Consumer medicine information

Eldepryl

Selegiline hydrochloride

BRAND INFORMATION

Brand name

Eldepryl Tablets

Active ingredient

Selegiline hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Eldepryl.

What is in this leaflet

This leaflet answers some of the common questions about ELDEPRYL tablets. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ELDEPRYL tablets against the benefits the medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What ELDEPRYL is used for

ELDEPRYL tablets are used to treat the symptoms of Parkinson's disease. This is a disease of the brain that affects movement.

People with Parkinson's disease do not have enough nerve cells in the part of the brain that controls movement. These nerve cells produce a substance called dopamine. It is a lack of dopamine which causes problems with movement.

ELDEPRYL tablets keep dopamine around longer, helping with difficulties in movement.

Before you take it

When you must not take it

Do not take ELDEPRYL tablets if:

  1. you have ever had an allergic reaction to:
  • medicines containing selegiline
  • any of the ingredients listed at the end of this leaflet.
  1. you have taken or are taking antidepressants known as selective serotonin reuptake inhibitors (SSRIs) such as Prozac® (fluoxetine), Aropax® (paroxetine) or Zoloft® (sertraline) within the last five weeks.
  2. you are taking pethidine (a strong pain killer) or other opiates (check with your doctor or pharmacist). Serious side effects could occur if you start to take ELDEPRYL tablets at the same time as these medicines.
  3. you are taking antidepressants known as monoamine oxidase inhibitors (MAOIs) such as Aurorix® (moclobemide), Nardil® (phenelzine) or Parnate® (tranylcypromine) or have taken these medications within the last two weeks.
  4. you are taking antidepressants known as tricyclic antidepressants (TCAs) such as Tofranil® (imipramine), Anafranil® (clomipramine), Tryptanol® (amitriptyline) or have taken these medications in the last two weeks.
  5. the expiry date on the pack has passed.
    If you take this medicine after the date has passed it may have no effect at all, or worse, an entirely unexpected effect.
  6. the packaging is torn or shows signs of tampering.

Before you start to take it

You must tell your doctor if:

  1. you are allergic to any other medicines or other substances such as foods, dyes or preservatives.
  2. you have or have ever had any other health problems especially:
  • stomach ulcers
  • liver or kidney disease
  • high blood pressure (hypertension)
  • psychosis (a condition causing abnormal thoughts)
  • heart problems (angina or abnormal rhythm).

ELDEPRYL tablets could make these conditions worse.

  1. you are or plan to become pregnant or to breast feed. The effects of this medicine in pregnant and breastfeeding women are unknown.
  2. you are taking any oral contraceptives.
  3. you are taking any medicine that inhibits monoamine oxidase (e.g., linezolid to treat bacterial infections)
  4. you are taking any other medications having a dopamine effect (e.g. Madopar®, Sinemet®) or tramadol (e.g. Tramal®).

If you have not told your doctor about any of the above, tell them before you start taking ELDEPRYL tablets.

How to take it

Follow all directions given to you by your doctor and pharmacist carefully.

They may differ from the information contained in this leaflet.

ELDEPRYL tablets are available only on prescription and it is usually co-prescribed with other medicines used in treating Parkinson's disease (e.g. Madopar®, Sinemet®). After taking ELDEPRYL tablets for a short time, your doctor may decrease the amount of Madopar®or Sinemet®that you are taking.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How to take it

Swallow the prescribed dose of this medicine with a large glass of water while standing upright.

Do not stop taking it without your doctor's advice, because your symptoms of Parkinson's disease may worsen.

If you forget to take it

If it is almost time to take your next dose, skip the dose that you have missed and take your next dose when you are meant to. Otherwise take it as soon as you remember, then go back to taking your tablets as usual.

Do not double a dose to make up for a dose that you have missed.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital if you think that you or anyone else may have taken too many ELDEPRYL tablets. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Side effects

Check with your doctor or pharmacist as soon as possible if you have any problems while you are taking ELDEPRYL tablets, even if you think that the problems are not connected with the medicine or are not listed in this leaflet.

Like all medicines, ELDEPRYL tablets can cause side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

The most common side effects of ELDEPRYL tablets tend to be due to its interaction with certain drugs such as Madopar®and Sinemet®. These are usually mild in nature and normally disappear when your doctor lowers your dose of Madopar®or Sinemet®after you have started taking ELDEPRYL tablets.

