Selegiline Hydrochloride 5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Selegiline hydrochloride 5mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg of selegiline hydrochloride.
3. Pharmaceutical Form Tablets
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Selegiline is indicated for the treatment of Parkinson’s disease and symptomatic parkinsonism. It may be used alone, in early parkinson’s disease to delay the need for levodopa, or as an adjunct to levodopa.
4.2 Posology and method of administration
10 mg 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 of 5 mg, taken at breakfast and lunch.
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 Contraindications
Known hypersensitivity to selegiline hydrochloride or any of the excipients.
Selegiline should not be used in combination with selective serotonin reuptake inhibitors (SSRIs) (e.g. citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin noradrenaline reuptake inhibitors (e.g. venlafaxine), tricyclic antidepressants, sympathomimetics, monoamine oxidase inhibitors (e.g. linezolid), and opioids (e.g. pethidine) (see section 4.5).
Selegiline is contra-indicated in patients receiving treatment with serotonin-agonists (e.g. sumatriptan, naratriptan, zolmitriptan and rizatriptan).
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.
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.
Selegiline should not be used in patients with other extrapyramidal disorders not related to dopamine deficiency.
4.4 Special warnings and precautions for use
Since selegiline potentiates the effects of levodopa, the adverse effects of levodopa may be increased, especially if patients are receiving levodopa therapy with high doses. When selegiline is added to the maximum tolerated dose of levodopa, involuntary movements and agitation may occur. These patients should be monitored. These undesirable effects disappear after levodopa doses reduction. Dosage of levodopa could be reduced to about 30% in combination with selegiline (see section 4.2). When an optimum dose of levodopa is reached, adverse effects from the combination are less than those observed with levodopa on its own.
This medicinal product contains lactose, patients with the rare hereditary problem of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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.
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.
The selectivity for MAO-B following administration of conventional selegiline tablets may be diminished with doses above 10mg/day and therefore the risk of hypertension is rising up. A nonselective dose of selegiline above 10mg/day has not been determined. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO has not been determined, but with doses higher than 10mg/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.
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.
Although conventional tablets of selegiline, at doses of 5 to 10mg/day, have been in widespread use for many years, the full spectrum of possible responses to selegiline may not have been observed to date. Therefore patients should be observed closely for atypical responses.
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
Interactions between non-selective MAO-inhibitors and pethidine as well as selegiline and pethidine have been described. The mechanism of this interaction is not fully understood and therefore, the concomitant administration of the selective MAO-B inhibitor selegiline and pethidine is contraindicated.
Selegiline should not be administered with any type of antidepressants.
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, diarrhoea, fever, hypertension, which can be part of the serotonin 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. When selegiline is used at its recommended dose, it selectively inhibits MAO-B. The combined use of the SSRI, fluoxetine and selegiline, should only be used under clinical supervision. Use of selegiline beyond the recommended dose could lead to non-selectivity and serious adverse effects.
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.
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 dizziness, tremor, seizures and changes in behavioural and mental status.
MAO inhibitors
Concomitant administration of selegiline and MAO inhibitors may cause central nervous and cardiovascular system disorders (see section 4.4).
Associations not recommended
Selegiline should not be given in conjunction with non-specific MAO inhibitors, e.g. linezolid.
Oral contraceptives
The combination of selegiline and oral contraceptives should be avoided, as this combination may increase the bioavailability of selegiline.
Concomitant use of nasal decongestants, hypertensive agents, antihypertensives, psychostimulants, central suppressant drugs (sedatives, hypnotics) and alcohol should be avoided.
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.
A time interval of 24 hours is recommended between the discontinuation of selegiline and initiation of serotonin agonist.
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.
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.
4.6 Fertility, pregnancy and lactation
Pregnancy: Selegiline hydrochloride is indicated for parkinson’s disease. This tends to be a disease of the elderly, past child bearing age. Very limited data on pregnant patients are available. Clinical data on exposed pregnancy are not available. Studies in animals have shown reproductive toxicity only at high multiple of human doses. Therefore, as a precautionary measure, it is preferable to avoid use of selegiline during the entire pregnancy.
Lactation: 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. Due to the potential harmful effect on the nursing infant, selegiline should not be used during breast-feeding.
4.7 Effects on ability to drive and use machines
Even when used as directed, this drug may cause dizziness and alter the ability to react to such an extent as to impair the ability to drive, operate machinery or work in unsteady places. This applies to a greater extent at the start of treatment and when switching to another preparation, as well as in combination with alcohol. 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).
Nervous system disorders Common: dizziness, headache Uncommon: mild transient sleep disorder Not known: vertigo, insomnia, tiredness, syncope
Gastro intestinal disorders Common: nausea, dry mouth
Not known: diarrhoea, loss of appetite, other gastrointestinal disorders
Renal and urinary disorders
Not known: urinary retention, micturition disorders
Skin and subcutaneous tissue disorders Rare: skin reactions.
