Orion Pharma (Ireland) Ltd

Eldepryl 5 mg Tablets

Each tablet contains 5 mg of selegiline hydrochloride.

For a full list of excipients, see section 6.1

Tablet.

A white or almost white, round, convex uncoated tablet having a single scoreline on one face.

Eldepryl is indicated for the treatment of Parkinson's disease, or symptomatic parkinsonism. Eldepryl may be used alone in early Parkinson's disease to delay the need for levodopa (with or without decarboxylase inhibitor). Eldepryl may also be used in the management of patients with Parkinson's disease not adequately controlled by conventional therapy or in whom on-off symptoms or other dyskinesias develop during maximal levodopa therapy.

Adults only:

5-10 mg daily either alone or as an adjunct to levodopa or levodopa/peripheral decarboxylase inhibitor. Eldepryl 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 Eldepryl is added to a levodopa regimen it is possible to reduce the levodopa dosage by an average of 30%.

Hypersensitivity to selegiline or any other component of the product.

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 10 mg daily) the selectivity begins to diminish resulting in increased inhibition of mono amine oxidase-A. Thus in higher doses there is a risk of hypertension after ingestion of food rich in tyramine.

Parkinson's disease patients treated with dopamine agonists and other dopaminergic treatments such as selegiline have been reported as exhibiting impulse control disorders and compulsions like pathological gambling, increased libido, hypersexuality, binge eating, shopping and different kinds of compulsive/repetitive activities (punding).

During Selegiline treatment, the possibility of hypertensive reaction as an interaction with indirect sympathomimetic drugs has to be taken into account. Foods containing tyramine have not been reported to induce hypersensitivity reactions during selegiline treatment at doses used in the treatment of Parkinson's disease. Concomitant use with non-selective mono amine oxidase inhibitors (including linezolid) may cause severe hypertension or hypotension, and therefore selegiline should not be given concurrently with non-specific monoamine oxidase inhibitors.

No tolerability problems have been reported when a combination of selegiline and moclobemide, an inhibitor of mono-amine oxidase-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 hypersensitivity reactions are unlikely when selegiline and moclobemide are used together, dietary restrictions (excluding foods with a large amount of tyramine such as aged cheese and yeast products) are recommended when prescribing this combination.

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 other serotonin reuptake inhibitors such as, sertraline, paroxetine, venlafaxine and fluvoxamine. Since the mechanisms of these reactions are not fully understood, it is recommended to avoid the combination of selegiline with serotonin reuptake inhibitors. Although citalopram has generally less interactions than fluoxetin caution is advised on concomitant use of selegiline and citalopram. 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.

Interactions between non-selective mono-amine oxidase 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 is also a potential interacting medicament.

Dopamine should be used with caution in patients receiving selegiline.

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, the appropriate cautiousness during the concomitant administration of selegiline and oral contraceptives should be applied.

There is no information on use during pregnancy or lactation. Selegiline should not be used in these situations.

None known.

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, nausea, agitation, confusion, hallucinations, headache, postural hypotension, cardiac arrhythmias and vertigo, may become more emphasised when selegiline is added to the maximum tolerated levodopa dose. 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.

The frequencies of adverse events are ranked according to the following: Common (1/100 to <1/10), Rare (1/10,000 to <1/1,000), Not known (cannot be estimated from the available data).

* Parkinson's disease patients treated with dopamine agonists and other dopaminergic treatments such as selegiline have been reported as exhibiting impulse control disorders and compulsions like pathological gambling, increased libido, hypersexuality, binge eating, shopping and different kinds of compulsive/repetitive activities (punding).

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

Theoretically, over-dosage 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 treatment is symptomatic.

Pharmacotherapeutic group: Monoamine oxidase B inhibitors, ATC-code: N04BD01.

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 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 is readily absorbed from the gastro-intestinal tract. The maximal concentrations are reached in 0.5-0.75h after oral administration in fasting state. The bioavailability is low; 10% (on 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 is rapidly distributed throughout the body, the apparent volume of distribution being 500 l after an intravenous 10 mg dose. 75-85% of selegiline is bound to plama proteins at therapeutic concentrations. Selegiline inhibits enzyme MAO-B irreversibly and enzyme activity only increases again after new enzyme is synthesized. The strong inhibitory effect of platelet enzyme MAO-B activity after single 10 mg dose lasts over 24 h, and the platelet enzyme MAO-B activity returns to normal level approximately after 2 weeks.

Selegiline is rapidly metabolised mainly in the liver, into active metabolites desmethylselegiline, l-methamphetamine and to l-amphetamine. In vitro studies indicate that CYP2B6 is the main hepatic cytochrome P450 (CYP) enzyme involved in the metabolism of selegiline with a possible contribution of CYP3A4 and CYP2A6. 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 1.5-3.5 hours for selegiline. The total body clearance of selegiline is about 240 l/hour. The metabolites of selegiline are excreted mainly via the urine with approximately 15% occurring in the faeces.

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

Mannitol (E421)

Maize starch

Microcrystalline cellulose

Povidone

Magnesium stearate

Not applicable.

3 years.

Do not store above 25°C. Store in the original container.

White polyethylene bottle with polyethylene closure placed in cardboard outer carton and aluminium foil blister-packs placed in cardboard outer carton.

Pack sizes: 30, 50, 60, 100 tablets.

Not all pack sizes may be marketed.

No special requirements.

Orion Corporation

Orionintie 1

FIN-02200 Espoo

Finland

PA 1327/3/1

Date of first authorisation: 03 January 1996

Date of last renewal: 03 January 2006

July 2010