Tell your doctor if you notice any of the following and they worry you:

  • body aches and pains
  • constipation
  • diarrhoea
  • dizziness
  • dry mouth
  • headaches
  • light headedness or feeling faint
  • nausea, vomiting
  • sleep disorders
  • stomach pains
  • sweating more than usual
  • abnormal thinking.
  • increased desire for sex
  • compulsive behaviours such as - gambling, shopping, eating, and repetitive purposeless activities.

Tell your doctor immediately, or go to the nearest casualty at your local hospital if you notice any of the following:

  • increase in unusual body movements
  • mood/mental changes (e.g. agitation, confusion, depression, hallucinations)
  • chest pains
  • breathing problems.

Tell your doctor if you notice anything else that is making you feel unwell.

Some people may get other side effects while using ELDEPRYL tablets.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

After taking it

Storage

Keep your tablets in the bottle until it is time to take them.

If you take the tablets out of the bottle, they may not keep as well.

Keep ELDEPRYL tablets in a cool dry place where the temperature stays below 25 degrees C.

Do not store ELDEPRYL tablets or any other medicine in the bathroom or near a sink. Do not leave it in the car or on windowsills.

Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets which are left over.

Product description

What ELDEPRYL tablets look like

ELDEPRYL tablets are a round white tablet with a break line on one side. It is available in bottles of 100 tablets.

Ingredients

Active ingredient:
5 mg selegiline hydrochloride per tablet.

Inactive ingredients:

  • starch-maize
  • microcrystalline cellulose
  • mannitol
  • povidone
  • magnesium stearate.

ELDEPRYL tablets do not contain gluten, sucrose, tartrazine or any other azo dyes.

Supplier

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards NSW 2065
Australia

Australian Registration Number:
AUST R 47465.

This leaflet was revised in December 2017.

BRAND INFORMATION

Brand name

Eldepryl Tablets

Active ingredient

Selegiline hydrochloride

Schedule

S4

 

1 Name of Medicine

Selegiline hydrochloride.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

2079-54-1.
Eldepryl (selegiline hydrochloride) is a laevorotatory acetylenic derivative of phenethylamine. It is also known as L-deprenyl. Its chemical name is (R)-methyl (-methylphenylethyl) prop-2-ynlamine hydrochloride.
It is a white to near-white crystalline powder, freely soluble in water, chloroform and methanol and has a molecular weight of 223.75.

2 Qualitative and Quantitative Composition

For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet: each round white tablet contains 5 mg selegiline hydrochloride.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Selegiline is 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, i.e. it is converted by MAO to an active moiety which combines irreversibly with the active site of the enzyme and/or the enzyme's essential flavine adenine dinucleotide (FAD) cofactor. 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 the brain is type B. At the recommended dose, selegiline has greater affinity with type B than for type A active sites and serves as a selective inhibitor of MAO type B (MAO-B). However, this selectivity is dose dependent and at higher doses (above 20 mg/day), the selectivity of selegiline starts to diminish, resulting in increased inhibition of MAO-A. The precise dose at which selegiline becomes a nonselective inhibitor of all MAO is unknown.
In CNS neurones, MAO plays an important role in the catabolism of catecholamines (dopamine, noradrenaline and adrenaline) and serotonin. MAOs are also important in the catabolism of various exogenous amines found in a variety of foods and drugs. MAO in the gastrointestinal 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'. This has been documented with nonselective MAO inhibitors.
It has been shown in several in vitro and in vivo experiments that selegiline does not potentiate the 'cheese reaction' effect. However, the pathophysiology of the 'cheese reaction' is complicated and is not fully understood. Selegiline's apparent freedom from this reaction may be due to its selective inhibition of MAO-B at clinically used doses (≤ 10 mg/day); and selegiline's ability to prevent tyramine and other indirect acting sympathomimetics from displacing noradrenaline from adrenergic neurones (see Section 4.4 Special Warnings and Precautions for Use).
The rate of MAO-B regeneration following discontinuation of selegiline 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.
Selegiline may have pharmacological effects unrelated to MAO-B inhibition. There is some evidence that it may increase dopaminergic activity by inhibiting dopamine reuptake at the synapse.
Effects resulting from selegiline administration may also be mediated through its metabolites. Three of its principal metabolites may have pharmacological actions of their own. l-Amphetamine and l-methamphetamine interfere with neuronal uptake and enhance release of several neurotransmitters (e.g. noradrenaline, dopamine, serotonin). However, l-amphetamine and l-methamphetamine have significantly less activity than the corresponding d-isomer. In animal studies, the third metabolite, N-desmethylselegiline, appears to act as a selective inhibitor of MAO-B. The extent to which each of these metabolites contributes to the effects of selegiline is unknown.

