SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Zelapar 1.25 mg Oral Lyophilisate.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Zelapar Oral Lyophilisate contains 1.25 mg of selegiline hydrochloride, equivalent to 1.05 mg selegiline free base.

Each tablet contains 1.25mg of aspartame (source of Phenylalanine)

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Oral lyophilisate.

A pale yellow round tablet with the letter A on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adjunctive therapy in combination with levodopa (with a peripheral decarboxylase inhibitor) in the treatment of Parkinson's disease. Zelapar in combination with maximal levodopa therapy is indicated particularly in patients who experience fluctuations in their condition such as 'end-dose' type fluctuations, 'on-off' symptoms or other dyskinesias.

Zelapar may be used alone in early Parkinson's disease for symptomatic relief and/or to delay the need for levodopa.

4.2 Posology and method of administration

Posology

When prescribed as monotherapy for the first time in the early stage of

Parkinson's disease or as an adjuvant to levodopa, the dose of Zelapar is one 1.25 mg

unit.

When Zelapar adjunctive therapy is prescribed a reduction (10 to 30%) in the dose of levodopa is usually required. Reduction of the levodopa dose should be gradual in steps of 10% every 3 to 4 days.

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. Method of administration

The unit should be placed on the tongue in the morning, at least five minutes before breakfast and allowed to dissolve.

The unit will dissolve rapidly (in less than 10 seconds) in the mouth. The patient should not eat, drink, rinse or wash-out out their mouth for five minutes after taking their medicine to enable selegiline to be absorbed pre-gastrically.

Do not push the Zelapar tablet through the foil blister. Peel back the foil and carefully remove the unit.

Unused tablets must be disposed of after three months of a sachet opening.

4.3 Contraindications

Hypersentitivity to the active substance or to any of the excipients.

Patients receiving treatment with serotonin-agonists (e.g. sumatriptan, naratriptan, zolmitriptan and rizatriptan).

Patients with phenylketonuria due to the content of aspartame, a source of phenylalanine.

Concomitant use with pethidine and other opioids.

Patients with other extrapyramidal disorders not related to dopamine deficiency. Patients with active duodenal or gastric ulcer.

Patients who are being treated with antidepressant drugs, including tricyclic antidepressants, MAO inhibitors and selective serotonin reuptake inhibitors (SSRIs), e.g citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and serotonin noradrenaline reuptake inhibitors (SNR) (e.g.venlafaxine). See section 4.5 interactions.

Concomitant use with sympathomimetics or monoamine oxidase inhibitors, e.g. linezolid.

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.

The contraindications which apply to levodopa must be taken into account.

4.4 Special warnings and precautions for use

One unit of Zelapar contains 1.25 mg selegiline. It is recommended that patients be warned that the correct dose of Zelapar is one oral lyophilisate.

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.

Patients with hepatic or renal dysfunction

Selegiline should be used with caution in severe hepatic or renal 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.

Patients taking other MAO inhibitors

The selectivity for MAO-B following administration of conventional selegiline tablets may be diminished with doses above 10 mg/day. A non-selective dose of Zelapar above 10 mg/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 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.

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).

Patients taking levodopa

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.

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. These patients should be monitored. When selegiline is added to the maximum tolerated dose of levodopa, involuntary movements and agitation may occur. These undesirable effects disappear after levodopa doses reduction. 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.

The addition of selegiline to levodopa may not be beneficial in those patients who experience fluctuations in response which are not dose dependent.

Doping screening tests

The use of selegiline may produce a positive result in doping screening tests.

Other

Mouth ulcers may occur during treatment with Zelapar 1.25 mg oral lyophilisate.

Although conventional tablets of selegiline, at doses of 5 to 10 mg/day, have been in widespread use for many years, the full spectrum of possible responses to Zelapar 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 Concomitant use contraindicated (see section 4.3)

Serotonin agonists

Patients receiving treatment with serotonin-agonists (e.g. sumatriptan, naratriptan, zolmitriptan and rizatriptan).

Antidepressants

Selegiline should not be administered with any type of antidepressant.

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 serotonin syndrome, concomitant administration of selegiline and SSRIs or SNRIs is contraindicated.

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.

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.

Tricyclic antidepressants

Severe CNS toxicity 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.