Not known: hair loss
Cardiac disorders
Common: bradycardia
Uncommon: supraventricular tachycardia
Not known: chest pain, arrythmias, angina pectoris, palpitations
Vascular disorders Common: hypotension Rare: postural hypotension Not known: hypertension
Investigations
Common: transient transaminase increase (ALAT), mild hepatic enzymes increased Psychiatric disorders
Common: confusion, hallucination, psychoses Uncommon: mood change.
Not known: hypersexuality, depression, agitation, anxiety, irritability
Eye disorders:
Not known: blurred vision
General disorders and administrative site conditions:
Not known: ankle oedema, excessive perspiration, loss of balance
Musculoskeletal and connective tissue disorders Very common: hyperkinesia Not known: myopathy
Respiratory, thoracic and mediastinal disorders Not known: dyspnoea
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, and insomnia) 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%). Once the optimum levodopa dose level has been established, the side-effects produced by this combination will usually be less than those caused by the levodopa therapy on its own.
4.9 Overdose
No cases of overdosage are known. Selegiline is rapidly metabolized and the metabolite rapidly excreted. In cases of suspected overdosage the patient should be kept under observation for 24-48 hours.
However, experience gained during the development of selegiline containing drug formulations reveals that some individuals exposed to doses of 600 mg/day selegiline suffered severe hypotension and psychomotor agitation.
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 inhibitor overdosage can progress over 24 hours (e.g. drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucination, alternating hypertension (sometimes with sub-arachnoid haemorrhage), hypotension, vascular collapse, rapid and irregular pulse, precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, ataxia, tremor, convulsions, hypomania, psychosis, euphoria, coma, severe muscle spasms and extrapyramidal symptoms).
There is no specific antidote and treatment should be symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group:
Monoamine-oxidase (MAO) inhibitor, type B Antiparkinsonian agent ATC-CODE: N04B D01
Selegiline is a selective monoamine oxidase-B (MAO-B) inhibitor which prevents dopamine breakdown in the brain. The inhibitory effect of a single 10 mg dose lasts for 24 hours. It also inhibits the re-uptake of dopamine at the pre-synaptic 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 patients with early phase parkinsonism showed that patients receiving selegiline monotherapy manage significantly longer without levodopa therapy than controls on 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 non-selective MAO-inhibitors.
5.2. Pharmacokinetic Properties
Absorption
Selegiline is a lipophilic substance and is absorbed rapidly from the intestinal tract in humans. Maximum serum concentrations of selegiline and its metabolites are achieved 0.5 - 2 h after oral administration.
Distribution
When administered at therapeutic doses, 94 % of selegiline is bound to plasma proteins. Its volume of distribution is up to 300 l. Selegiline and its metabolites cross the blood-brain barrier.
Metabolism
Selegiline is metabolized mainly in the liver. It undergoes a marked first-pass effect. In humans, 3 main metabolites have been identified in the plasma, cerebrospinal fluid and in the urine (demethylselegiline, L-methamphetamine and L-amphetamine). The stereo-isomeric configuration is not altered by metabolism. No in vivo racemisation could be demonstrated.
Excretion
14C-selegiline has a plasma clearance of 1.7 ml/min/kg. Total clearance of selegiline in humans is 500 l/h (median value). Native selegiline was not demonstrated in the urine. The metabolites are predominantly (70 - 85 %) excreted with the urine, a small proportion being excreted with the faeces. The 24-h recovery rate is between 30 and 90 %. Excretion of L-methamphetamine and L-amphetamine increases with increasing urine acidity, without affecting the clinical response.
5.3. Preclinical Safety Data
The acute toxic range for rats, mice and dogs is approximately 800-3000 times that of the recommended therapeutic dose of conventional tablets of selegiline (5-10mg/day). The corresponding therapeutic margin from subchronic and chronic toxicity studies is 20-40 times, with only the reactions being attributable to the pharmacological effect, i.e. no organ-toxic effects being detected. There is no evidence of mutagenic, or teratogenic effects or changes
influencing fertility or reproduction with non-toxic doses. After long-term administration, no accumulation reactions and no morphological signs of progressive organ alterations were observed.
Studies have not been performed to date to evaluate the carcinogenic potential of selegiline, but chronic human use of conventional selegiline appears to have given no cause for concern in this respect.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate, microcrystalline cellulose, maize starch, povidone, stearic acid.
6.2. Incompatibilities
Not applicable
6.3. Shelf Life
5 years.
6.4. Special Precautions for Storage
Do not store above 25°C. Store in the original package.
6.5. Nature and Contents of Container
Blister strips consisting of transparent PVC/PVdC foil and aluminum foil. Blister packs of 30, 50, 60 or 100 tablets.
6.6. Instruction for Use/Handling
None.
7 MARKETING AUTHORISATION HOLDER
ratiopharm GmbH Graf-Arco-Str. 3 89079 Ulm Germany
8. Marketing Authorisation Number
PL 15773/0063
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
16/10/2005
10 DATE OF REVISION OF THE TEXT
24/09/2014