4.1. Therapeutic indications

Selegiline is indicated for the treatment of Parkinson's disease, or symptomatic parkinsonism. It may be used alone in early Parkinson's disease for symptomatic relief to delay the need for levodopa (with or without decarboxylase inhibitor) or as an adjunct to levodopa (with or without decarboxylase inhibitor). Selegiline in combination with maximal levodopa therapy is indicated particularly in patients who experience fluctuations in their condition such as 'end-dose' type fluctuations, 'on-off' symptoms or other dyskinesias.

4.2. Posology and method of administration

Posology

10 mg daily either alone or as an adjunct to levodopa or levodopa/peripheral decarboxylase inhibitor. When selegiline is added to a levodopa regimen it is possible to reduce the levodopa dosage by an average of 10 -30%. Reduction of the levodopa dose should be gradual in steps of 10% every 3 to 4 days.

No dosage adjustment is required for patients with renal or hepatic impairment.

Method of administration

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.

4.3. Contraindications

Eldepryl is contra-indicated in patients with known hypersensitivity (including severe dizziness or hypotension) to selegiline or any of the excipients listed in section 6.1.

Eldepryl is contra-indicated in patients receiving treatment with serotonin-agonists (e.g. sumatriptan, naratriptan, zolmitriptan and rizatriptan).

Selegiline is also contra-indicated for concomitant use with pethidine and other opioids.

Selegiline should not be used in patients who are being treated with antidepressant drugs, including MAO inhibitors tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors (SNRI) (e.g. venlafaxine) and selective serotonin reuptake inhibitors (e.g citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. See section 4.5 interactions).

Selegiline should also not be used with other drugs which are also monoamine oxidase inhibitors, e.g. linezolid.

Selegiline should not be used in combination with sympathomimetics (see section 4.5).

Selegiline should not be used in patients with active duodenal or gastric ulcer.

Selegiline should not be used in patients with other extrapyramidal disorders not related to dopamine deficiency.

Selegiline in combination with levodopa is contra-indicated in severe cardiovascular disease, arterial hypertension, hyperthyroidism, phaeochromocytoma, narrow-angle glaucoma, prostatic adenoma with appearance of residual urine, tachycardia, arrhythmias, severe angina pectoris, psychoses, advanced dementia and thyrotoxicosis.

4.4. Special warnings and precautions for use

The precise dose at which selegiline becomes a non-selective inhibitor of all MAO has not been determined, but with doses higher than 10 mg/day there is a theoretical risk of hypertension after ingestion of tyramine-rich food.

Concomitant treatment with medicines which inhibit MAO-A, (or non-selective MAO inhibitors) can cause hypotensive reactions. Hypotension, sometimes sudden in onset, has been reported with conventional selegiline.

Serotonin syndrome

Concomitant administration of Eldepryl and buprenorphine/opioids may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

Special care should be taken when administering selegiline to patients who have labile hypertension, cardiac arrhythmias, severe angina pectoris, psychosis or a history of peptic ulceration as aggravation of these conditions may occur during treatment

Although serious hepatic toxicity has not been observed, caution is recommended in patients with a history of hepatic dysfunction. Transient or continuing abnormalities with a tendency for elevated plasma concentrations of liver enzymes have been described during long-term therapy with conventional tablets of selegiline.

Selegiline should be used with caution in severe liver or kidney dysfunction.

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).

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 and that a meta analysis and large cohort studies concluded that there was no significant difference in mortality in patients treated with selegiline to those treated with comparators or with the association selegiline/levodopa.

Studies have related the risk of an increased hypotensive response to concomitant administration of selegiline and levodopa, in patients with cardiovascular risk.

The addition of selegiline to levodopa may not be beneficial in those patients who experience fluctuations in response which are not dose dependent.

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.

Since selegiline potentiates the effects of levodopa, the adverse effects of levodopa may be increased. When selegiline is added to the maximum tolerated dose of levodopa, involuntary movements and agitation may occur. Levodopa should be reduced by about 10 to 30% when selegiline is added to the treatment (see section 4.2 Posology and Method of Administration). When an optimum dose of levodopa is reached, adverse effects from the combination are less than those observed with levodopa on its own.

Parkinson's disease patients treated with dopamine agonists and other dopaminergic treatments 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). These may also be possible with selegiline but very few cases have been reported to date.

4.5. Interaction with other medicinal products and other forms of interaction

Association contra-indicated (see section 4.3)

Sympathomimetics

Because of the risk of hypertension, co-administration of selegiline and sympathomimetics is contraindicated.