Mechanism of action.

No data available.

Clinical trials.

Selegiline as monotherapy in the early phase of Parkinson's disease.

Four randomised, double blind, placebo controlled, parallel group studies, involving 501 patients treated with selegiline and 498 patients treated with placebo, have been conducted to the end of 1994 where the primary outcome measure was time to initiation of levodopa. The largest trial, the DATATOP study, randomised 800 patients to four different treatment regimens. These regimens were selegiline (10 mg once daily); vitamin E; a combination of selegiline with vitamin E; and placebo. The primary outcome measure was time to requirement for levodopa as additional therapy. An analysis of the primary endpoint after 12 months into the trial showed that, of those patients who were treated with selegiline, 97/399 (24.3%) had progressed to the point of requiring additional therapy (levodopa). Of those patients who had received vitamin E or placebo, 176/401 (43.9%) required the addition of levodopa. The results demonstrated that selegiline delayed onset of the stage where levodopa was required, the delay in commencement of levodopa being approximately 7-9 months in the particular group studied. Overall, selegiline was shown in these four studies to significantly delay the need to introduce levodopa by 5-9 months, compared to the placebo group. Evidence was less clear as to whether selegiline exerted a symptomatic effect.

Selegiline as adjunctive therapy in the early and middle phases of Parkinson's disease.

Six randomised, double blind, placebo controlled, parallel or crossover studies, involving 157 patients treated with selegiline in combination with levodopa and 157 patients treated with placebo in combination with levodopa, have been conducted in patients in the early and middle phases of Parkinson's disease to the end of 1995. When levodopa was added to selegiline therapy, or both drugs were given together, to de novo patients with Parkinson's disease, optimal clinical conditions, in terms of disability, was maintained with levodopa doses 50-80% lower than if selegiline was not coadministered. Increases in daily levodopa dosage were significantly smaller in the selegiline + levodopa group, compared to the placebo + levodopa group, over time (up to 5 years). Levodopa dosing frequency was significantly in favour of patients on selegiline + levodopa compared to those on placebo + levodopa (i.e. less levodopa doses/day in the former group). Additionally, patients treated with selegiline + levodopa had attenuated deterioration in their disability scores, compared to the placebo + levodopa group.
The conclusions from these studies were that the need to increase levodopa dose was slowed down.
For information on the adverse events reported in the clinical trials, see Section 4.8 Adverse Effects (Undesirable Effects).

5.2 Pharmacokinetic Properties

General characteristics.

Selegiline is readily absorbed from the gastrointestinal tract. The maximum concentrations are reached in 0.5 hours after oral administration. The bioavailability is low, on average 9.4 ± 5.9% of unchanged selegiline from a 10 mg oral dose reaches the systemic circulation. A substantial increase in selegiline bioavailability (up to threefold) occurs when selegiline is administered with food high in fat.
Selegiline is a lipophilic, slightly basic compound which quickly penetrates into tissues, including the brain. It is rapidly distributed throughout the body, with the apparent volume of distribution being 508 ± 182 litres after an intravenous 10 mg dose. Selegiline is strongly bound to plasma proteins, especially to macroglobulins and, to a lesser extent, to albumin.
Selegiline is rapidly metabolised, mainly in the liver, into N-desmethylselegiline (the major metabolite), l-methamphetamine and 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, these three metabolites have been identified in plasma and urine after single and multiple doses of selegiline. Following the oral administration of a single dose of 10 mg selegiline hydrochloride, for example, N-desmethylselegiline (mean t1/2 2.0 hours); l-amphetamine (mean t1/2 17.7 hours); and l-methamphetamine (mean t1/2 20.5 hours) were found in the serum and urine. Metabolites of selegiline are excreted mainly via the urine, with about 15% occurring in the faeces. Over a period of 48 hours, urinary excretion of these metabolites accounted for 45% of the dose administered. The mean elimination half-life of an intravenous 10 mg dose of selegiline is 1.6 ± 0.3 hours. The total body clearance of selegiline is about 240 L/hour. The half-life of an oral 10 mg dose of selegiline is 1.2 - 1.8 hours.

