that compared the effects of added selegiline or placebo in patients receiving levodopa/carbidopa. Selegiline was significantly superior to placebo on all three principal outcome measures employed; change from baseline in daily levodopa/carbidopa dose, the amount of 'off' time, and patient self-rating of treatment success. Beneficial effects were also observed on other measures of treatment success (e.g., measures of reduced end of dose akinesia, decreased tremor and sialorrhea, improved speech and dressing ability and improved overall disability as assessed by walking and comparison to previous state).

CONTRAINDICATIONS:
Selegiline hydrochloride is contraindicated in patients with a known hypersensitivity to this drug.

Selegiline hydrochloride is contraindicated for use with meperidine. This contraindication is often extended to other opioids. (See DRUG INTERACTIONS.)

WARNINGS:
Selegiline should not be used at daily doses exceeding those recommended (10 mg/day) because of the risks associated with non-selective inhibition of MAO. (See CLINICAL PHARMACOLOGY.)

The selectivity of selegiline for MAO B may not be absolute even at the recommended daily dose of 10 mg a day and selectivity is further diminished with increasing daily doses. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg a day.

Severe CNS toxicity associated with hyperpyrexia and death have been reported with the combination of tricyclic antidepressants and non-selective MAOIs (Phenelzine, Tranylcypromine). A similar reaction has been reported for a patient on amitriptyline and selegiline. Another patient receiving protriptyline and selegiline developed tremors, agitation, and restlessness followed by unresponsiveness and death two weeks after selegiline was added. Related adverse events including hypertension, syncope, asystole, diaphoresis, seizures, changes in behavioral and mental status, and muscular rigidity have also been reported in some patients receiving selegiline and various tricyclic antidepressants.

Serious, sometimes fatal, reactions with signs and symptoms that may include hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations of the vital signs, and mental status changes that include extreme agitation progressing to delirium and coma have been reported with patients receiving a combination of fluoxetine hydrochloride and non-selective MAOIs. Similar signs have been reported in some patients on the combination of selegiline (10 mg a day) and selective serotonin reuptake inhibitors including fluoxetine, sertraline, and paroxetine.

Since the mechanisms of these reactions are not fully understood, it seems prudent, in general, to avoid the combination of selegiline and tricyclic antidepressants as well as selegiline and selective serotonin reuptake inhibitors. At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with a tricyclic antidepressant or selective serotonin reuptake inhibitors. Because of the long half lives of fluoxetine and its active metabolite, at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of treatment with selegiline.

PRECAUTIONS:
General: Some patients given selegiline may experience an exacerbation of levodopa associated side effects, presumably due to the increased amounts of dopamine reacting 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.

Information for the Patient: Patients should be advised of the possible need to reduce levodopa dosage after the initiation of selegiline hydrochloride 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. While hypertensive reactions with selegiline associated with dietary influences have not been reported, documented experience is limited.

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.

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

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Assessement 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 an in vivo chromosomal aberration assay. While these studies provide some resurrance 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, Teratogenic Effects, Pregnancy Category C: No teratogenic effects were observed in a study of embryo-fetal development in Sprague-Dawley rats at oral doses of 4, 12, and 36 mg/kg or 4, 12, and 35 times the human therapeutic dose on a mg/m2 basis. No teratogenic effects were observed in a study of embryo-fetal development in New Zealand White rabbits at oral doses of 5, 25, and 50 mg/kg or 10, 48, and 95 times the human therapeutic dose on a mg/m2 basis; however, in this study, the number of litters produced at the two higher doses was less than recommended for assessing teratogenic potential. In the rat study, increases in total resorptions and percent post-implantation loss, and a decrease in the number of live fetuses per dam occurred at the highest dose tested. In a peri- postnatal development study in Sprague-Dawley rats oral doses of 4, 16, and 64 mg/kg or 4, 15, and 62 times the human therapeutic dose on a mg/m2 basis, an increase in the numbers if stillbirths and decrease in the number of pups per dam, pup survival, and pup body weight (at birth and throughout the lactation period) were observed at the two highest doses. At the highest dose tested, no pups born alive survived to Day 4 postpartum. Postnatal development at the highest dose tested in dams could not be evaluated because of the lack of surviving pups. The reproductive performance of the untreated offspring was not assessed.

There are no adequate and well-controlled studies in pregnant women. Selegiline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 pediatric patients have not been evaluated.

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 hydrochloride and selective serotonin reuptake inhibitors and selegiline hydrochloride. (See WARNINGS for details.)

ADVERSE REACTIONS:
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.