PRODUCT MONOGRAPH

PrSELEGILINE

Selegiline Hydrochloride Tablets USP

(l-Deprenyl Hydrochloride Tablets USP)

5 mg

Antiparkinsonian Agent

AA Pharma Inc. DATE OF REVISION:

1165 Creditstone Road, Unit 1 March 19, 2021
Vaughan, Ontario
L4K 4N7

Submission Control No: 249480

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 PRODUCT MONOGRAPH
Pr
SELEGILINE
Selegiline Hydrochloride Tablets USP
(I-Deprenyl Hydrochloride Tablets USP)
5 mg

THERAPEUTIC CLASSIFICATION

Antiparkinsonian Agent

ACTIONS AND CLINICAL PHARMACOLOGY

Selegiline hydrochloride is an irreversible inhibitor of the enzyme monoamine oxidase (MAO).

Because selegiline has greater affinity for type B than type A MAO, it can serve as a selective

inhibitor of MAO-B if it is administered at the recommended dose.

Selegiline may have pharmacological effects unrelated to MAO-B inhibition. There is some

evidence that it may increase dopaminergic activity by interfering with dopamine re-uptake at the

synapse. Effects resulting from selegiline administration may also be mediated through its

metabolites. Two of its three principle metabolites, amphetamine and methamphetamine, have

pharmacological actions of their own, they interfere with neuronal re-uptake and enhance the

release of several neurotransmitters (e.g., norepinephrine, dopamine, serotonin). The extent to

which these neurotransmitters contribute to selegiline’s effects are unknown.

Rationale for the use of selective MAO-B inhibitors 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 and project to the striatum. Early in

the course of the disease, the deficit in the capacity of these neurons to synthesize dopamine can

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be overcome by the administration of exogenous levodopa. After several years of levodopa

therapy, the response to a given dose of levodopa is often accompanied by side effects

(dyskinesia, on-off phenomena, freezing).

MAO-B inhibitors may be useful under these conditions because by blocking the catabolism of

dopamine, they increase the net amount of dopamine available. In patients with advanced

Parkinson’s Disease, the addition of selegiline to levodopa (usually with a decarboxylase

inhibitor) has been shown to improve the therapeutic effect of levodopa.

Recently, in newly diagnosed patients, selegiline was shown to delay the need to implement

levodopa therapy.*

The mechanisms of action of selegiline, both in newly diagnosed and in severely incapacitated

patients, is unknown.

Hypertensive Crisis (“Cheese Reaction”)

MAOs are widely distributed throughout the body; their concentration is especially high in liver,

kidney, stomach, intestinal wall and brain. In the intestine, type A is the predominant MAO; it is

thought to provide vital protection from exogenous amines (e.g. tyramine) that have the capacity

to displace norepinephrine from storage sites and thereby cause a hypertensive crisis. MAO-A

catabolizes the exogenous amines which are found in a variety of foods (fermented cheese, red

wine, herring) and drugs (over-the-counter cough/cold medications). Since MAO-A in the gut is

not inhibited by therapeutic doses of selegiline, in theory, patients may take medications

*
Parkinson Study Group: Effect of Deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1989; 321:
1364-1371.

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containing pharmacologically active amines and consume tyramine-containing foods without the

risk of uncontrolled hypertension.

To date, clinical experience appears to confirm this prediction: hypertensive crises have not been

reported in selegiline treated patients. 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).

Attention to the dose dependent nature of selegiline’s selectivity is critical if it is to be

used without restrictions being placed on diet and concomitant drug use (See WARNINGS

and PRECAUTIONS).

Pharmacokinetics

The extremely short half-life of selegiline (< 0.15 hours following a 10 mg i.v. dose) is consistent

with the inability to detect unchanged selegiline in the serum and urine following oral

administration.

Only preliminary information about the details of the pharmacokinetics of selegiline hydrochloride

and its metabolites is available. In a 7-day study undertaken to investigate the effect of selegiline

on the kinetics of an oral hypoglycemic agent, subjects were given a 10 mg dose of selegiline

hydrochloride for seven consecutive days. Serum levels of intact selegiline were below the limit of

detection (<10 ng/mL). Trough levels of the three metabolites were as follows: N-

desmethylselegiline, the major metabolite, was not detectable; the levels of amphetamine and

methamphetamine were 3.5 ng/mL, and 8.0 ng/mL, respectively.

