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.
Sealed sachets - 3 years.
Opened sachets - 3 months.
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).
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.
Not applicable.
Gelatin
Mannitol
Glycine
Aspartame
Citric Acid anhydrous
Grapefruit flavour
Yellow Colouring (yellow iron oxide [E172], hypromellose [E464]).
Oral lyophilisate.
A pale yellow round tablet with the letter A on one side.
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.
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.
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.
Pharmacotherapeutic group: Monoamine oxidase B inhibitors, ATC Code: N04B D01
Zelapar selectively inhibits MAO-B. It prevents dopamine and β-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 β-phenylethylamine over 24 hours is simply related to the area under the selegiline plasma concentration-time curve after any selegiline product. Urinary β-phenylethylamine increase reflects the degree of inhibition of MAO-B. Zelapar gives rise to a similar increase in β-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.
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, N-desmethylselegiline, l-methamphetamine and l-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 l-methamphetamine) and the remainder in the faeces.
21/08/2015
Zelapar 1.25 mg Oral Lyophilisate.
Cephalon UK Limited
Ridings Point
Whistler Drive
Castleford
West Yorkshire
WF10 5HX
United Kingdom
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.
PL 16260/0031
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)
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.
Patients taking levodopa
Some studies concluded in an increased risk of mortality in patients receiving selegiline and levodopa compared to those receiving levodopa only.). 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.
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.
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 per day.
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.
No special requirements.
04 June 2010
