Eldepryl Tablets 10 mg

Selegiline hydrochloride 10 mg

Full list of excipients, see section 6.1.

Tablets for oral administration.

Selegiline is indicated for the treatment of Parkinson's disease, or symptomatic parkinsonism. It may be used alone to delay the need for levodopa (with or without decarboxylase inhibitor) or as an adjunct to levodopa (with or without decarboxylase inhibitor).

10 mg daily either alone or as an adjunct to levodopa or levodopa/peripheral decarboxylase inhibitor. Selegiline may be administered either as a single dose in the morning or in two divided doses of 5 mg, taken at breakfast and lunch. When selegiline is added to a levodopa regimen it is possible to reduce the levodopa dosage by an average of 30%.

Known hypersensitivity to selegiline or other components of the formulation.

Selegiline should be administered cautiously to patients with peptic or duodenal ulcer, labile hypertension, cardiac arrhythmias, severe angina pectoris, severe liver or kidney dysfunction or psychosis. In higher doses (more than 30 mg daily) the selectivity of selegiline begins to diminish resulting in increased inhibition of MAO-A. Thus in higher doses there is a risk of hypertension after ingestion of food rich in tyramine.

Foods containing tyramine have not been reported to induce hypertensive reactions during selegiline treatment at doses used in the treatment of Parkinson's disease.

A concomitant use of nonselective MAO-inhibitors may cause severe hypotension.

No tolerability problems have been reported when a combination of selegiline and moclobemide, an inhibitor of MAO-A, has been used. However, when they are used together, the tyramine sensitivity factor may increase up to 8-9 (being 1 for selegiline alone and 2-3 for moclobemide alone). Although tyramine induced hypertensive reactions are unlikely when selegiline and moclobemide are used together, dietary restrictions (excluding foods with large amounts of tyramine such as aged cheese and yeast products) are recommended when using this combination.

Interactions between nonselective MAO-inhibitors and pethidine, as well as selegiline and pethidine have been described. The mechanism of this interaction is not fully understood and therefore, use of pethidine concomitantly with selegiline should be avoided. Tramadol may also potentially interact with Selegiline.

Dopamine should be used with caution in patients receiving Selegiline.

Serious reactions with signs and symptoms that may include diaphoresis, flushing, ataxia, tremor, hyperthermia, hyper/hypotension, seizures, palpitation, dizziness and mental changes that include agitation, confusion and hallucinations progressing to delirium and coma have been reported in some patients receiving a combination of selegiline and fluoxetine. Similar experience has been reported in patients receiving selegiline and four serotonin reuptake inhibitors, fluvoxamine, sertraline, paroxetine or venlafaxine. Since the mechanisms of these reactions are not fully understood, it is recommended to avoid the combination of selegiline with fluoxetine, sertraline, paroxetine or venlafaxine. A minimum period of five weeks should be allowed between discontinuation of fluoxetine and initiation of selegiline treatment, due to the long half-lives of fluoxetine and its active metabolite. As the half-lives of selegiline and its metabolites are short, a wash-out period of 14 days after selegiline treatment would be sufficient before starting fluoxetine. The concomitant use of selegiline and citalopram has been investigated in healthy volunteers. No signs of clinically relevant pharmacokinetic or pharmacodynamic interactions between the two drugs were observed.

Severe CNS toxicity has been reported in patients with the combination of tricyclic antidepressants and selegiline. In one patient receiving amitriptyline and selegiline this included hyperpyrexia and death, and another patient receiving protriptyline and selegiline experienced tremor, agitation, and restlessness followed by unresponsiveness and death two weeks after selegiline was added. Other adverse reactions occasionally reported in patients receiving a combination of selegiline with various tricyclic antidepressants include hyper/hypotension, dizziness, diaphoresis, tremor, seizures, and changes in behavioural and mental status. Since the mechanisms of these reactions are not fully understood, it is recommended to be cautious when using selegiline together with tricyclic antidepressants.

Concomitant use of oral contraceptives (tablets containing the combination of gestodene/ethinyl estradiol or levonorgestrel/ethinyl estradiol) and selegiline may cause an increase in the oral bioavailability of selegiline. Thus appropriate caution during the concomitant administration of selegiline and oral contraceptives should be applied.

The available safety data concerning the use during pregnancy and lactation is insufficient to justify the use of selegiline in these patient groups.

No effects on ability to drive or operate machines.