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The rate of MAO-B regeneration following discontinuation of treatment has not been quantified. It

is this rate, dependent upon de novo protein synthesis, which seems likely to determine how fast

normal MAO-B activity can be restored.

Comparative Bioavailability

A randomized, single-dose, double-blinded, standard, Two-Treatment, Three-Period, Reference

Replicated, crossover comparative bioavailability study conducted under fasting conditions, was

performed on healthy male volunteers. The results obtained from 48 healthy volunteers who

completed the study are summarized in the following table. The rate and extent of absorption of

selegeline and N-desmethyl selegiline were measured and compared following a single oral dose

(2 x 5 mg tablet) of SELEGILINE (Selegiline Hydrochloride) 5 mg tablet (AA pharma Inc.) and

MYLAN-SELEGILINE (Selegiline Hydrochloride) 5 mg tablet (Mylan Pharmaceuticals ULC).

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 (Selegiline hydrochloride)
(2 x 5 mg)
From Measured Data
Geometric Mean
Arithmetic Mean (CV%)
Ratio of Geometric 90% Confidence
Parameter Test* Reference†
Means (%) Interval (%)
AUCT 5422.2 5458.3
99.3 89.2 – 110.6
(pg•h/mL) 7265.4 (73.7) 7883.7 (90.6)

AUCI 5865.6 5893.7

99.5 89.5 – 110.6
(pg•h/mL) 8120.3 (74.4) 8905.1 (92.2)

Cmax 3497.3 3398.7

102.9 90.2 – 117.4
(pg/mL) 4357.8 (63.6) 4723.2 (97.7)

Tmax§ (h) 0.89 (45.0) 0.86 (49.2)

T1/2§ (h) 5.64 (31.9) 5.63 (35.7)

* SELEGILINE (Selegiline Hydrochloride) 5 mg Tablets (AA pharma Inc.).
† MYLAN-SELEGILINE (Selegiline Hydrochloride) 5 mg Tablets (Mylan Pharmaceuticals ULC)
were purchased in Canada.
§ Expressed as the arithmetic mean (CV%) only.

INDICATIONS

SELEGILINE (selegiline hydrochloride) may be of value:

– as an adjunct to levodopa (with or without a decarboxylase inhibitor) in the management of the

signs and symptoms of Parkinson’s Disease.

– in newly diagnosed patients before symptoms begin to affect the patient’s social or

professional life, at which time more efficacious treatment becomes necessary.

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 CONTRAINDICATIONS

SELEGILINE (selegiline hydrochloride) is contraindicated in patients with known hypersensitivity

to this drug.

SELEGILINE should not be used in patients with other extrapyramidal disorders such as

excessive tremor or tardive dyskinesia, or in patients with severe psychosis or profound

dementia.

SELEGILINE is contraindicated in combination with meperidine (see DRUG INTERACTIONS).

This contraindication is often extended to other opioids as well.

SELEGILINE should not be used in patients with active peptic ulcer.

WARNINGS

SELEGILINE (selegiline hydrochloride) 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 ACTIONS AND CLINICAL PHARMACOLOGY).

The selectivity of selegiline hydrochloride for MAO-B may not be absolute at the recommended

daily dose of 10 mg/day, and selectivity is further diminished with increasing daily doses. The

precise dose at which selegiline hydrochloride becomes a non-selective inhibitor of all MAO is

unknown, but may be in the range of 30 to 40 mg per day.

Postmarketing cumulative reports suggest that serious CNS adverse events might occur when

selegiline hydrochloride is combined with tricyclic antidepressants (TCAs) and selective serotonin

re-uptake inhibitors (SSRIs).

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Hyperpyrexia and death have been reported with the combination of tricyclic antidepressants and

non selective monoamine oxydase inhibitors (MAOIs) such as phenelzine and tranylcypromine.