MAO inhibitors

Selegiline should not be given in conjunction with non-specific MAO inhibitors, e.g. linezolid.

Concomitant administration of selegiline and MAO inhibitors may cause central nervous and cardiovascular system disorders (see section 4.4).

Four patients receiving altretamine and a monamine oxidase inhibitor experienced symptomatic hypotension after four to seven days of concomitant therapy.

Sympathomimetics

Because of the risk of hypertension, co-administration of selegiline and sympathomimetics, including nasal decongestants 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, use of pethidine concomitantly with selegiline should be avoided (see section 4.3).

Concomitant use not recommended

Dopamine

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.

Oral contraceptives or drugs for hormone replacement therapy The 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.

Concomitant use of hypertensive or anti-hypertensive agents, psychostimulants, central suppressant drugs (sedatives, hypnotics) and alcohol should be avoided.

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.

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. Selegiline should not be used by mothers when breastfeeding as information is lacking concerning whether selegiline passes into breast milk.

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.

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 breastfeeding.

4.7 Effects on ability to drive and use machines

Zelapar has major influence (e.g may cause dizziness) on the ability to drive and use machines, therefore patients should avoid these activities.

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

The undesirable effects are listed below as MedDRA preferred term by system organ class and frequency. Frequencies are defined as: undesirable effects very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>

1/10,000 to <1/1,000), not known (cannot be established from the available data).

The following undesirable effects have been reported with Zelapar during clinical trials and/or post-marketing use.

System Organ Class	Frequency	Undesirable effects
Psychiatric disorders	common	confusion, depression, hallucinations, insomnia,
	uncommon	abnormal dreams, agitation, anxiety, psychoses
Nervous system disorders	common	dizziness, dyskinesia (including akinesia, bradykinesia), headache, impaired balance, tremor,
Ear and labyrinth disorders	common	vertigo
Cardiac disorders	uncommon	angina pectoris
Vascular disorders	common	hypertension, hypotension
Respiratory, thoracic and mediastinal disorders	common	nasal congestion, sore throat
	uncommon	dyspnoea
Gastrointestinal disorders	very common	stomatitis
	common	constipation, diarrhoea, dry mouth, mouth ulceration, nausea
Skin and subcutaneous tissue disorders	common	sweating increased
Musculoskeletal and connective tissue disorders	common	arthralgia, back pain, muscle cramps
General disorders and administration site conditions	common	fatigue
	uncommon	chest pain, irritability
Injury, poisoning and procedural complications	common	fall

The following undesirable effects have been reported with selegiline.

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	uncommon	mood change, mild transient sleep disorder
	not known	hypersexuality
Eye disorders	uncommon	blurred vision
Cardiac disorders	common	bradycardia
	uncommon	Arrhythmias, palpitations, supraventricular tachycardia
Vascular disorders	uncommon	orthostatic hypotension
Skin and subcutaneous tissue disorders	uncommon	hair loss, skin eruptions
	rare	skin reactions
Musculoskeletal and connective tissue disorders	uncommon	myopathy
Renal and urinary disorders	uncommon	micturition disorders
	not known	urinary retention
General disorders and administration site conditions	uncommon	ankle oedema
Investigations	common	mild hepatic enzymes increased
	uncommon	transient transaminase increase (ALAT), transient increase in liver enzyme values

In the first 5 years of marketing experience with Zelapar, the following adverse reactions were reported: nausea, confusional state, dizziness, hallucinations and vertigo.

As selegiline potentiates the effect of levodopa, the side-effects of levodopa (restlessness, hyperkinesia, dyskinesia, agitation, confusion, hallucination, postural hypotension, cardiac arrhythmias) may be emphasised unless the dosage of levodopa is reduced. The most common undesirable effect reported for conventional selegiline tablets is dyskinesia (4% of patients). 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.

Reporting of suspected adverse reactions

Reporting 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Zelapar is rapidly metabolised and the metabolites rapidly excreted. In cases of suspected overdosage the patient should be kept under observation for 24 to 48 hours.

No specific information is available about clinically significant overdoses with Zelapar. However, experience gained in use of conventional tablets of selegiline reveals that some individuals exposed to doses of 600 mg/day suffered severe hypotension and psychomotor agitation.