Pethidine, tramadol, buprenorphine and other opioids

The concomitant administration of the selective MAO-B inhibitor selegiline and pethidine and other opioids is contraindicated. Tramadol and buprenorphine are also potential interacting medicaments.

Eldepryl should be used cautiously when co-administered with buprenorphine/opioids as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).

Selegiline should not be administered with any type of antidepressant.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs)

When selegiline is used at its recommended dose, it selectively inhibits MAO-B. The combined use of the SSRI, fluoxetine and Eldepryl, should only be used under clinical supervision.

Serious reactions with signs and symptoms that may include diaphoresis, flushing, ataxia, 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 two other serotonin reuptake inhibitors, sertraline and paroxetine. There is a potential risk of interaction with fluvoxamine and venlafaxine.

Because of the risk of confusion, hypomania, hallucination and manic episodes, agitation, myoclonus, hyperreflexia, incoordination, shivering, tremor, convulsion, ataxia, diaphoresis, diarrhea, fever, hypertension, which can be part of the serotonine syndrome, concomitant administration of selegiline and SSRIs or SNRIs is contraindicated.

Use of Eldepryl beyond the recommended dose could lead to non-selectivity and serious adverse effects.

Death has been reported to occur following the initiation of therapy with non-selective MAO inhibitors shortly after discontinuation of fluoxetine. Fluoxetine should not be used less than 14 days after discontinuation of selegiline. Since fluoxetine has a very long elimination half-life, at least 5 weeks should be allowed after stopping fluoxetine and before starting selegiline.

Selegiline should not be started until 2 weeks after stopping sertraline. For all other serotonin reuptake inhibitors, a time interval of 1 week is recommended between discontinuation of the serotonin reuptake inhibitor and initiation of selegiline. In general, selegiline should not be introduced after a drug that is known to interact with selegiline, until after 5 half-lives of that drug have elapsed.

At least 14 days should lapse between the discontinuation of selegiline and initiation of treatment with any drug known to interact with selegiline.

A time interval of 24 hours is recommended between the discontinuation of selegiline and initiation of serotonin agonists.

Patients being treated with selegiline currently or within the past 2 weeks should receive dopamine only after careful risk-benefit assessment, as this combination enhances the risk of hypertensive reactions.

Tricyclic antidepressants

Severe CNS toxicity (serotonin syndrome) 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. Therefore, the concomitant use of selegiline and tricyclic antidepressants is contraindicated.

MAO inhibitors

Concomitant administration of selegiline and MAO inhibitors may cause central nervous and cardiovascular system disorders (see section 4.4).

Serotonin agonists

Selegiline should not be used in combination with serotonin agonists (e.g. sumatriptan, naratriptan, zolmitriptan, rizatriptan, lasmiditan) due to the risk of severe interactions (potentially leading to serotonin syndrome).

Associations not recommended

Oral contraceptives

The combination of selegiline and oral contraceptives or drugs for hormone replacement therapy, should be avoided, as this combination may increase the bioavailability of selegiline.

Concomitant administration of amantadine and anticholinergic drugs can lead to an increased occurrence of side-effects.

In view of the high degree of binding to plasma proteins by selegiline particular attention must be given to patients who are being treated with medicines with a narrow therapeutic margin such as digitalis and/or anticoagulants.

Four patients receiving altretamine and a monamine oxidase inhibitor experienced symptomatic hypotension after four to seven days of concomitant therapy.

Concomitant treatment with medicinal products, with a narrow therapeutic index, such as digitalis and/or anticoagulants, requires caution and careful monitoring.

Concomitant use of hypertensive agents, antihypertensives, psychostimulants, central suppressant drugs (sedatives, hypnotics) and alcohol should be avoided.

Food interactions

As selegiline is a specific MAO-B inhibitor, foods containing tyramine have not been reported to induce hypertensive reactions during selegiline treatment at recommended dosage (i.e., it does not cause the so-called “ cheese-effect ”). Therefore, no dietary restrictions are required. However, in case of combination of selegiline and conventional MAO inhibitors or MAO-A, dietary restrictions (i.e. avoidance of food with large amounts of tyramine such as aged cheese and yeast products) are recommended.

4.6. Fertility, pregnancy and lactation

Selegiline is indicated for the treatment of Parkinson's disease which, in most cases, is a disease occurring after childbearing age.