Similarly, the combined use of tricyclic antidepressants and selegiline hydrochloride has been

associated with hyperpyrexia, tremors, agitation, restlessness, reduced level of consciousness

and in rare instances fatalities. Related adverse events also seen after this combination included

hypertension, syncope, asystole, diaphoresis, seizure, change in behavioural and mental status,

and muscular rigidity.

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

MAOI’s. Similar signs have been reported in some patients on the combination of selegiline

hydrochloride (10 mg/day) and selective serotonin re-uptake inhibitors including fluoxetine,

sertraline and paroxetine.

Since the mechanisms of these reactions are not fully understood, it seems prudent, in general,

to avoid this combination of selegiline hydrochloride and tricyclic antidepressants as well as

selegiline hydrochloride and selective serotonin re-uptake inhibitors. At least 14 days should

elapse between discontinuation of selegiline hydrochloride and initiation of treatment with a

tricyclic antidepressant or selective serotonin re-uptake 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 hydrochloride.

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 PRECAUTIONS

General

Some patients given SELEGILINE (selegiline hydrochloride) may experience an exacerbation of

levodopa-associated side effects, presumably due to the increased amounts of dopamine

reacting with supersensitive post-synaptic receptors. These effects may often be mitigated by

reducing the dose of levodopa 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 hydrochloride. Consequently the full spectrum of

possible responses to selegiline hydrochloride may not have been observed in the premarketing

evaluation of the drug. It is advisable, therefore, to observe the patients closely for atypical

responses.

Information for Patients

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

selegiline hydrochloride therapy. The patients (or their families, if the patient is incompetent)

should be advised not to exceed the recommended daily dose of 10 mg. The risk of using higher

daily doses of selegiline hydrochloride should be explained, and a brief description of the

“hypertensive crisis” (“cheese reaction”) provided. While hypertensive reactions with selegiline

hydrochloride 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

MAO inhibitor induced hypertensive reactions. In particular, patients should be urged to report,

immediately, any severe headache or other atypical or unusual symptoms not previously

experienced.

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Laboratory Tests

Transient or continuing abnormalities with a tendency for elevated levels of liver enzymes have

been described during long term therapy. Although serious hepatic toxicity has not been

observed, caution is recommended in patients with a history of hepatic dysfunction. 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 a man receiving selegiline and meperidine, as well as other medications. Symptoms

resolved over days when the combination was discontinued. This case 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. While it cannot be said definitively that all of these

reactions were caused by this combination, they are all compatible with this well recognized

interaction.

Although the database of documented clinical experience is limited, MAO inhibitors are ordinarily

contraindicated for use with meperidine. This warning is often extended to other opioids (see

CONTRAINDICATIONS).

It is also prudent to avoid the concomitant use of selegiline hydrochloride and selective serotonin

re-uptake inhibitors and tricyclic antidepressants (see WARNINGS).

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Other than the possible exacerbation of side effects in patients receiving levodopa therapy, no

interactions attributed to the combined use of selegiline hydrochloride and other drugs have been

reported. However, because the database of documented clinical experience is limited, the level

of reassurance provided by this lack of adverse reporting is uncertain (see WARNINGS and

PRECAUTIONS).

Carcinogenesis

Long-term studies in mice and rats have shown no evidence of a carcinogenic effect or significant

histopathological toxicity, with selegiline.

Use During Pregnancy

Insufficient animal reproduction studies have been done with selegiline to conclude that selegiline

poses no teratogenic potential. However, one rat study carried out at doses as much as 180 fold

the recommended human dose revealed no evidence of a teratogenic effect. It is not known

whether selegiline hydrochloride can cause fetal harm when administered to a pregnant woman

or can affect reproductive capacity. SELEGILINE should be given to a pregnant woman only if

clearly needed.

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.

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Pediatric Use

The effects of selegiline hydrochloride in children under 18 have not been evaluated.

ADVERSE REACTIONS

Introduction

The side effects of selegiline hydrochloride are usually those associated with excessive

dopaminergic stimulation. The drug may potentiate the side effects of levodopa, therefore,

adjustments of drug dosages may be required. Some of the most serious adverse

reactions reported with the combination of selegiline hydrochloride and levodopa were

hallucinations and confusion, particularly visual hallucinations.

Although a cause and effect relationship has not been established, a tendency to a progressive

rise in several liver enzymes has been reported after long term therapy.

