Selegiline Hydrochloride Tablets 10 Mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Selegiline Hydrochloride Tablets 10mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 10mg Selegiline hydrochloride.
3 PHARMACEUTICAL FORM
White uncoated tablets
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of Parkinson's disease, or symptomatic Parkinsonism. Selegiline may be used alone in early Parkinson’s disease to delay the need for Levodopa (with or without decarboxylase inhibitor). Selegiline may also be used as an adjunct to Levodopa (with or without decarboxylase inhibitor).
4.2 Posology and method of administration
Adults including elderly: 10mg 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 taken at breakfast and lunch. When Selegiline is added to a levodopa regimen, it may be possible to reduce the Levodopa dosage by an average of 30%.
Method of Administration For oral administration.
Special Populations
Hepatic impairment
No data are known on dose adjustment in patients with mild hepatic impairment
Renal impairment
No data are known on dose adjustment in patients with mild renal impairment
4.3. Contra-indications
Hypersensitivity to Selegiline and/or any other excipients.
Selegiline should not be used in combination with selective serotonin reuptake inhibitors (SSRI), serotonin noradrenaline reuptake inhibitor (SNRI) (venlafaxine), tricyclic antidepressants, sympathomimetics, monoamine oxidase inhibitors (e.g. linezolide), and opioids (pethidine )(see section 4.5).
Selegiline should not be used in patients with active duodenal or gastric ulcer.
When selegiline is prescribed in combination with levodopa, the contraindications which apply to levodopa must be taken into account.
4.4. Special Warnings and Precautions for Use
Since the selegiline potentiates the effect of levodopa, the side effects of levodopa may be more pronounced, especially if patients are receiving levodopa therapy with high doses. These patients should be monitored. The addition of selegiline to levodopa therapy may cause creation of involuntary movements and/or agitation. These undesirable effects disappear after levodopa doses reduction. Dosage of levodopa could be reduced to about 30 % in combination with selegiline.
If selegiline is administered at dose higher than recommended one (10 mg), selegiline may lose its MAO-B selectivity and therefore the risk of hypertension is rising up.
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.
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.
4.5. Interactions with other Medicaments and other forms of Interaction
Because Selegiline potentiates the effects of Levodopa the side effects of Levodopa might be emphasised, particularly when the patient is on a very high dosage of Levodopa. The addition of Selegiline to maximal doses of Levodopa may cause involuntary movement and/or agitation. Such side effects disappear when the Levodopa dosage is decreased. Concurrent Levodopa treatment may need to be reduced by 30% when Selegiline is added to the treatment. When an optimal Levodopa dose has been established, the side effects of the combination have found to be fewer than for Levodopa alone.
Association contra-indicated (see section 4.3)
Sympathomimetics
Because of the risk of hypertension, co-administration of selegiline and sympathomimetics is contraindicated.
Pethidine
The concomitant administration of the selective MAO-B inhibitor selegiline and pethidine is contraindicated as serious and potentially fatal interactions between these drugs including CNS excitation or depression, myoclonus, rigidity, hyperthermia, hypotension or hypertension have been reported.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs)
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.
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.
Tricyclic antidepressants
Severe central nervous system toxicity (serotonin syndrome), sometimes associated with hypertension, hypotension, diaphoresis has been occasionally reported in patients with the combination of tricyclic antidepressants and selegiline. Therefore, the concomitant use of selegiline and tricyclic antidepressants is contraindicated
Concomitant use with moclobemide should be avoided.
MAO inhibitors
Concomitant administration of selegiline and MAO inhibitors may cause severe hypotension (see section 4.4).
Associations not recommended
Oral contraceptives
The combination of selegiline and oral contraceptives should be avoided, as this combination may increase the bioavailability of selegiline.
Concomitant treatment with medicinal products, with a narrow therapeutic index such as digitalis and/or anticoagulants, requires caution and careful monitoring.
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
Very limited data on pregnant patients are available.
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.
