Selegiline Hydrochloride Tablets 5 Mg
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Selegiline Hydrochloride Tablets 5mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Selegiline Hydrochloride HSE 5mg
3 PHARMACEUTICAL FORM
Tablet
A white, round shaped tablets, embossed "SEL5" on one side and break line on the other side
The score line is not intended for breaking the tablet
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Selegiline is indicated for the treatment of Parkinson's disease or symptomatic Parkinsonism which is being treated with levodopa alone or levodopa and peripheral decarboxylase inhibitor.
Selegiline, in conjunction with levodopa treatment, is particularly indicated in patients during maximal levodopa treatment who develop on/off symptoms or other dyskinesias.
4.2 Posology and method of administration Dosage (dose and interval) and duration
When used as an adjunct to established Levodopa therapy, the initial dose of Selegiline is 5mg in the morning.
If symptoms are very severe e.g. on/off symptoms and little response is achieved with 5mg Selegiline daily, the dose of Selegiline can be increased to 10mg in the morning.
Dosage adjustment in renal or liver insufficiency, dialysis, concomitant disease
No dosage adjustment is indicated
Maximum tolerated daily dose and the maximum dose for an entire course of therapy
The maximum recommended daily dose is 10mg, although no problems have been reported with overdosage (due to the low toxicity of Selegiline hydrochloride).
Monitoring advice
No special monitoring required.
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
Selegiline is contra-indicated
• In patients with known hypersensitivity (including severe dizziness or hypotension) to selegiline or any of the excipients used in this product.
• In patients receiving treatment with serotonin-agonists (e.g. sumatriptan, naratriptan, zolmitriptan and rizatriptan).
• for concomitant use with pethidine and other opioids (see section 4.5).
• in patients who are being treated with antidepressant drugs including MAO inhibitors tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI) (e.g citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)and serotonin noradrenalin reuptake inhibitor (venlafaxine) and sympathomimetics,(See section 4.5 interactions).
• with other drugs which are also monoamine oxidase inhibitors, e.g. linezolid.
• 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 active duodenal or gastric ulcer.
• Selegiline should not be used in patients with other extrapyramidal disorders not related to dopamine deficiency.
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.
Selegiline should be administered cautiously to patients with history of or who have peptic or duodenal ulceration, labile hypertension, cardiac arrhythmias, severe angina pectoris, or psychosis 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.
In higher doses (higher than recommended one ,10 mg) the selectivity of selegiline begins to diminish resulting in loss of its MAO-B selectivity and increased inhibition of MAO-A. Thus in higher doses there is a risk of hypertension.
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 maximum tolerated dose of 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. 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.
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.
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.
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 Interaction with other medicinal products and other forms of interaction
Sympathomimetics
Because of the risk of hypertension, co-administration of selegiline and sympathomimetics is contraindicated.
Selegiline should not be administered with any type of antidepressant.
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. The concomitant administration of the selective MAO-B inhibitor selegiline and pethidine is contraindicated. (see contra-indications).
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.
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.
Therefore, the concomitant use of selegiline and tricyclic antidepressants is contraindicated.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenalin reuptake inhibitors (SNRIs)
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.
Serious reactions with signs and symptoms that may include diaphoresis, flushing, ataxia, tremor, 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 selegiline 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 nonselective MAO inhibitors shortly after discontinuation of fluoxetine. Fluoxetine
should not be used less than 14 days after discontinuation of selegiline. Since fluoxetine and its active metabolite have long half-lives; therefore MAO inhibitor therapy should not be started until at least 5 weeks should be allowed after stopping/discontinuation of 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.
Selegiline should not be given in conjunction with non-specific MAO inhibitors, e.g. linezolid.
Associations not recommended
MAO inhibitors
Concomitant administration of selegiline and MAO inhibitors may cause severe hypotension (see section 4.4).
Oral contraceptives
The combination of selegiline and oral contraceptives or drugs for hormone replacement therapy, should be avoided, as this combination may multiply the bioavailability of selegiline.
In view of the high degree of binding to plasma proteins by selegiline particular attention must be given to patients who are being concomitantly treated with medicines with a narrow therapeutic margin/index such as digitalis and/or anticoagulants, requires caution and careful monitoring.
Concomitant use of nasal decongestants, hypertensive agents, antihypertensives, psychostimulants, central suppressant drugs (sedatives, hypnotics) and alcohol should be avoided.
Concomitant administration of amantadine and anticholinergic drugs can lead to an increased occurrence of side-effects.
Four patients receiving altretamine and a monamine oxidase inhibitor experienced symptomatic hypotension after four to seven days of concomitant therapy.
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.
Very limited data on pregnant patients are available.
The available safety data concerning the use during pregnancy and lactation is insufficient to justify the use of selegiline in these patient groups.
Studies in animals have shown reproductive toxicity at only 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. 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
As even when used correctly, this medicine selegiline 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 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:
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
In monotherapy, selegiline has been found to be well tolerated. Dry mouth, transient rise of serum alanine aminotransferase (ALAT) values and sleeping disorders have been reported more frequently than in patients receiving placebo. Because selegiline potentiates the effects of levodopa, the adverse reactions/ side-effects of levodopa, e.g. restlessness, hyperkinesis, abnormal movements (such as dyskinesias), nausea, agitation, confusion, hallucinations, headache, postural hypotension, cardiac arrhythmias and vertigo, may be enhanced in combination therapy (levodopa should be given in association with a peripheral decarboxylase inhibitor), particularly if the dose of levodopa is too high. Such adverse reactions usually disappear when the levodopa dosage is decreased. Levodopa dosage can be reduced by an average of 30% when selegiline is added to the treatment. 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.