In prospective clinical trials, the following adverse effects, (listed in decreasing order of

frequency), led to the discontinuation of selegiline hydrochloride: 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 rarely as a cause of discontinuation of treatment include anxiety,

drowsiness/lethargy, nervousness, dystonia, increased episodes of freezing, increased tremor,

weakness, excessive perspiration, constipation, weight loss, burning lips/mouth, ankle edema,

gastrointestinal bleeding and hair loss.

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In controlled clinical trials involving a very limited number of patients (N=49 receiving selegiline

hydrochloride; N=50 receiving placebo) the following adverse reactions were reported (incidences

are devoid of practical statistical significance):

INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS IN CLINICAL TRIALS

A. IN COMBINATION WITH LEVODOPA

Number of Patients Reporting

Events
SELEGILINE PLACEBO
HYDROCHLORI
DE
ADVERSE EVENT (N =49)
Nausea 10 3
Dizziness/Lightheaded/Fainting 7 1
Abdominal pain 4 2
Confusion 3 0
Hallucinations 3 1
Dry mouth 3 1
Vivid dreams 2 0
Dyskinesia 2 5
Headache 2 1
The following events were reported once in either or both groups:
Ache, generalized 1 0
Anxiety/tension 1 1
Anemia 0 1
Diarrhea 1 0
Hair loss 0 1
Insomnia 1 1
Lethargy 1 0
Leg pain 1 0
Low back pain 1 0
Malaise 0 1
Palpitations 1 0
Urinary retention 1 0
Weight loss 1 0

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B. IN MONOTHERAPY

The incidence of adverse reactions occurring in trials using selegiline hydrochloride as

monotherapy has not been fully reported to date. Serious adverse reactions were as follows:

depression, chest pain, myopathy and diarrhea. Other reported adverse reactions included

insomnia, headache, nausea, dizziness and vertigo.

In all prospectively monitored clinical investigations, enrolling approximately 920 patients,

the following adverse events, classified by body system, were reported.

Central Nervous System

Motor / Coordination / Extrapyramidal: increased tremor, chorea, loss of balance, restlessness,

blepharospasm, increased bradykinesia, facial grimace, falling down, heavy leg, muscle twitch,

myoclonic jerks, stiff neck, tardive dyskinesia, dystonic symptoms, dyskinesia, involuntary

movements, freezing, festination, increased apraxia, muscle cramps.

Mental Status / Behavioural / Psychiatric: hallucinations, dizziness, confusion, anxiety,

depression, drowsiness, behaviour / mood change, dreams / nightmares, tiredness, delusions,

disorientation, lightheadedness, impaired memory, increased energy, transient high, hollow

feeling, lethargy/malaise, apathy, overstimulation, vertigo, personality change, sleep disturbance,

restlessness, weakness, transient irritability.

Pain / Altered Sensation: headache, back pain, leg pain, tinnitus, migraine, supraorbital pain,

throat burning, generalized ache, chills, numbness of toes/fingers, taste disturbance.

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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.

Genitourinary/Gynecologic/Endocrine

Transient anorgasmia, nocturia, prostatic hypertrophy, urinary hesitancy, urinary retention,

decreased penile sensation, urinary frequency.

Skin and Appendages

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

Miscellaneous

Asthma, diplopia, shortness of breath, speech affected. Toxic delirium has also been reported

with selegiline hydrochloride when used as adjunctive therapy to levodopa treatment.

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 SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms:

No specific information is available about clinically significant overdoses with selegiline

hydrochloride. However, experience gained during the development of selegiline hydrochloride

reveals that some individuals exposed to doses of 600 mg/day d,l, selegiline suffered severe

hypotension and psychomotor agitation.

Since the selective inhibition of MAO-B by selegiline hydrochloride is achieved only at doses

recommended for the treatment of Parkinson’s disease (i.e. 10 mg), 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 inhibitors:

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 MAO inhibitor overdose may not appear

immediately. Delays of up to 12 hours between ingestion of the 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 overdose. 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.

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The clinical picture of MAO inhibitor overdose varies considerably; its severity may be a function

of the amount of drug consumed. The central nervous system 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:

Because there is no recorded experience with selegiline overdose, the following

suggestions, based on the management of non-selective MAO inhibitor poisoning, might

be applicable.

