Pharmacology

Pharmacodynamics. The mechanisms of selegiline's beneficial adjunctive action in the treatment of Parkinson disease are not fully understood, but the following explanations are offered, most of which emphasize its role as a neuroprotective agent:

Pharmacokinetics. Important points of various pharmacokinetic studies are as follows:

Formulations and methods of delivery. Two special methods of delivery are transdermal and fast-dissolving oral formulation.

Transdermal. The selegiline transdermal system has novel pharmacokinetic and pharmacodynamic properties. Compared with oral administration, transdermal selegiline leads to sustained plasma concentrations of the parent compound, increasing the amount of drug delivered to the brain and decreasing metabolite production, thereby reducing the risk of interactions with tyramine-rich foods. A selegiline transdermal system, Emsam®, approved by the United States Food and Drug Administration, has unique pharmacokinetic and pharmacodynamic properties that allow inhibition of central nervous system MAO-A and MAO-B enzymes while substantially avoiding inhibition of intestinal and liver MAO-A enzyme (20). Administration of selegiline by this method results in an increase in the plasma concentrations of selegiline and a decrease in the formation of its metabolites, indicating that the extensive first-pass effect is avoided when selegiline is given transdermally. This novel transdermal system provides targeted MAO inhibition and avoids the need for dietary restrictions at the minimum effective dose of 6 mg/24 hours, but the precaution is necessary at higher doses of the 9-mg or 12-mg patches. Clinical trials and postmarketing studies of transdermal selegiline have established that doses between 6 and 12 mg over 24 hours are well tolerated and effective for major depressive disorder (01).

Results of an experimental study show that therapeutic amounts of selegiline can be easily delivered by transdermal iontophoresis with simple gel patches of modest surface area (07).

Fast-dissolving oral formulation. A fast-dissolving formulation of selegiline avoids first-pass metabolism and has been shown to improve efficacy and tolerability. Zydis selegiline has been shown to be a safe and effective therapy for Parkinson disease with motor fluctuations and wearing off. One double-blind, placebo-controlled, parallel-design trial of fast-dissolving selegiline formulation Zelapar showed no significant difference in improvement in percentage of off time as compared to placebo, but combined analysis with a parallel study that showed a significant improvement in off time with selegiline suggested overall efficacy. An orally disintegrating tablet is suitable for patients who report adverse events after initial treatment with conventional selegiline or who suffer from swallowing difficulties.

Selegiline nasal gel. To enhance the bioavailability and concentration of selegiline in the brain, a mucoadhesive nasal thermosensitive gel (SNT-gel) was prepared using Poloxamer 407-Chitosan combination and tested in rats (18). Results showed a significant increase in brain dopamine, a reduction in monoamine oxidase B level, and an increase in catalase activity and level of reduced glutathione following treatment with SNT-gel, indicating its effectiveness, which was also supported by histopathology examination of brain tissues.

Drug monitoring. Metabolites of selegiline include l-methamphetamine, l-amphetamine, and desmethylselegiline, which is highly addictive psychostimulant and one of the most abused drugs. In order to differentiate medical selegiline users form illicit methamphetamine abusers, it is important to distinguish between the l-isomers and d-isomers in urine samples. The urine sample is screened using headspace-solid phase microextraction-gas chromatography-mass spectrometry, which detects both methamphetamine and amphetamine in addition to selegiline and desmethylselegiline. To quantitate methamphetamine and amphetamine, a standard addition method shows that the ratio of amphetamine to methamphetamine is 0.27, which is in the range of selegiline ingestion (17).

Clinical trials

Evidence supporting the efficacy of selegiline was obtained in randomized, controlled clinical trials in 1999 that compared the effects of added selegiline or placebo in patients receiving levodopa and carbidopa. Selegiline was significantly superior to placebo on all three principal outcome measures employed: (1) change from baseline in daily levodopa and carbidopa dose, (2) the amount of "off" time, and (3) patient self-rating of treatment success. Beneficial effects were also observed on other measures of treatment success (eg, measures of reduced end of dose akinesia, decreased tremor and sialorrhea, improved speech and dressing ability, and improved overall disability as assessed by walking and comparison to previous state).

In a 12-week randomized and placebo-controlled phase 3 trial on Japanese patients with early Parkinson disease, selegiline monotherapy was well tolerated and reduced the total Unified Parkinson Disease Rating Scale part I + II + III score (11).

Regional cerebral blood flow (rCBF) was measured in patients with Parkinson disease and depression treated with selegiline-levodopa combination as well as age-matched controls by using single photon emission computed tomography. These results indicate that selegiline controlled not only worsening of motor function and cognitive function in Parkinson disease but also aggravation of depression and restrained a fall in whole-brain rCBF more significantly in the levodopa-selegiline group than in the levodopa group (04).

