Continuing Education Activity

Selegiline, a monoamine oxidase (MAO) inhibitor, is FDA-approved as an adjunct treatment in the management of patients with Parkinson disease and as a treatment for a major depressive disorder (MDD) in adults. Selegiline is also used off-label for early Parkinson disease and the treatment of attention-deficit/hyperactivity disorder (ADHD). This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, and monitoring, of selegiline, so providers can direct patient therapy in treating indicated disorders as part of the interprofessional team.

Objectives:

• Identify the mechanism of action of selegiline.
• Summarize the approved and off-label indications for using selegiline.
• Review the potential adverse effects and drug-drug interactions of selegiline.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with selegiline.

Indications

Selegiline, a monoamine oxidase (MAO) inhibitor, was invented by Zoltan Ecseri at the Hungarian pharma company. Many years later, in 1989, it got the first FDA approval for the treatment of depression. 

FDA-approved-Indications

• Adjunct treatment in the management of patients with Parkinson disease

• Treatment for a major depressive disorder (MDD) in adults

Off-label Uses

• Treatment for early Parkinson disease[1]

• Treatment of attention-deficit/hyperactivity disorder (ADHD)[2]

Mechanism of Action

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO), an enzyme that catabolizes norepinephrine, serotonin, and dopamine. The blockage of this enzyme prevents the reuptake of these neurotransmitters in the CNS, conferring increased levels of the biologically active monoamines at the synaptic cleft. With lower doses, selegiline exhibits selective B-type monoamine oxidase (MAO-B) inhibition. Loss of dopamine-containing neurons in the substantia nigra of the midbrain and resultant depletion of dopamine in the striatum is the cause of Parkinson disease. Therefore, the selective inhibition of MAO-B is desired for the treatment of Parkinson disease because MAO-B primarily metabolizes dopamine.[3] 

In contrast, selective inhibition of MAO-B is not the desired outcome when using selegiline to treat MDD. Inhibition of MAO-A and MAO-B is implicated as selegiline's effective mechanism of action when used to treat MDD. The monoamine hypothesis of depression predicts the underlying pathophysiologic basis of depression as a depletion in serotonin, norepinephrine, and dopamine levels in the central nervous system.[4] Because increasing the levels of all three of these monoamines is often the targeted outcome for treating MDD, nonselective inhibition of both MAO subtypes is preferred.

As with most psychotropic medications, the mechanism of action of selegiline is not fully understood. Although the above-proposed mechanisms are widely accepted, other proposed mechanisms may contribute to selegiline's clinical efficacy. There is a hypothesis that selegiline's metabolites, including amphetamine, may play a role in its mechanism of action by augmenting the release of monoamine neurotransmitters.[5] Additionally, selegiline may have neuroprotective effects that prevent progression in Parkinson disease through increases in production of neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) that protect neurons from the inflammatory process. This induction and activation of multiple anti-oxidative stress and anti-apoptosis factors may preserve healthy brain tissue.[6]

Administration

Selegiline is administered via two different routes and in three different forms.

Oral Route:  Selegiline is given as either capsule or oral disintegrating tablet (ODT) form, producing low plasma concentration levels, which provide the selective inhibition of MAO-B that is desirable for the treatment of Parkinson disease. Capsules and tablets are available in 5 mg strength. Dosing for Parkinson disease in these capsules and tablets forms is 5 mg twice daily. 

Orally disintegrating tablets are available in 1.25 mg strength. Dosing for Parkinson disease in ODT forms is 1.25 mg once daily in the morning with breakfast and without any liquid. Patients should avoid eating food or drinking liquids for 5 minutes before and after taking ODT selegiline. ODT tablets are sealed in foil backing tamper-resistant packaging. Peel back the foil backing of one blister as prescribed with dry hands and gently remove the tablet. Place it on top of the tongue, where it gets disintegrated in a few seconds.

• Patients with Hepatic Impairment: In patients with mild or moderate hepatic impairment (Child-Pugh score 5 to 9), the daily maintenance dose of selegiline ODT should be decreased from 2.5 mg to 1.25 mg daily, depending on the patient's clinical response. Selegiline ODT is not recommended in patients with severe hepatic impairment (Child-Pugh score greater than 9).

• Patients with Renal Impairment:  No dose adjustment is required in patients with mild to moderate renal impairment (CrCL 30-89 mL/min). The patient's clinical response should determine the daily maintenance dose. Selegiline ODT is not recommended in patients with severe renal impairment and patients with end-stage renal disease  (CrCl <30 mL/min).

Transdermal Route: The other route of administration of selegiline, in which a patch is applied to the patient's skin to facilitate absorption of the medication directly into the blood, bypassing the first-pass metabolism. The transdermal route achieves greater plasma concentration levels than the oral route; the elevated levels of selegiline produce the anti-depressive effect, nonselective MAO inhibition, desired to treat the major depressive disorder.

• It is available in 6 mg/24 hr, 9 mg/24 hr, and 12 mg/24 hr strengths, each box containing 30 patches. Clinicians should not use selegiline in patients with creatinine clearance below 30 ml/min or those in Child-Pugh Class C.

• The patch should be applied to intact and dry skin on the outer surface of the upper arm, the upper torso (below the neck and above the waist), or upper thighs once every 24 hours. The patch's usual starting and target dose is 6 mg/24 hours. However, based on the patient's clinical improvement, if dose increases are recommended, it should occur in dose increments of 3 mg every 24 hours ( maximum daily dose of 12 mg) at every two weeks or longer intervals.