Treatment of overdose with non-selective MAO inhibitors 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 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 mechanically supported ventilatory assistance, as required.

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Body temperature should be monitored closely. Intensive management of hyperpyrexia may be

required. Maintenance of fluid and electrolyte balance is essential.

DOSAGE AND ADMINISTRATION

The recommended dosage of SELEGILINE (selegiline hydrochloride) as monotherapy in newly

diagnosed patients, or as an adjunct to levodopa (usually with a decarboxylase inhibitor) is 10 mg

per day administered as divided doses of 5 mg each taken at breakfast and lunch.

When SELEGILINE adjunctive therapy is added to the existing levodopa therapeutic regime, a

reduction, usually of 10 to 30% in the dose of levodopa (in some instances a reduction of the

dose of SELEGILINE to 5 mg/day) may be required during the period of adjustment of therapy or

in case of exacerbation of adverse effects.

Doses higher than 10 mg/day should not be used. There is no evidence that additional benefit

will be obtained from the administration of higher doses. Furthermore, higher doses will result in a

loss of selectivity of selegiline hydrochloride towards MAO-B with an increase in the inhibition of

type MAO-A. There is an increased risk of adverse reactions with higher doses as well as an

increased risk of a hypertensive episode (“cheese reaction”).

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 PHARMACEUTICAL INFORMATION

Drug Substance

Proper/Common Name: selegiline hydrochloride, USP

Chemical Names: (–)-(R)-N,α-Dimethyl-N-2-propynylphenethylamine hydrochloride

Structural Formula:

Molecular Formula: C13H17N ▪ HCl

Molecular Weight: 223.74 g/mol

Description: Selegiline hydrochloride is a white to near white crystalline powder which is freely

soluble in water, chloroform and methanol. It has a melting point of 141ºC-144ºC and a pH (2%

aqueous solution) of 3.5-4.5. Its optical rotation is between -10.0ºC and -12.0ºC at 25ºC in a 10%

aqueous solution.

Composition

In addition to selegiline hydrochloride, each tablet contains the non-medicinal ingredients citric

acid, lactose, magnesium stearate and microcrystalline cellulose.

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Stability and Storage Recommendations

Store at room temperature 15ºC to 30ºC. Protect from light.

AVAILABILITY OF DOSAGE FORMS

SELEGILINE 5 mg: Each round, white, flat-faced, bevelled-edge tablet, engraved ‘S5’ on one

side, contains 5 mg of the l-isomer of selegiline hydrochloride. Available in bottles of 100.

PHARMACOLOGY

Two Types of Monoamine Oxidase

Monoamine oxidase (MAO) is an enzymatic system which deaminates monoamine transmitters

and other similar amines. Two forms of MAO have been identified: Type A and Type B. The

natural substrate of MAO-A includes serotonin and adrenaline, those of MAO-B include

phenylethylamine, benzylamine and methyl-histamine. Tyramine, dopamine, noradrenaline, and

tryptamine are substrates for both types of enzyme. This specificity is not absolute and can be

influenced by the concentration of the substrate. The distribution of the two types of MAO varies

greatly between organs and species. In the human intestine, 75% of the total activity of MAO is of

Type A. In the human brain, about 70% of total MAO activity is of Type B, whereas in rat only 5%

is of MAO-B.

Inhibition of MAO-B by Selegiline

Selegiline is an irreversible inhibitor of MAO-B. In vitro, 10-6M appears to be the optimal

concentration to inhibit MAO-B, while leaving MAO-A practically unaffected. Although many

studies have reported using doses as high as 10 mg/kg in rats, the maximum doses in rats which

Page 20 of 29
block MAO-B activity without significantly affecting the MAO-A are between 0.25 mg to 0.5 mg/kg.

Blocking MAO-B results in an increase of dopamine in the central nervous system.

