Zelapar 1.25 mg Oral Lyophilisate.

Each Zelapar Oral Lyophilisate contains 1.25 mg of selegiline hydrochloride, equivalent to 1.05 mg selegiline free base. For excipients, see section 6.1.

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

Oral lyophilisate.

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

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.

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 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.

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.

No dosage adjustment is required for patients with renal or hepatic impairment.

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.

Zelapar is contra-indicated in patients with known hypersensitivity (including severe dizziness or hypotension) to conventional selegiline tablets or liquid or any of the excipients used in this product.

Zelapar is contra-indicated in patients receiving treatment with serotonin-agonists (e.g. sumatriptan, naratriptan, zolmitriptan and rizatriptan).

Zelapar is contra-indicated in patients with phenylketonuria due to the content of aspartame, a source of phenylalanine.

Selegiline is also contra-indicated for concomitant use with pethidine and other opioids.

Selegiline should not be used in patients with other extrapyramidal disorders not related to dopamine deficiency.

Selegiline should not be used in patients with active duodenal or gastric ulcer.

Selegiline should not be used in patients who are being treated with antidepressant drugs, including MAO inhibitors and selective serotonin reuptake inhibitors (e.g citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. See section 4.5 interactions).

Selegiline should also not be used with other drugs which are also monoamine oxidase inhibitors, e.g. linezolid.

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.

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.

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 MAOB 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 MAOA, (or non-selective MAO inhibitors) can cause hypotensive reactions. Hypotension, sometimes sudden in onset, has been reported with conventional selegiline.

Since selegiline potentiates the effects of levodopa, the adverse effects of levodopa may be increased. When selegiline is added to the maximum tolerated dose of levodopa, involuntary movements and agitation may occur. 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.

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.

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

Selegiline should not be administered with any type of antidepressant.

When selegiline is used at its recommended dose, it selectively inhibits MAO-B. The combined use of the SSRI, fluoxetine and Zelapar, should only be used under clinical supervision. Use of Zelapar 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.

Death has been reported to occur following the initiation of therapy with nonselective MAO inhibitors shortly after discontinuation of fluoxetine. Fluoxetine and its active metabolite have long half-lives; therefore MAO inhibitor therapy should not be started until at least 5 weeks after discontinuation of fluoxetine. 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 nonspecific MAO inhibitors, e.g. linezolid.

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.

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

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.

Foodstuffs containing tyramine have not been found to cause hypertensive reactions during therapy with conventional selegiline tablets at dosages recommended for the treatment of Parkinson's disease. As the selectivity of action of Zelapar for MAOB is identical to that of conventional tablets of selegiline given in the same dosage (10 mg), no adverse interactions with foodstuffs containing tyramine are anticipated with Zelapar.

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.

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

Interactions between non-selective MAOinhibitors 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 contraindications).

Selegiline is indicated for the treatment of Parkinson's disease which, in most cases, is a disease occurring after childbearing age. As no work has been done to assess the effects of selegiline on pregnancy and lactation, it should not be used in such cases.

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

Even when used correctly, this medicine can affect reaction capacity to the extent that driving or operating machinery is affected and therefore patients should avoid these activities.

The following undesirable effects have been reported with Zelapar during clinical trials and/or post-marketing use. They 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 and <1/10), uncommon (1/1000 and <1/100).

The following undesirable effects have been reported with selegiline, with an uncommon frequency (1/1000 and <1/100). Undesirable effects are listed below as MedDRA preferred term by system organ class.

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 may be emphasised unless the dosage of levodopa is reduced. The most common undesirable effect reported for conventional 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.

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 60 mg/day suffered severe hypotension and psychomotor agitation.

Since the selective inhibition of MAOB 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 MAOA and MAOB. Consequently, the signs and symptoms of overdose may resemble those observed with non-selective MAOIs (e.g. tranylcypromine, isocarboxazide and phenelzine) and are dizziness, ataxia, irritability, pyrexia, tremor, convulsions, hypomania, psychosis, convulsions, euphoria, respiratory depression, hypotension, hypertension (sometimes with sub-arachnoid haemorrhage), coma and extra-pyramidal symptoms.

ATC Code: N04B D01

Zelapar selectively inhibits MAOB. It prevents dopamine and βphenylethylamine 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 5hydroxytryptamine (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 MAOB in blood platelets can lead to a slight potentiation of the circulatory effects of any tyramine not broken down by gastrointestinal MAOA 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 βphenylethylamine over 24 hours is simply related to the area under the selegiline plasma concentration-time curve after any selegiline product. Urinary βphenylethylamine increase reflects the degree of inhibition of MAOB. Zelapar gives rise to a similar increase in βphenylethylamine 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 endofdose 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.

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, Ndesmethylselegiline, lmethamphetamine and lamphetamine, 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 lmethamphetamine) and the remainder in the faeces.

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.

Gelatin

Mannitol

Glycine

Aspartame

Citric Acid anhydrous

Grapefruit flavour

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

Not applicable.

Sealed sachets - 3 years.

Opened sachets - 3 months.

Do not store above 25°C.

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.

No special requirements.

Cephalon Limited

1 Albany Place

Hyde Way

Welwyn Garden City

Hertfordshire

AL7 3BT

United Kingdom

PL 21799/0017

18/09/2008

18/09/2008