It is unknown whether selegiline is excreted in human breast milk. The excretion of selegiline in milk has not been studied in animals. Physicochemical 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
As selegiline may cause dizziness, patients should be advised not to drive or use machines if they experience this adverse reaction 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 an offence (called ‘statutory defence’) if:
- The medicine has been prescribed to treat a medical or dental problem and
- You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
- It was not affecting your ability to drive safely
4.8 Undesirable effects
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).
Psychiatric disorders Uncommon: mood change.
Not known: hypersexuality, depression, confusion, psychosis, agitation,
Nervous system disorders Common: dizziness, headache.
Uncommon: mild transient sleep disorder Not known: tremor, vertigo
Cardiac disorders
Common: bradycardia
Uncommon: supraventricular tachycardia
Vascular disorders Rare: postural hypotension Not known: hypotension,
Gastro intestinal disorders Common: nausea.
Uncommon: dry mouth
Not known: constipation, diarrhoea, vomiting, stomatitis, sore throat
Skin and subcutaneous tissue disorders Rare: skin reactions.
Musculoskeletal and connective tissue disorders Not known: back pain, muscle cramps, joint pain,
Renal and urinary disorders
Not known: urinary retention, difficulty in micturition,
Investigations
Common: mild hepatic enzymes increased.
In combination with levodopa
Since selegiline potentiates the effect of levodopa, side effects of levodopa (restlessness, hyperkinesis, abnormal movements, agitation, confusion, hallucination, postural hypotension, cardiac arrhythmias) may be enhanced in combined therapy (levodopa should be usually given in association with a peripheral decarboxylase inhibitor). Selegiline combination therapy may permit further reduction of levodopa dose (even by 30 %).
4.9 Overdose
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 non-selective MAO-inhibitor (central nervous and cardiovascular system disorders). Symptoms of non selective MAO inhibitors overdosage can progress over 24 hours to include agitation, tremor, alternating low and high blood pressure, respiratory depression ,severe muscle spasms, hyperpyrexia, coma and convulsions. There is no specific antidote and the treatment should be symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Selegiline is a selective MAO-B inhibitor which prevents dopamine breakdown in the brain. It also inhibits the re-uptake 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 or endogenous dopamine.
Selegiline is a highly potent, selective irreversible inhibitor of the monoamine oxidase type B enzyme. It inhibits the uptake of tyramine, noradrenaline and dopamine into the catecholaminergic nerve endings, an effect which is reversible and independent of MAO-B inhibition.
It also increases the turnover rate of dopamine and facilitates the release of dopamine in the rat striatum, with no substantial effect on the postsynaptic dopaminergic receptor.
Selegiline prevents the neurotoxic effect of 6-hydroxydopamine on the striatum and prevents the selective neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) (causing parkinsonism in man and parkinson-like symptoms in animals) on the nigrostriatal dopaminergic system. It also enhances superoxide dismutase activity in the striatum, an effect independent of MAO-B inhibition.
5.2 Pharmacokinetic properties
Selegiline is rapidly absorbed from the gastrointestinal tract and crosses the blood-brain barrier. It is metabolised to methylamphetamine and amphetamine which are excreted in the urine.
5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Also contains magnesium stearate, mannitol, E460, E553.
6.2 Incompatibilities
None known
6.3 Shelf life
Two years from the date of manufacture.
Shelf-life after dilution/reconstitution Not applicable.
Shelf-life after first opening Not applicable.
6.4 Special precautions for storage
Store below 25°C in a dry place.
Protect from light.
6.5 Nature and contents of container
The product may be supplied in blister packs in cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250pm white rigid PVC.
(ii) Surface printed 20pm hard temper aluminium foil with 5-6g/m2 PVC and PVdC compatible heat seal lacquer on the reverse side.
Pack sizes: 28s, 30s, 56s, 60s, 84s, 100s, 112s.
6.6 Special precautions for disposal
None stated
7 MARKETING AUTHORISATION HOLDER
Actavis UK Limited
(Trading style: Actavis)
Whiddon Valley BARNSTAPLE N Devon EX32 8NS
8 MARKETING AUTHORISATION NUMBER(S)
PL 00142/0366
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
8 November 1995 / 11 October 2000
10 DATE OF REVISION OF THE TEXT
15/04/2014