In monotherapy, selegiline has been found to be well tolerated. Dry mouth, transient rise of serum alanine aminotransferase (ALAT) values and sleeping disorders have been reported more frequently than in patients receiving placebo. Because selegiline potentiates the effects of levodopa, the adverse reactions of levodopa, e.g. abnormal movements (such as dyskinesias), nausea, agitation, confusion, hallucinations, headache, postural hypotension, cardiac arrhythmias and vertigo, may be emphasised, particularly if the dose of levodopa is too high. Such adverse reactions usually disappear when the levodopa dosage is decreased. Levodopa dosage can be reduced by an average of 30% when selegiline is added to the treatment. Micturition difficulties and skin reactions have also been reported during selegiline treatment. Follow-up of these possible adverse reactions is important.

Hypersexuality has been very rarely reported in association with selegiline use, either as monotherapy or in combination with other dopaminergic antiparkinsonian medication.

A summary of the undesirable effects in terms of frequency of occurrence is shown below.

No overdosage cases are known. However, experience gained during selegiline's development reveals that some individuals exposed to doses of 600 mg/day selegiline suffered severe hypotension and psychomotor agitation.

Theoretically, overdosage causes significant inhibition of both MAO-A and MAO-B and thus, symptoms of overdosage may resemble those observed with non-selective MAO-inhibitors, such as different central nervous and cardiovascular system disorders (e.g. drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucination, hypertension, hypotension, vascular collapse, rapid and irregular pulse, precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis). There is no specific antidote and the treatment is symptomatic.

Selegiline is a selective MAO-B-inhibitor which prevents dopamine breakdown in the brain. It also inhibits the reuptake of dopamine at the presynaptic dopamine receptor. These effects potentiate dopaminergic function in the brain and help to even out and prolong the effect of exogenous and endogenous dopamine. Thus, selegiline potentiates and prolongs the effect of levodopa in the treatment of parkinsonism.

Double-blind studies on early phase Parkinsonian patients showed that patients receiving selegiline monotherapy manage significantly longer without levodopa therapy than controls receiving placebo. These patients could also maintain their ability to work longer.

The addition of selegiline to levodopa (with or without decarboxylase inhibitor) therapy helps to alleviate dose related fluctuations and end of dose deterioration.

When selegiline is added to such a regimen it is possible to reduce the levodopa dosage by an average of 30%. Unlike conventional MAO-inhibitors, which inhibit both the MAO-A and MAO-B enzyme, selegiline is a specific MAO-B inhibitor and can be given safely with levodopa.

Selegiline HCl does not cause the so called "cheese effect" either when used alone as monotherapy, or when used with other drugs, except for moclobemide or nonselective MAO-inhibitors.

Selegiline HCl is readily absorbed from the gastrointestinal tract. The maximal concentrations are reached in half an hour after oral administration. The bioavailability is low; 10% (on the average; interindividual variation is large) of unchanged selegiline can reach the systemic circulation.

Selegiline is a lipophilic, slightly basic compound which quickly penetrates into tissues, also into brain. Selegiline HCl inhibits MAO irreversibly and enzyme activity only increases again after new enzyme is synthesised. The inhibitory effect of a single 10 mg dose lasts for 24 hours. Selegiline is rapidly distributed throughout the body, the apparent volume of distribution being 500 litres after an intravenous 10 mg dose. 75-85 % of selegiline is bound to plasma proteins at therapeutic concentrations.

Selegiline is rapidly metabolised, mainly in the liver, into desmethylselegiline, l-methamphetamine and to l-amphetamine. In humans, the three metabolites have been identified in plasma and urine after single and multiple doses of selegiline. The mean elimination half-life is 1.6 hours for selegiline. The total body clearance of selegiline is about 240 L/hour. Metabolites of selegiline are excreted mainly via the urine with about 15% occurring in the faeces.

No mutagenicity or carcinogenicity due to selegiline have emerged in routine studies.

Mannitol, maize starch, microcrystalline cellulose, povidone, and magnesium stearate.

No other incompatibilities noted.

36 months: Bottle

36 months: Blister

HDPE bottle; Do not store above 25 °C. Keep the container tightly closed.

Al/Al blister; Do not store above 25 °C. Store in the original package.

White polyethylene bottle with polyethylene closure; 50, 100 tablets

Al/Al blister; 30, 50, 60, 100 tablets

White HDPE bottle with HDPE screw cap: 50, 100 tablets

None.

Orion Corporation, Orionintie 1, FIN-02200 Espoo, Finland

PL 27925/0005

1.7.1993/Renewal July 2007

June 2009