SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

Selegiline hydrochloride 5mg Tablets

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 Parkinsons disease and symptomatic
parkinsonism. It may be used alone, in early parkinsons 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 parkinsons 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 patients 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:

4.8

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.

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
14

C-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.

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 25C. 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.

MARKETING AUTHORISATION HOLDER

ratiopharm GmbH
Graf-Arco-Str. 3
89079 Ulm
Germany

8.

Marketing Authorisation Number

PL 15773/0063

DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION
16/10/2005

10

DATE OF REVISION OF THE TEXT

24/09/2014