Characteristics in patients.

Selegiline is metabolized quickly, but due to irreversible MAO-B inhibition, the duration of clinical effect does not depend on the elimination time of selegiline and, therefore, once daily dosing can be applied.
No information is available yet concerning polymorphic metabolism or the effect of renal or hepatic insufficiency on the metabolism of selegiline.

5.3 Preclinical Safety Data

Genotoxicity.

Selegiline did not induce gene mutations in Salmonella typhimurium or chromosomal damage in an in vivo chromosomal aberration assay. No definitive mammalian gene mutation assay has been performed.
Selegiline did not impair fertility in rats at oral doses up to 100 mg/kg/day.

Carcinogenicity.

Selegiline showed no evidence of carcinogenicity in a 78 week study in mice at dietary levels up to 30 mg/kg/day and a 104 week study in rats at dietary levels up to 17.5 mg/kg/day.

4 Clinical Particulars

4.1 Therapeutic Indications

Eldepryl is indicated for the treatment of patients with Parkinson's disease. It can be used as monotherapy in the early phases of the disease and as adjunctive therapy with levodopa (with/ without a peripheral decarboxylase inhibitor).

4.3 Contraindications

Known hypersensitivity to selegiline or any other components of the formulation.
When selegiline is prescribed in combination with levodopa, the contraindications which apply to levodopa must be taken into account.

Pethidine.

Pethidine is contraindicated in combination with MAOIs because of reports of serious, sometimes fatal, reactions in patients receiving this combination and in patients who have discontinued MAOI therapy and are then started on pethidine within two weeks of discontinuation. (This warning is often extended to other opioids.) Agitation, delirium, irritability, hyperpyrexia, restlessness, rigidity, stupor and sweating have been reported with the concomitant use of pethidine and selegiline. The mechanism of action is not fully understood.

Selective serotonin reuptake inhibitors.

There have been reports of serious, sometimes fatal, reactions in patients receiving selective serotonin reuptake inhibitors (SSRIs) in combination with selegiline and in patients who have recently discontinued SSRIs and are then started on a MAOI. Agitation, ataxia, cold sweats, hypertension, mania, pseudophaeochromocytoma, 'serotonergic reaction' and shivers have been reported with the concomitant use of selegiline and SSRIs, particularly fluoxetine. Similar experience has been reported in patients receiving selegiline and venlafaxine.
Since the mechanisms of these reactions are also not fully understood, it is recommended to avoid the combination of selegiline and SSRIs. Although citalopram has generally less interactions than fluoxetine, caution is advised on concomitant use of selegiline and citalopram.
At least five weeks should be allowed between discontinuation of, for example, fluoxetine, sertraline or paroxetine and initiation of selegiline therapy, due to the long t1/2 of these SSRI drugs and/or their active metabolites. A two week period between selegiline discontinuation and SSRI initiation would be sufficient, because of the short t1/2 of selegiline and its active metabolites.

4.4 Special Warnings and Precautions for Use

Identified precautions.

General.

The recommended dose of 10 mg/day should not be exceeded because of the risks associated with nonselective inhibition of MAO, i.e. 'cheese reactions' (see Section 5 Pharmacological Properties). In higher doses (> 20 mg/day), the selectivity of selegiline starts to diminish, resulting in increased inhibition of MAO-A. The possibility of a hypertensive reaction at higher doses (> 20 mg/day) of selegiline after ingestion of food or drugs rich in various exogenous amines has to be taken into account. Even at the recommended dose of 10 mg/day the selectivity of selegiline for MAO-B may not be absolute. The precise dose at which selegiline becomes a nonselective inhibitor of all MAO is unknown.
Some patients on adjunctive therapy may experience 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 10-30%.
Selegiline should be given cautiously to patients with peptic or duodenal ulcer, labile hypertension, cardiac arrhythmias, severe angina pectoris or psychosis, as selegiline may exacerbate these conditions.
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).
Some studies concluded in an increased risk of mortality in patients receiving selegiline and levodopa compared to those receiving levodopa only. However, it is noteworthy that multiple methodological bias were identified in these studies that a meta-analysis and large cohort studies concluded that there was no significant difference in mortality in patients treated with selegiline compared to those treated with comparators or with the association selegiline/ levodopa.

Use in hepatic impairment.

Selegiline should be used cautiously in patients with severe liver or kidney dysfunction, as there is no pharmacokinetic information available on selegiline or it's metabolites in these patients (see Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

Selegiline should be used cautiously in patients with severe liver or kidney dysfunction, as there is no pharmacokinetic information available on selegiline or it's metabolites in these patients (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

No data available.

Paediatric use.

The effects of selegiline in children have not been evaluated.

Effects on laboratory tests.

Transient increases in liver transaminases have been reported during selegiline treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Monoamine oxidase inhibitors.

Moclobemide. No tolerability problems have been reported when selegiline and moclobemide, a reversible inhibitor of MAO-A, have been used in combination. However, when used together the exogenous amine sensitivity factor may increase. A diet low in exogenous amines such as tyramine is recommended for patients taking the combination.
Concomitant administration of selegiline and MAO inhibitors may cause central nervous and cardiovascular system disorders.
Nonselective MAOIs. Combined use of nonselective MAOIs (including linezolid) with selegiline may cause severe hypertension or hypotension.

Pethidine.

See Section 4.3 Contraindications.

Serotonergic drugs.

Treatment with heterogenous serotonergic drugs in patients primarily with psychiatric illness, taken alone or in combination with other drugs such as MAOIs, has been uncommonly associated with symptoms of myoclonus, tremor, confusion, restlessness, ataxia and hyper-reflexia (see Section 5.1 Pharmacodynamic Properties, Clinical trials). While usually short-lived, it can lead to intensive care admissions and is potentially fatal. The occurrence of the serotonin syndrome may occur after use of SSRIs, tricyclic antidepressants (TCAs), tetracyclic antidepressants, 3-4-methylenedioxy-metamphetamine (MDMA or ecstasy) and other 5-HT potentiating agents, and the antipsychotic drug, clozapine. The treatment of choice is cessation of the drugs responsible. Treatment with the 5-HT receptor antagonists cyproheptadine, methysergide and propranolol may shorten the syndrome duration.

SSRIs.

See Section 4.3 Contraindications.

Tricyclic antidepressants.

Severe CNS toxicity has been reported in patients when a combination of tricyclic antidepressants and selegiline have been used. In one patient receiving amitriptyline and selegiline this included hyperpyrexia and death; 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 hypertension/ 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 avoid concomitant use of selegiline together with tricyclic antidepressants.
At least two weeks should be allowed between discontinuation of a tricyclic antidepressant and initiation of selegiline therapy, due to the long t1/2 of some tricyclics and their active metabolite(s). A two week period between selegiline discontinuation and tricyclic antidepressant initiation would be sufficient, because of the short t1/2 of selegiline and its active metabolites.

Oral contraceptives.

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

Other.

In clinical trials, interactions between dopamine and selegiline have been reported occasionally resulting in a hypertensive reaction.
There have also been reports that concomitant use of tramadol with selegiline may adversely interact.
During selegiline treatment, the possibility of a hypertensive reaction as a result of an interaction with indirect sympathomimetic drugs has to be taken into account.
Foods containing various exogenous amines such as tyramine have not been reported to induce hypertensive reactions during selegiline treatment at doses used in the treatment of Parkinson's disease.
Studies have related the risk of an increased hypotensive response to concomitant administration of selegiline and levodopa, in patients with cardiovascular risk.
Caution is advised when selegiline is taken in combination with other centrally acting medicinal products and substances. The concomitant intake of alcohol should be avoided.
Caution should be exercised in patients receiving MAO inhibitors during general anaesthesia in surgery. MAO inhibitors, including selegiline, may potentiate the effects of CNS depressants used for general anaesthesia. Transient respiratory and cardiovascular depression, hypotension and coma have been reported (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B2)
Insufficient animal reproduction studies have been performed to conclude that selegiline poses no teratogenic risk. However, one rat study carried out at doses of up to 30 mg/kg/day revealed no evidence of a teratogenic effect.
The effects of selegiline in human pregnancy are unknown. The available safety data concerning the use of selegiline during pregnancy is insufficient to justify use in this patient group. Therefore, selegiline should not be given to pregnant women unless the expected benefit clearly outweighs any potential risk.
It is not known whether selegiline is excreted in human milk. The excretion of selegiline in milk has not been studied in animals. Physiochemical data in selegiline point to excretion in breast milk and a risk to the suckling child cannot be excluded. Selegiline should not be used during breastfeeding.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
In monotherapy, selegiline has been found to be well tolerated. Dry mouth, transient rise of serum alanine aminotransferase values and sleeping disorders have been reported more frequently than in patients receiving placebo. Because selegiline potentiates the clinical efficacy 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 worsen when selegiline is added to the maximum tolerated levodopa dose. Micturition difficulties and skin reactions have also been reported during selegiline treatment. Follow-up of these possible adverse reactions is important.