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

Pregnancy

Studies in animals have shown reproductive toxicity only at high multiple of human doses. As a precautionary measure, it is preferable to avoid the use of selegiline in pregnancy.

Breast-feeding

It is unknown whether selegiline is excreted in human breast milk. The excretion of selegiline in milk has not been studied in animals. Physico-chemical data on selegiline point to excretion in breast milk and a risk to the suckling child cannot be excluded. Selegiline should not be used during breast-feeding.

4.7. Effects on ability to drive and use machines

Even when used correctly, this medicine may cause dizziness or can affect reaction capacity to the extent that driving or operating machinery is affected and therefore patients should be advised not to drive or use machines if they experience these adverse reactions during treatment.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8. Undesirable effects

The following undesirable effects have been reported with selegiline during clinical trials and/or post-marketing use. They are listed below as MedDRA preferred term by system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Very common (≥ 1/10); Common (≥ 1/100 to <1/10); Uncommon (≥ 1/1 000 to <1/100); Rare (≥ 1/10 000 to <1/1 000); Very rare (<1/10 000), Not known (cannot be established from the available data).

System Organ Class

Frequency

Undesirable effects

Infections and infestations

Uncommon

Pharyngitis

Blood and lymphatic system disorders

Uncommon

Leucocytopenia, thrombocytopenia

Metabolism and nutrition disorders

Uncommon

Loss of appetite

Psychiatric disorders

Common

Sleeping disorders, confusion, hallucinations, depression

Uncommon

Abnormal dreams, agitation, anxiety, psychoses, mood change

Not known

Impulse control disorders and compulsions*

Nervous system disorders

Common

Abnormal movements (such as dyskinesias, akinesia, bradykinesia), dizziness, headache, impaired balance, tremor

Uncommon

mild transient sleep disorder

Eye disorders

Uncommon

Blurred vision

Ear and labyrinth disorders

Common

Vertigo

Cardiac disorders

Common

Bradycardia

Uncommon

Arrhythmias, palpitations, angina pectoris, supraventricular tachycardia

Vascular disorders

Common

hypotension, hypertension

Uncommon

Orthostatic hypotension

Rare

Postural hypotension

Respiratory, thoracic and mediastinal disorders

Common

Nasal congestion, sore throat

Uncommon

Dyspnoea

Gastrointestinal disorders

Very common

Stomatitis

Common

Nausea, constipation, diarrhoea, mouth ulceration

Uncommon

Dry mouth

Hepato-biliary disorders

Uncommon

Transient rise of serum alanine aminotransferase (ALAT)

Skin and subcutaneous tissue

Common

Sweating increased

Uncommon

Hair loss, skin eruptions

Rare

Skin reactions

Muskuloskeletal and lymphatic system disorders

Common

Arthralgia, back pain, muscle cramps

Uncommon

Myopathy

Renal and urinary disorders

Uncommon

Micturition disorders

Not known

Urinary retention

General disorders and administration site conditions

Common

Fatigue

Uncommon

Chest pain, irritability, ankle oedema

Injury, poisoning and procedural Complications

Common

Fall

Investigations

Common

Mild hepatic enzymes increased

* Parkinson's disease patients treated with dopamine agonists and other dopaminergic treatments have been reported as exhibiting impulse control disorders and compulsions like pathological gambling, increased libido, hypersexuality, binge eating and compulsive eating, compulsive spending or buying/shopping, and different kinds of compulsive/repetitive activities (punding). These may also be possible with selegiline but very few cases have been reported to date.

As selegiline potentiates the effect of levodopa (levodopa should be usually given in association with a peripheral decarboxylase inhibitor), the side-effects of levodopa may be emphasised unless the dosage of levodopa is reduced. Selegiline combination therapy may permit further reduction of levodopa dose (even by 30 %).The most common undesirable effect reported for conventional tablets is dyskinesia (4% of patients) other side effects include restlessness, hyperkinesis, abnormal movements, agitation, confusion, hallucination, postural hypotension, cardiac arrhythmias . Once the optimum levodopa dose level has been established, the side-effects produced by the combination will usually be less than those caused by the levodopa therapy on its own.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Selegiline is rapidly metabolised and the metabolites rapidly excreted. In cases of suspected overdosage the patient should be kept under observation for 24 to 48 hours.

No overdosage cases are known. 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).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 which can progress over 24 hours to include, different central nervous and cardiovascular system disorders. These include agitation, irritability, hyperactivity, drowsiness, tremor, severe headache, hallucination, alternating low and high blood pressure dizziness, faintness, 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 is symptomatic.