Selegiline

Selegiline is indicated for the treatment of Parkinson's disease, or symptomatic parkinsonism. It may be used alone in early Parkinson's disease for symptomatic relief to delay the need for levodopa (with or without decarboxylase inhibitor) or as an adjunct to levodopa (with or without decarboxylase inhibitor). Selegiline 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.

Posology

10 mg daily either alone or as an adjunct to levodopa or levodopa/peripheral decarboxylase inhibitor. When selegiline is added to a levodopa regimen it is possible to reduce the levodopa dosage by an average of 10 -30%. 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

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.

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

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

Selegiline should not be used in patients who are being treated with antidepressant drugs, including MAO inhibitors tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors (SNRI) (venlafaxine) and selective serotonin reuptake inhibitors.

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

Selegiline should not be used in combination with sympathomimetics.

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

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

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.

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.

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

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.

Selegiline should be used with caution in severe liver or kidney dysfunction.

Caution should be exercised in patients receiving MAO inhibitors during general anaesthesia in surgery.). When an optimum dose of levodopa is reached, adverse effects from the combination are less than those observed with levodopa on its own.

Parkinson's disease patients treated with dopamine agonists and other dopaminergic treatments have been reported as exhibiting impulse control disorders and compulsions like pathological gambling, increased libido, hypersexuality, binge eating, shopping and different kinds of compulsive/repetitive activities (punding). These may also be possible with selegiline but very few cases have been reported to date.

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

Even when used correctly, this medicine may cause dizziness or can affect reaction capacity to the extent that driving or operating machinery is affected and therefore patients should be advised not to drive or use machines if they experience these adverse reactions during treatment.

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 offence (called 'statutory defence') if:

oThe medicine has been prescribed to treat a medical or dental problem and

oYou have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

oIt was not affecting your ability to drive safely

The following undesirable effects have been reported with selegiline during clinical trials and/or post-marketing use. They are listed below as MedDRA preferred term by system organ class and frequency. 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).

* Parkinson's disease patients treated with dopamine agonists and other dopaminergic treatments have been reported as exhibiting impulse control disorders and compulsions like pathological gambling, increased libido, hypersexuality, binge eating, shopping and different kinds of compulsive/repetitive activities (punding). These may also be possible with selegiline but very few cases have been reported to date.

As selegiline potentiates the effect of levodopa (levodopa should be usually given in association with a peripheral decarboxylase inhibitor), the side-effects of levodopa may be emphasised unless the dosage of levodopa is reduced. Selegiline combination therapy may permit further reduction of levodopa dose (even by 30 %).The most common undesirable effect reported for conventional tablets is dyskinesia (4% of patients) other side effects include restlessness, hyperkinesis, abnormal movements, agitation, confusion, hallucination, postural hypotension, cardiac arrhythmias. 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Selegiline 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 overdosage cases are known. 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).However, experience gained during selegiline's development reveals that some individuals exposed to doses of 600 mg/day selegiline suffered severe hypotension and psychomotor agitation.

Theoretically, overdosage causes significant inhibition of both MAO-A and MAO-B and thus, symptoms of overdosage may resemble those observed with non-selective MAO-inhibitors which can progress over 24 hours to include, different central nervous and cardiovascular system disorders. These include agitation, irritability, hyperactivity, drowsiness, tremor, severe headache, hallucination, alternating low and high blood pressure dizziness, faintness, vascular collapse, rapid and irregular pulse, precordial pain, respiratory depression and failure, severe muscle spasms, hyperpyrexia, diaphoresis coma and convulsions. There is no specific antidote and the treatment is symptomatic.

Pharmacotherapeutic group: Monoamine oxidase B inhibitors, ATC-code: N04BD01

Selegiline is a selective MAO-B-inhibitor which prevents dopamine breakdown in the brain. It also inhibits the reuptake of dopamine at the presynaptic 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. 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 selegiline 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.

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.

Double-blind studies on early phase Parkinsonian patients showed that patients receiving selegiline monotherapy manage significantly longer without levodopa therapy than controls receiving 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 HCl does not cause the so called "cheese effect" either when used alone as monotherapy, or when used with other drugs, except for moclobemide or nonselective MAO-inhibitors.

Absorption

Selegiline HCl is readily absorbed from the gastrointestinal tract. The maximal concentrations are reached in 0.5-0.75h after oral administration in fasting state. The bioavailability is low; 10% (on the average; interindividual variation is large) of unchanged selegiline can reach the systemic circulation.

Selegiline is a lipophilic, slightly basic compound which quickly penetrates into tissues, also into brain.

Distribution

Selegiline is rapidly distributed throughout the body, the apparent volume of distribution being 500 1 after an intravenous 10 mg dose. 75-85% of selegiline is bound to plasma proteins at therapeutic concentrations. Selegiline HCl inhibits enzyme MAO-B irreversibly and enzyme activity only increases again after new enzyme is synthesised. The strong inhibitory effect platelet enzyme MAO-B activity after single 10 mg dose lasts over 24 h, and the platelet enzyme MAO-B activity returns to normal level approximately after 2 weeks

Biotransformation

Selegiline is rapidly metabolised, mainly in the liver, into active metabolites desmethylselegiline, l-methamphetamine and to l-amphetamine, with elimination half-lives of 2.1h, 20.5 h and 17.7 h respectively. In vitro studies indicate that CYP2B6 is the main hepatic cytochrome P450 (CYP) enzyme involved in the metabolism of selegiline with a possible contribution of CYP3A4 and CYP2A6.

Selegiline AUC and desmethylselegiline AUC increase 2.7 fold and 1.5 fold respectively from day 1 to day 8 on dosing 10 mg od. However, the half-lives of selegiline (range, 1.5-3.5 h) and desmethylselegiline (range, 3.4 - 5.3 h) were found to be relatively short. Accordingly, the short half-lives of these compounds failed to predict the apparent accumulation.

The most likely explanation for the significant increase in selegiline and desmethylselegiline concentrations in serum which was observed during the 8-day multiple dose administration of selegiline HCl is saturation of MAO-B binding sties in tissues, as the rapid elimination of both selegiline and desmethyl selegiline cannot explain the apparent accumulation observed. However, decrease in the first-pass metabolism of selegiline on multiple dosing cannot be ruled out.

Elimination

In humans, the three metabolites have been identified in plasma and urine after single and multiple doses of selegiline. The mean elimination half-life is 1.5-3.5 h for selegiline. The total body clearance of selegiline is about 240 I/h. The metabolites of selegiline are excreted mainly via the urine with about 15% occurring in the faeces.

No other incompatibilities noted.

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

None.

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain