Action And Clinical Pharmacology: Selegiline 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 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 catabolises 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 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).
Only preliminary information about the details of the pharmacokinetics of selegiline 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 for 7 consecutive days.
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.
Indications And Clinical Uses: 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.
Contra-Indications: 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 Precautions, Drug Interactions). This contraindication is often extended to other opioids as well.
Selegiline should not be used in patients with active peptic ulcer.
Manufacturers’ Warnings In Clinical States: Selegiline should not be used at daily doses exceeding those recommended (10 mg/day) because of the risks associated with nonselective inhibition of MAO (see Pharmacology).
The selectivity of selegiline 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 becomes a nonselective inhibitor of all MAO is unknown but may be in the range of 30 to 40 mg/day.
Postmarketing cumulative reports suggest that serious CNS adverse events might occur when selegiline is combined with tricyclic antidepressants (TCAs) and selective serotonin re-uptake inhibitors (SSRIs).
Hyperpyrexia and death have been reported with the combination of tricyclic antidepressants and nonselective MAO inhibitors such as phenelzine and tranylcypromine. Similarly, the combined use of tricyclic antidepressants and selegiline 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 behavioral 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 and nonselective MAO inhibitors. Similar signs have been reported in some patients on the combination of selegiline (10 mg a 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 and tricyclic antidepressants as well as selegiline and selective serotonin re-uptake inhibitors. At least 14 days should elapse between discontinuation of selegiline 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 5 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 supersensitive postsynaptic 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. Consequently the full spectrum of possible responses to selegiline 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 the Patient: Patients should be advised of the possible need to reduce levodopa dosage after initiation of selegiline 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 should be explained, and a brief description of the hypertensive crisis (“cheese reaction”) provided. While hypertensive reactions with selegiline 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 inhibitors 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: 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 MAO inhibitors.
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 and selective serotonin re-uptake inhibitors and tricyclic antidepressants (see Warnings).
Other than the possible exacerbation of side effects in patients receiving levodopa therapy, no interactions attributed to the combined use of selegiline 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: Studies have not been performed to date to evaluate the carcinogenic potential of selegiline.
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 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.
Lactation: It is not known whether selegiline 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.
Children: The effects of selegiline in children under 18 have not been evaluated.
Adverse Reactions: The side effects of selegiline are usually those associated with excessive dopaminergic stimulation. The drug may potentiate the side effects of levodopa, therefore, adjustment of drug dosages may be required. Some of the most serious adverse reactions reported with the combination of selegiline 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: 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.
In controlled clinical trials involving a very limited number of patients (N=49 receiving Eldepryl; N=50 receiving placebo) the following adverse reactions were reported (incidences are devoid of practical statistical significance).
The incidence of adverse reactions occurring in trials using selegiline 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, enroling approximately 920 patients, the following adverse events, classified by body system, were reported.
CNS: 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/Behavioral/Psychiatric: hallucinations, dizziness, confusion, anxiety, depression, drowsiness, behavior/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.
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 when used as adjunctive therapy to levodopa treatment.
Symptoms And Treatment Of Overdose: Symptoms: No specific information is available about clinically significant overdoses with selegiline. However, experience gained during the development of selegiline reveals that some individuals exposed to doses of 600 mg/day of selegiline suffered severe hypotension and psychomotor agitation.
Since the selective inhibition of MAO-B by selegiline is achieved only at doses recommended for the treatment of Parkinson’s Disease (i.e., 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 nonselective MAO inhibitors (e.g., tranylcypromine and phenelzine).
Overdose with Nonselective MAO Inhibitors: Note: This section is provided for reference; it dose not describe events that have actually been observed with selegiline in overdose.
Characteristically, signs and symptoms of nonselective 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 2 days following the ingestion of such drugs in overdose is strongly recommended.
The clinical picture of MAO inhibitor overdose varies considerably; its severity may be a function of the amount of drug consumed. The CNS 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, opisthotonos, 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 nonselective MAO inhibitor poisoning, might be applicable.
Treatment of overdose with nonselective 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 CNS stimulation, including convulsions, should be treated with diazepam, given slowly i.v. Phenothiazine derivatives and CNS stimulants should be avoided. Hypotension and vascular collapse should be treated with i.v. fluids and, if necessary, blood pressure titration with an i.v. 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. 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 as monotherapy in newly diagnosed patients, or as an adjunct to levodopa (usually with a decarboxylase inhibitor) is 10 mg/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 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 hypertensive episode (“cheese reaction”).
Availability And Storage: Each almost white, flat tablet, scored on one side with the other face engraved with “E”, contains: 5 mg of the l-isomer of selegiline HCl (formerly l-deprenyl HCl). Nonmedicinal ingredients: citric acid, lactose, magnesium stearate, microcrystalline cellulose. Bottles of 60. Store between 15 and 30°C.
ELDEPRYL® Draxis Health Selegiline HCl Antiparkinsonian Agent