Micturition difficulties and skin reactions have also been reported during selegiline treatment. Follow-up of these possible adverse reactions is important.
Hypersexuality has been very rarely reported in association with selegiline use, either as monotherapy or in combination with other dopaminergic antiparkinsonian medication.
A summary of the undesirable effects in terms of frequency of occurrence is shown below.
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 |
Mood change. | |
|
Not known |
Hypersexuality | |
|
Nervous system disorders |
Common |
Abnormal movements (such as dyskinesias akinesia, bradykinesia), vertigo, dizziness , headache, impaired balance, tremor |
|
Uncommon |
Mild transient sleep disorder | |
|
Eye disorders |
Uncommon |
Blurred vision |
|
Cardiac disorders |
Common |
Bradycardia |
|
Uncommon |
Supraventricular tachycardia | |
|
Rare |
Cardiac arrhythmia, Palpitations, angina pectoris | |
|
Common |
hypotension, hypertension | |
|
Vascular disorders |
Uncommon |
Orthostatic hypotension |
|
Rare |
Postural hypotension | |
|
Respiratory, thoracic and mediastinal disorders |
Common |
Nasal congestion, sore throat |
|
Uncommon |
Dyspnoea | |
|
Very common |
Stomatitis | |
|
Gastrointestinal disorders |
Common |
Nausea, constipation, diarrhoea, mouth ulceration |
|
Uncommon |
Dry mouth | |
|
Hepato-biliary disorders |
Common |
Transient rise of serum alanine aminotransferase (ALAT) |
|
Common |
Sweating increased | |
|
Skin and subcutaneous tissue |
Uncommon |
Hair loss, skin eruptions |
|
Rare |
Skin reactions | |
|
Muskuloskeletal and lymphatic system disorders |
Common |
Arthralgia, back pain, muscle cramps |
|
Uncommon |
Myopathy | |
|
Rare /Uncommon |
Micturition difficulties | |
|
Renal and urinary 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. Transient rise of serum alanine aminotransferase (ALAT) |
4.9 Overdose
No over dosage problems have been reported, due to the low toxicity of Selegiline hydrochloride and its rapid metabolism to, and excretion of, the metabolites. If overdosage is suspected, the patient should be monitored for 24-48 hours.
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.
Overdoses have no specific clinical picture. 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), therefore the overdosage causes significant inhibition of both MAO-A and MAO-B. The symptoms of overdosage may resemble those observed with non-selective MAO-inhibitors which can progress over 24 hours to include, such as different central nervous and cardiovascular system disorders (e.g. drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucination, tremor, alternating hypertension and hypotension, 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group
Selective monoamine oxidase type B (MAO-B) inhibitor Mechanism of action (if known)
Selegiline hydrochloride inhibits the MAO-B induced metabolism of dopamine in the brain, and inhibits re-uptake at the pre-synaptic dopamine receptor.
Pharmacodynamic effects
Selegiline administration has been associated with isolated reports of hypotension and nausea. Confusion or psychosis have also been reported.
5.2 Pharmacokinetic properties
a) General characteristics of the active substance Absorption
Selegiline hydrochloride is rapidly (t'A of absorption 0.39hours) and completely absorbed from the gastro-intestinal tract and crosses the blood-brain barrier. Food does not appear to affect the bioavailability of the drug. Peak plasma concentrations (37-45pg/l) are achieved between 0.5 and 2.0 hours post-dose.
Distribution
The drug is rapidly distributed throughout the body and highly bound (94%) to plasma proteins. Selegiline hydrochloride crosses the blood-brain barrier.
Biotransformation, to active metabolites, inactive metabolites and in the case of prodrugs, to the active substance
Selegiline hydrochloride is extensively metabolised, most probably in the liver, to the l-amphetamine, l-methylamphetamine and desmethylselegiline derivatives. The biological half-life of the drug and metabolites is 39 hours and the plasma clearance is 1.7ml/min/kg.
Elimination
An average of 52% of the dose is excreted in the urine in 24 hours and 73% in 72 hours, mostly as the metabolites methylamphetamine and amphetamine. Only 15% is excreted in faeces.
b) Characteristics in patients
As above
Preclinical safety data
5.3
See 4.6 a) above. Selegiline has not been sufficiently tested for reproductive toxicity. Studies with selegiline revealed no evidence of mutagenic or carcinogenic effects. The only safety concerns for human use derived from animal studies were effects associated with an exaggerated pharmacological action.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose BP Maize Starch BP Povidone K-30 BP Citric Acid Monohydrate BP Purified Water BP Magnesium Stearate BP
6.2 Incompatibilities
None known
6.3 Shelf life
Shelf life of the product as packaged for sale 2 years
Shelf life after dilution or reconstitution according to directions
Not applicable
Shelf life after first opening the container
Not applicable
6.4 Special precautions for storage
Store in a dry place, below 25°C, protected from light.
6.5 Nature and contents of container
Tablets are packed in either HDPE (tubular) tablet containers with HDPE caps and tamper-evident tear strip (7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112 & 120 tablets)
Or
In strips (Aluminium lidding foil and polyamide/Aluminium/PVC base), or PVdC coated PVC/Aluminium blisters (60g/m2 PVdC on 250pm PVC/20pm Al) containing 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112 & 120 tablets.
6.6 Special precautions for disposal
No special instructions
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Limited
3 Howard Road
Eaton Socon
St Neots
Cambridgeshire
PE19 8ET
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0381
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/09/1995 / 25/03/2009
10 DATE OF REVISION OF THE TEXT
20/03/2014