Since the selective inhibition of MAO-B by selegiline hydrochloride is achieved only at doses in the range recommended for the treatment of Parkinson's disease, overdoses are likely to cause significant inhibition of both MAO-A and MAO-B. Consequently, the signs and symptoms of overdose may resemble those observed with non-selective MAOIs (central nervous and cardiovascular system disorders) and are dizziness, ataxia, irritability, pyrexia, tremor, convulsions, hypomania, psychosis, euphoria, respiratory depression, severe muscle spasms, hypotension, hypertension (sometimes with sub-arachnoid haemorrhage), coma and extra-pyramidal symptoms. There is no specific antidote and treatment should be symptomatic.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Monoamine oxidase B inhibitors, ATC Code: N04B D01

Zelapar selectively inhibits MAO-B. It prevents dopamine and /phenylethylamine breakdown in the brain. Selegiline can be used as monotherapy and permits the initiation of treatment with levodopa to be significantly postponed. It potentiates and prolongs the effect of concomitantly administered levodopa. Since it does not interfere with the breakdown of 5-hydroxytryptamine (serotonin) or noradrenaline, it does not cause any hypertensive crises or changes in the plasma or urinary metabolites of these monoamines. Although dietary restrictions are not necessary during Zelapar treatment, the inhibition of MAO-B in blood platelets can lead to a slight potentiation of the circulatory effects of any tyramine not broken down by gastrointestinal MAO-A during absorption. This effect is no greater with Zelapar than with conventional selegiline in equal doses.

The magnitude of increase in the urinary excretion of /phenylethylamine over 24 hours is simply related to the area under the selegiline plasma concentration-time curve after any selegiline product. Urinary /phenylethylamine increase reflects the degree of inhibition of MAO-B. Zelapar gives rise to a similar increase in /-phenylethylamine as 10 mg conventional selegiline tablets.

Combined with levodopa therapy selegiline reduces, in particular, fluctuation in the condition of patients who suffer from parkinsonism, e.g. on-off symptoms or end-of-dose akinesia.

In a clinical trial where patients were switched from 10 mg conventional selegiline tablets to 1.25 mg Zelapar oral lyophilisate, control of motor symptoms was maintained.

Zelapar may be useful in those patients with Parkinson's disease who experience difficulties in swallowing.

5.2 Pharmacokinetic properties

Zelapar dissolves completely within 10 seconds of placing on the tongue and, in contrast to conventional tablets, selegiline is absorbed primarily pregastrically.

The plasma concentrations of selegiline following single doses of Zelapar 1.25 mg are of the same order as those obtained with conventional 10 mg tablets of selegiline, but are much less variable. The range of AUCs for plasma selegiline is 0.22 to 2.82 ng.h/ml for Zelapar 1.25 mg and 0.05 to 23.64 ng.h/ml for conventional 10 mg tablets. The Cmax ranges are 0.32 to 4.58 ng/ml and 0.07 to 16.0 ng/ml respectively.

After Zelapar 1.25 mg, plasma concentrations of selegiline metabolites, #-desmethylselegiline, /-methamphetamine and /-amphetamine, were reduced by between 88% and 92% in comparison with the concentrations reached after conventional selegiline tablets 10 mg.

Ninety-four per cent of plasma selegiline is reversibly bound to plasma protein. Selegiline is mainly eliminated by metabolism. It is excreted mainly in the urine as metabolites (mainly /-methamphetamine) and the remainder in the faeces.

5.3 Preclinical safety data

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.

6.1 List of excipients

Gelatin

Mannitol

Glycine

Aspartame

Citric Acid anhydrous Grapefruit flavour

Yellow Colouring (yellow iron oxide [E172], hypromellose [E464]).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Sealed sachets - 3 years. Opened sachets - 3 months.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PVC/PE/PVdC blister packs sealed with aluminium foil enclosed in a paper/PE/aluminium foil/PE sachet. Each pack contains 10, 30, 60 or 100 oral lyophilisates. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

MARKETING AUTHORISATION HOLDER

Cephalon UK Limited Ridings Point Whistler Drive Castleford West Yorkshire WF10 5HX United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16260/0031

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/09/2008

10    DATE OF REVISION OF THE TEXT

18/08/2015