Specific Population

Pregnancy Implication: Selegiline is FDA pregnancy category C medicine. There is a lack of data on the fetal harm associated with the maternal use of selegiline. Animal studies show selegiline use during pregnancy is associated with developmental toxicity at doses greater than those used clinically.

Breastfeeding Implication: Insufficient data exist on the excretion of selegiline or its metabolites in breast milk and its effect on breastfed babies. Because of the serious potential for adverse effects in breastfed infants (including the potential for hypertensive reactions), advise the lactating women that breastfeeding is not advised during treatment with selegiline and for a week after the last dose. 

Pediatric Patients: Effectiveness and safety in pediatric patients are not established.

Geriatric Patients: Geriatric patients experienced higher incidences (hypertension, orthostatic/postural hypotension) of adverse reactions than non-geriatric patient groups.

Adverse Effects

Selegiline may cause a hypertensive crisis, a severe elevation of blood pressure when the patient consumes the medication concurrently with food, drink, or supplements rich in tyramine.

Other dangerous adverse effects include sudden sleep episodes, orthostatic hypotension, arrhythmias, mental status alteration, hallucinations, extrapyramidal symptoms, dyskinesia, and serotonin syndrome.

Common adverse effects of selegiline xerostomia and constipation are predominantly due to the drug's anticholinergic effects. Other commonly reported adverse reactions are headaches, dizziness, insomnia, and nausea.

Abrupt cessation of selegiline is not advisable because of the risk of antidepressant and antiparkinsonian discontinuation syndromes.[7]

Adverse effects specific to the form of administration exist. For the transdermal route, a black box warning for the antidepressant use of selegiline cautions antidepressants in pediatric and young adult populations due to an increase in the risk of suicidal thoughts and behaviors. Selegiline is not FDA-approved for bipolar depression as it may precipitate a manic episode. Transdermal use commonly causes skin irritation at the site of application. The ODT form can cause buccal mucosa irritation.[7]

Contraindications

Use of selegiline within ten days before elective surgery is contraindicated due to adverse effects on blood pressure.

Transdermal selegiline is contraindicated for use in children younger than 12 years and patients of any age with pheochromocytoma.

Patients should discontinue transdermal selegiline for at least two weeks before starting any of the following medications: carbamazepine, serotonin reuptake inhibitors, clomipramine, imipramine, tramadol, propoxyphene, methadone, pentazocine, and dextromethorphan. Conversely, transdermal selegiline therapy should not start within five half-lives of the previously listed medications.

Oral selegiline should not be used concomitantly with cyclobenzaprine, dextromethorphan, St John's wort, methadone, propoxyphene, tramadol, and other MAO inhibitors. 

Selegiline, in any form, should not be used if there is a previously identified hypersensitivity to selegiline, and all forms are contraindicated with concomitant use of the medication meperidine.[8]

Selegiline metabolism involves many subunits of the cytochrome P450 system. The 2B6 subunit plays a significant role in metabolism, so interactions and impairments with this enzyme are clinically important. Patients with hepatic impairment may need adjustment of selegiline dosage, and selegiline ODT is not recommended for patients with severe hepatic impairment. Likewise, selegiline ODT should be avoided in patients with less than 30 mL/min creatinine clearance.

Monitoring

Patients taking selegiline should receive education about the risks associated with the medication usage and specific symptoms they can self-monitor. Prescribers do not have the luxury of continuous monitoring; therefore, patient awareness is crucial for medication safety. The importance of close monitoring increases when initiating the medication or when the dosage is adjusted.[9]

• Blood pressure requires monitoring in patients taking selegiline to decrease falls associated with orthostatic hypotension and prevent hypertensive crisis and long-term effects of elevated blood pressure.

• Patients require monitoring for symptoms of Parkinsonism and serotonin syndrome. 

• Box warnings exist for the risk of suicidal thoughts and behavior, especially in younger adults. Behavior, mood, and suicidality need assessment in patients taking selegiline to prevent psychiatric disturbances and death.

• Periodic skin examinations are warranted, especially in patients using the transdermal form of selegiline.

Toxicity

A hypertensive crisis caused by selegiline is due to toxic levels of adrenergic metabolites. Recommended treatment includes intravenous phentolamine, labetalol, or nitroprusside to rapidly decrease harmful blood pressure levels. Signs of end-organ damage should require assessment and treatment accordingly.[10]

Enhancing Healthcare Team Outcomes

While a neurologist most commonly prescribes selegiline, the patient is often followed by the primary care provider, which can be an MD, DO, NP, or PA. However, given the adverse event profile and interactions of this drug, therapy management, and monitoring are best accomplished with an interprofessional healthcare team that also includes nursing staff and pharmacists, as well as mental health professionals. This approach will maximize therapeutic efficacy and minimize potential adverse events. [Level 5]

Patients taking selegiline require education about the risks associated with medication usage and specific symptoms they can self-monitor. Blood pressure monitoring is necessary for patients taking selegiline to decrease falls related to orthostatic hypotension and prevent hypertensive crisis and long-term effects of elevated blood pressure. Patients require monitoring for symptoms of Parkinsonism and serotonin syndrome. Behavior, mood, and suicidality also require assessment in patients taking selegiline to prevent psychiatric disturbances and death. Periodic skin examinations are warranted, especially in patients using the transdermal form of selegiline—the importance of close monitoring increases when starting the medication or making dosage adjustments. Pharmacists should verify dosing, check for drug interactions, and provide patient counseling. Nursing will also reinforce these points and remind the patient about the need to avoid tyramine-containing foods. If the patient sees a mental health practitioner, they should be aware that the patient is taking selegiline and report back to the prescriber if they observe any signs of issues with therapy. These are but a few examples of how interprofessional teamwork optimizes patient outcomes.