The rate of recovery of MAO-B activity after selegiline treatment is based on the rate of synthesis

of new enzymes; it also depends on the dose and the organ. In the rat brain, 50% of the MAO-B

activity is recovered in about 8-12 days after a high dose (10 mg/kg) of selegiline. The same

enzyme recovery in the liver, however, takes only 3 days. In the pig brain, where the MAO-A /

MAO-B ratio is very similar to that in the human brain, the recovery of MAO-estimated by positron

emission tomography is 6.5 days after a tracer dose of radiolabelled selegiline along with 1 mg/kg

of non-labelled selegiline. In the monkey, a similar experiment showed that the MAO-B recovery

takes as long as 30 days. In addition to the inhibition of MAO-B, selegiline (10 mg/kg I.P.) inhibits

the uptake of dopamine and noradrenaline, and increases turnover of dopamine in rat brain

tissue. This effect of selegiline may explain the potentiation of levodopa response seen in animal

models such as the induced circling in nigral-lesioned rats.

Effects of Selegiline on Tyramine

By contrast to MAO-A inhibitors, selegiline does not potentiate the hypertensive effect of

tyramine. A study in rats comparing the blood pressure response of selegiline to intravenous

tyramine shows that selegiline 1 mg/kg administered chronically did not affect this response. In

contrast, clorgyline, a MAO-A inhibitor, at the same dose significantly potentiates the tyramine

response. The absence of potentiation of the tyramine response is explained by the fact that

selegiline blocks the uptake of tyramine into neurons.

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Abuse Liability

The fact that selegiline is metabolized into methamphetamine and amphetamine raises the

question on the possible physical abuse liability of this drug. The potential for addiction was

studied in rats comparing the results of oral (-)-selegiline 4 mg/kg, (+)-selegiline 5 mg/kg, (+)-

amphetamine 5 mg/kg, and ( )-amphetamine 6 mg/kg. After 6 weeks of treatment, withdrawal

symptoms were present in all the groups except in the group treated with (-)-selegiline. These

results suggest that in contrast to (+)/( )-amphetamine, (-)-selegiline has a very low probability

for physical dependence.

Longevity

In two independent studies, selegiline has been demonstrated to increase the mean and the

maximum lifespan of rats. In both studies, selegiline (0.25 mg/kg) was given subcutaneously

every day starting when the animals were 23 to 25 months old. The two studies used different

strains of rats with differing average lifespans. In the first study, the control group had an average

lifespan of 147.1 5.6 weeks with the longest living animal reaching 164 weeks compared to

197.9 2.4 weeks and 226 weeks respectively for the selegiline treated group. The second study

reports the additional surviving days after beginning of the treatment. The saline control group

had an additional average lifespan of 114.7 7.7 days with the longest living animal reaching

251 days compared to 133.7 8.3 days and 315 days respectively for the selegiline-treated

group. The first study also reported a significant (p<0.001) increase in sexual activity in animals of

the selegiline group.

Neuro Protection

Selegiline at 10 mg/kg for 4 days followed by 2 mg/kg for 7 to 8 days prevents the parkinsonism

induced by a 4 day treatment with 0.35 mg/kg of MPTP (methyl-phenyl- tetrahydropyridine) in

Page 22 of 29
monkeys. The latter compound is transformed into MPP+ (methyl-phenylpyridium) which destroys

nigro-striatal dopaminergic neurons. By blocking MAO-B, selegiline prevents the generation of

MPP+, hence the protective effect. Other mechanisms of action may be involved in this

neuroprotection. Experiments in mice show that selegiline at 0.25 mg/kg reduces the death of

nigrostriatal dopaminergic neurons when given 3 days after the administration of MPTP. This

finding suggests a second action of selegiline, independent from MAO-B inhibition. This neuronal

protection does not appear to be limited to dopaminergic neurons. An experiment using facial

nerve axotomy in rats, shows that selegiline (10 mg/kg every second day) increases by 2.2 times

the motoneurons surviving 21 days after axotomy.

Although these findings suggest the possibility of a neuroprotective effect of selegiline, it is not

clear however, how they can be related to human parkinsonism and its treatment.

