- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Posology10 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 administrationSelegiline may be administered either as a single dose in the morning or in two divided doses of 5 mg, taken at breakfast and lunch.
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.
SympathomimeticsBecause of the risk of hypertension, co-administration of selegiline and sympathomimetics is contraindicated.
Pethidine and other opioidsThe concomitant administration of the selective MAO-B inhibitor selegiline and pethidine and other opioids is contraindicated.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 antidepressantsSevere 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 inhibitorsConcomitant administration of selegiline and MAO inhibitors may cause central nervous and cardiovascular system disorders (see section 4.4).
Associations not recommended
Oral contraceptivesThe 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 interactionsAs 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.
PregnancyStudies 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-feedingIt 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.
|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|
|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|
|Uncommon||Arrhythmias, palpitations, angina pectoris, supraventricular tachycardia|
|Vascular disorders||Common||hypotension, hypertension|
|Respiratory, thoracic and mediastinal disorders||Common||Nasal congestion, sore throat|
|Gastrointestinal disorders||Very common||Stomatitis|
|Common||Nausea, constipation, diarrhoea, mouth ulceration|
|Hepato-biliary disordrers||Uncommon||Transient rise of serum alanine aminotransferase (ALAT)|
|Skin and subcutaneous tissue||Common||Sweating increased|
|Uncommon||Hair loss, skin eruptions|
|Muskuloskeletal and lymphatic system disorders||Common||Arthralgia, back pain, muscle cramps|
|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|
Reporting of suspected adverse reactionsReporting 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.
AbsorptionSelegiline HCl is readily absorbed from the gastrointestinal tract. The maximal concentrations are reached in 0.5-0.75h after oral administration in fasting state. 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.
DistributionSelegiline is rapidly distributed throughout the body, the apparent volume of distribution being 500 1 after an intravenous 10 mg dose. 75-85% of selegiline is bound to plasma proteins at therapeutic concentrations. Selegiline HCl inhibits enzyme MAO-B irreversibly and enzyme activity only increases again after new enzyme is synthesised. The strong inhibitory effect 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
BiotransformationSelegiline is rapidly metabolised, mainly in the liver, into active metabolites desmethylselegiline, l-methamphetamine and to l-amphetamine, with elimination half-lives of 2.1h, 20.5 h and 17.7 h respectively. 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.Selegiline AUC and desmethylselegiline AUC increase 2.7 fold and 1.5 fold respectively from day 1 to day 8 on dosing 10 mg od. However, the half-lives of selegiline (range, 1.5-3.5 h) and desmethylselegiline (range, 3.4 5.3 h) were found to be relatively short. Accordingly, the short half-lives of these compounds failed to predict the apparent accumulation.The most likely explanation for the significant increase in selegiline and desmethylselegiline concentrations in serum which was observed during the 8-day multiple dose administration of selegiline HCl is saturation of MAO-B binding sties in tissues, as the rapid elimination of both selegiline and desmethyl selegiline cannot explain the apparent accumulation observed. However, decrease in the first-pass metabolism of selegiline on multiple dosing cannot be ruled out.
EliminationIn 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 h for selegiline. The total body clearance of selegiline is about 240 I/h. The metabolites of selegiline are excreted mainly via the urine with about 15% occurring in the faeces.
Orion Pharma (UK) Limited
Oaklea Court, 22 Park Street, Newbury, Berkshire, RG14 1EA
+44 (0)1635 580 180
+44 (0)1635 520 300
+44 (0)1635 520 300