A comparison of randomized, placebo-controlled trials of selegiline with similar trials of rasagiline, which is also a monoamine oxidase inhibitor, showed that both drugs have comparable efficacy in improving symptoms in patients with early stage Parkinson disease (09). Real-life data have been used to compare progression of Parkinson disease between patients first prescribed either selegiline or rasagiline as their antiparkinsonian drugs (15). The similarity in time to levodopa in both groups suggests that there are no differences between selegiline and rasagiline in their effect on the natural history of Parkinson disease.

A metaanalysis of randomized clinical trials has shown that selegiline and levodopa combination therapy is superior to levodopa monotherapy for the improvement of clinical symptoms in patients with Parkinson disease, and the safety profile of combination therapy is comparable with that of levodopa monotherapy (06).

Indications

Selegiline hydrochloride is indicated as an adjunct in the management of parkinsonian patients being treated with levodopa and carbidopa who exhibit deterioration in the quality of their response to this therapy.

Off-label uses

Contraindications

Selegiline hydrochloride is contraindicated in patients with a known hypersensitivity to this drug and for concomitant use with opioids such as meperidine, tricyclic antidepressants, selective serotonin reuptake inhibitors, and nonselective monoamine oxidase inhibitors (phenelzine, tranylcypromine).

Goals and duration of treatment

The aim of selegiline therapy is neuroprotection in combination with levodopa therapy. The achievement of this goal remains undetermined, but the drug can be used safely for the long term. Long-term selegiline orally disintegrating tablets 2.5 mg/day is effective, safe, and well tolerated in patients with Parkinson disease who are experiencing “off” episodes during levodopa therapy. Patients with Parkinson disease on L-dopa who received selegiline within 5 years from the onset had better outcome as compared with those who received selegiline approximately 10 years from the onset (13). Selegiline use for 3 years or more in early Parkinson disease is associated with a slower progression of the disease as evaluated by Hoehn and Yahr stage transition times (22).

Long-term monotherapy with selegiline (10 mg/d) was effective and well tolerated in patients with early Parkinson disease in a 56-week prospective study who had previously completed the randomized, double-blind, placebo-controlled phase 3 trial of selegiline monotherapy for 12 weeks (12).

Dosing

Dosing of selegiline is typically 10 mg daily in two divided doses of 5 mg each, taken at breakfast and lunch. Once-daily transdermal patches deliver doses of 6 mg, 9 mg, or 12 mg.

Special considerations

Liver and kidney dysfunction. The elimination rate of selegiline is decreased in patients with impaired liver or kidney function and dosage adjustments may be required. Orally disintegrating tablets of selegiline should be avoided in severe hepatic impairment and in patients with renal insufficiency who have creatinine clearance less than 30 mL/min.

Pediatric. The effects of selegiline hydrochloride in pediatric patients have not been evaluated. Transdermal selegiline is contraindicated for use in children younger than 12 years.

Geriatric. Most of the clinical experience with selegiline is in geriatric patients.

Pregnancy. No teratogenic effects were observed in a study of embryo-fetal development in Sprague-Dawley rats (at oral doses 35 times the human therapeutic dose). No adequate and well-controlled studies have been administered in pregnant women. Selegiline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. This is usually not a problem in practice as Parkinson disease usually occurs in women beyond the child-bearing period.

The manufacturer of the selegiline transdermal patch recommends that breast feeding is not recommended during treatment and for 5 days after the final dose.

Anesthesia. Selegiline should be discontinued for at least 2 weeks before surgery if opioids, such as meperidine, are to be used for postoperative analgesia.

Interactions

Selegiline interacts adversely with opioids such as meperidine, tricyclic antidepressants, selective serotonin reuptake inhibitors, and nonselective monoamine oxidase inhibitors (phenelzine, tranylcypromine).

Adverse effects

Most of the cardiovascular adverse drug reactions of selegiline are due to a combination of levodopa and selegiline. Selegiline produces orthostatic hypotension and higher plasma norepinephrine levels after orthostatic testing.

Dyskinesias. Some patients given selegiline may experience an exacerbation of levodopa-associated side effects, such as dyskinesias, presumably due to the increased amounts of dopamine reacting with supersensitive postsynaptic receptors. These effects may often be mitigated by reducing the dose of levodopa and carbidopa by approximately 10% to 30%.

Orthostatic hypotension. Selegiline, in combination with levodopa, is associated with selective orthostatic hypotension. A possible explanation is nonselective inhibition of monoamine oxidase or of amphetamine and methamphetamine.

Hallucinations. Parkinson disease patients on selegiline therapy have a high incidence of hallucinations. These are more likely to occur in patients on long-term therapy in combination with levodopa.