Zelapar (Cephalon Limited)

Z

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.

No dosage adjustment is required for patients with renal or hepatic 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 MAO inhibitors and selective serotonin reuptake inhibitors (e.g citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. See section 4.5 interactions).

Concomitant use with other drugs which are also 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.

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.

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

Concomitant treatment with medicines which inhibit MAO

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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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 non

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

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 MAO

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 MAO

4.6 Pregnancy And Lactation

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.

4.7 Effects On Ability To Drive And Use Machines

Zelapar has major influence on the ability to drive and use machines, therefore patients should avoid these activities.

4.8 Undesirable Effects

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 (

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, with an uncommon frequency (

System Organ Class

Undesirable effects

Infections and infestations

pharyngitis

Blood and lymphatic system disorders

Leucocytopenia, thrombocytopenia

Metabolism and nutrition disorders

loss of appetite

Eye disorders

blurred vision

Cardiac disorders

Arrhythmias, palpitations

Vascular disorders

orthostatic hypotension

Skin and subcutaneous tissue disorders

hair loss, skin eruptions

Musculoskeletal and connective tissue disorders

myopathy

Renal and urinary disorders

micturition disorders

General disorders and administration site conditions

ankle oedema

Investigations

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 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.

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 60 mg/day suffered severe hypotension and psychomotor agitation.

Since the selective inhibition of MAO

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

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

Zelapar selectively inhibits MAO?

The magnitude of increase in the urinary excretion of ???

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

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, Ndesmethylselegiline, llamphetamine, 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 l

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. Pharmaceutical Particulars 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 And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Cephalon UK Limited

1 Albany Place

Hyde Way

Welwyn Garden City

Hertfordshire

AL7 3BT

United Kingdom

8. Marketing Authorisation Number(S)

PL 16260/0031

9. Date Of First Authorisation/Renewal Of The Authorisation

04 June 2010

10. Date Of Revision Of The Text

20 June 2010

Zelapar Cephalon Limited

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