TOXICOLOGY

Acute toxicity studies did not reveal any specific target organs of toxicity. Long-term toxicity

studies in mice, rats and dogs showed dose-dependent, amphetamine-like symptoms in all three

species. At high doses, significant reductions in body weight gain were recorded, as well as other

amphetamine-like pharmacodynamic actions, such as hypermotility, reduction in appetite and

changes in behaviour. There was no morphological evidence of organ damage. The effects were

reversible; they appeared at high doses, such that a minimum safety factor of 10 was estimated

between the “no-toxic-effect” dose of 1 mg/kg and the recommended human dose.

Page 23 of 29
Acute Toxicity

Species Route Sex LD50 (mg/kg)

Rat p.o. M 422 (332-535)
p.o. F 302 (227-407)
i.v. M 75 (67-84)
i.v. F 69 (61-78)

Mouse p.o. M 445 (363-545)

p.o. F 365 (287-463)
i.v. M 49 (42-59)
i.v. F 50 (41-62)

Dog p.o. M/F ca. 200

Multiple Dose Toxicity Studies

Duration Dose No. animals Non-toxic dose

Species (W/M)* (mg/kg) per group (mg/kg)
Rat 2W 0-80 20/20 -
4W 0-270 8/8 10

Rat 6M 0-30 10/10 30

Rat 6M 0-90 10/10 10

Dog 6M 0-30 5/5 3-10

plus
8W 2/2 ++

Dog 6M 0-20 2/2 5

*W = weeks; M = months; ++ = no withdrawal effects

Page 24 of 29
CARCINOGENICITY

Mice

Charles River mice received selegiline hydrochloride orally via the diet at doses of 3, 10 and

30 mg/kg/day for a minimum of 78 weeks continual dosing. There were two control groups.

All surviving animals from each group were sacrificed and necropsied. Mice who had

premature deaths were also necropsied. Mortality was similar in all groups. No notable

differences in the clinical signs. The 10 and 30 mg/kg/day males and females showed a

marked reduction in body weight gain when compared to the Controls. In regards to

differential blood counts and gross pathology, there were no notable intergroup differences.

Histopathology: There were no notable intergroup differences in the incidences of

neoplastic and non-neoplastic findings.

Rats

Sprague-Dawley rats were dosed with selegiline hydrochloride via the diet at concentrations

of 0.7, 3.5 and 17.5 mg/kg/day for 104 weeks. There were two control groups. Mortality

was similar in all groups. The majority of 17.5 mg/kg/day dose males and females were

noted to be more excitable than the Controls during the first 52 weeks of the study. There

was a slight reduction in body weight gain in males at 3.5 mg/kg/day, a moderate reduction

in females at 3.5 mg/kg/day and marked reductions in high dose males and females. A

reduction in food consumption was also seen in the high dose males. Under opthalmoscopy

and differential blood count examination, no notable intergroup differences were seen. Gross

pathology: There was a decrease in the number of animals with subcutaneous masses in the

High dose male group (10%) when compared to the Controls (26%). A decrease in the

number of animals with dermal masses recorded in the High dose male group (8%),

Page 25 of 29
compared to 20% in the controls was noted. In this study there was an increase in the

number of animals with small seminal vesicles in the High dose group (30%), compared to

12% in the Low and Intermediate dose groups and 8% in the Control. In females, there was

an increase in the incidence of enlargement of one adrenal (Control–4%, Low dose-16%,

Intermediate dose-18%, and High dose-26%). Histopathology Neoplastic Findings: There

was no statistically significant increase in tumours in any organ. Non-neoplastic Findings:

There were a variety of background changes normally seen in rats of this age and strain but

there was no evidence of a carcinogenic effect or significant histopathological toxicity.

REPRODUCTION STUDIES

Studies in reproduction revealed no teratogenic potential of selegiline in rats and rabbits, and

fertility in rats was not affected at doses up to 100 mg/kg. In studies on peri- and post-natal

development, toxic effects were observed primarily in the mothers and secondarily in the fetuses

and neonates. These effects were ascribed to the excessive pharmacodynamic action of doses of

16 mg/kg and higher. A no-toxic-effect level of 4 mg/kg was established in these studies.

Selegiline did not have any mutagenic potential in a number of tests on gene and chromosome

mutations in prokaryotic and eukaryotic cells as well as in cell culture and in vivo. Likewise, no

effects on DNA or induction of cell transformation processes, were noted.

Page 26 of 29
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