Clinical trials.

Table 1 summarises the adverse events reported in patients enrolled in double blind placebo controlled trials where selegiline had been used as monotherapy or as adjunctive therapy with levodopa. Included are all adverse events which occurred with an incidence of 1% or greater in any treatment group. An asterisk represents an incidence of < 1% for that treatment group; a dash indicates that the adverse event was not reported.

Selegiline and mortality.

In 1995, the UK Parkinson's Disease Research Group (PDRG) reported in a 5.6 year interim analysis of the long-term prospective study an increased overall mortality in the patient group randomised to receive selegiline and levodopa, when compared to those treated with levodopa only (Lees et al. 1995). This study has been the subject of considerable debate and criticism in the medical literature because of significant design and clinical research practice issues (Olanow et al. 1996; Gerlach et al. 1996; Breteler 1998). A further 21 months update (mean 6.8 years) on the study including all mortality information to the end of September 1995 was published in 1998 (Ben Shlomo et al.).
During 1996 to 1997, the British Medicines Control Agency (MCA) sponsored a study evaluating mortality among patients with Parkinson's disease on various treatments using data from their General Practice Research Database. This study, combined with the MCA's review of all available evidence from trials and observational studies, did not confirm the increased mortality risk in users of selegiline in combination with levodopa, which was seen in the PDRG study (Evans and Sivananthan 1997).
No other clinical trial to date has shown an increase in mortality associated with the use of selegiline (Birkmayer 1985, Caraceni 1996, Shoulson 1996, Di Rocco 1996, Fuell 1997, Thorogood 1998, (US) Parkinsons Study Group 1998). The need for a formal systematic review of all relevant trial data to assess survival, disability and the risk of dementia has been identified (Counsell 1998).

Postmarketing surveillance data.

Adverse events experienced by patients on monotherapy or adjunctive therapy from spontaneous reports have not been separated.
The estimated frequency of adverse events, for a body system, are listed in Table 2. Frequency has been grouped according to the following criteria: common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1,000 and < 1/100; rare: ≥ 1/10,000 and < 1/1,000; very rare: < 1/10,000; not known: cannot be estimated from the available data.

4.2 Dose and Method of Administration

Selegiline is administered as monotherapy in the early phase of the disease, or as adjunctive therapy with levodopa (with/ without a peripheral decarboxylase inhibitor). In each case the initial dose is 5 mg taken at breakfast and lunch. There is no evidence that additional benefit will be obtained from the administration of higher doses.
After two to three days of adjunctive therapy, an attempt may be made to reduce the dose of levodopa (10-30%) if levodopa related adverse reactions occur. Further reductions of levodopa may be possible during continued selegiline therapy.
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.
After the initiation of levodopa therapy, selegiline potentiates and extends the effect of levodopa, and thus a reduction of levodopa dosage is possible. By adding selegiline to levodopa therapy the fluctuations in disability, e.g. end-of-dose type fluctuations, can be reduced.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
Overdoses have no specific clinical picture. Since the selective inhibition of MAO-B by selegiline is achieved only at doses recommended for the treatment of Parkinson's disease (5 to 10 mg/day), overdoses may resemble those observed with nonselective MAO inhibitor (central nervous and cardiovascular system disorders). Symptoms of nonselective MAO inhibitors overdosage can progress over 24 hours to include drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucination, tremor, alternating high and low blood pressure, vascular collapse, rapid and irregular pulse, precordial pain, respiratory depression and failure, severe muscle spasms, hyperpyrexia, diaphoresis, coma and convulsions. There is no specific antidote and the treatment should be symptomatic.
No overdosage cases are known. However, experience gained during selegiline's development reveal that some individuals exposed to doses of 600 mg/day selegiline suffered severe hypertension and psychomotor agitation.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Inactive ingredients are: maize starch, microcrystalline cellulose, mannitol, povidone and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Tablets - 5 mg selegiline hydrochloride in bottles of 100 and 30* tablets.
(* Currently not marketed in Australia).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes