SELEGILINE HYDROCHLORIDE

Clinical safety rating: safe

Animal studies have demonstrated safety

How it works

Irreversible inhibitor of monoamine oxidase type B (MAO-B), preventing the breakdown of dopamine in the brain, thereby increasing dopaminergic activity.

What the body does with it

Metabolism	Hepatic metabolism primarily by CYP2B6 and CYP3A4; major metabolites: desmethylselegiline, amphetamine, and methamphetamine.
Excretion	Selegiline undergoes extensive hepatic metabolism via CYP2B6, CYP2C19, and CYP3A4 to its primary active metabolites, N-desmethylselegiline and L-amphetamine, which are further metabolized. Approximately 73% of a radiolabeled dose is excreted in the urine as metabolites (including selegiline and its metabolites) within 72 hours, with about 15% eliminated in the feces. Less than 1% of the dose is excreted unchanged in the urine.
Half-life	The terminal elimination half-life of selegiline is approximately 1.5 to 2 hours. The half-lives of its active metabolites are longer: N-desmethylselegiline ~4 hours, L-amphetamine ~17 hours, L-methamphetamine ~20 hours. Clinically, the MAO-B inhibition is irreversible, so the pharmacodynamic effect (elevation of dopamine) lasts much longer than the parent drug's presence. Once-daily dosing is sufficient despite the short half-life due to the sustained inhibition of MAO-B.
Protein binding	Selegiline is approximately 93-98% bound to plasma proteins, primarily to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	The volume of distribution (Vd) for selegiline is approximately 1.5 L/kg, indicating extensive tissue distribution. This large Vd reflects penetration into tissues, including the brain, which is the site of action for MAO-B inhibition.
Bioavailability	Oral: The bioavailability is low due to extensive first-pass metabolism, estimated at about 10%. Transdermal: Bioavailability is approximately 75% for the transdermal system, bypassing first-pass metabolism and providing more consistent plasma levels.
Onset of Action	Oral: Clinical effects (e.g., improvement in Parkinsonian symptoms) are typically observed within 1 to 2 hours after administration. Transdermal: Onset of MAO-B inhibition occurs within 2 to 4 hours after patch application.
Duration of Action	Oral: Inhibition of MAO-B lasts for approximately 24 hours or more due to irreversible binding, allowing once-daily dosing. The clinical effect on motor symptoms persists throughout the day. Transdermal: After patch removal, MAO-B activity returns to baseline over 2 to 3 days as new enzyme is synthesized.

Classification & Brands

Dosing & administration

Parkinson's disease: 5 mg orally twice daily with breakfast and lunch; 10 mg orally once daily in the morning is an alternative. Adjunct for depression: 20 mg orally daily in divided doses.

Dosage form	TABLET
Renal impairment	No specific dose adjustment guidelines. Use caution in severe renal impairment (GFR <15 mL/min) due to potential accumulation of metabolites.
Liver impairment	Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose by 50%. Child-Pugh C: Avoid use due to safety concerns.
Pediatric use	Safety and efficacy not established in pediatric patients; use not recommended.
Geriatric use	Start at lower end of dosing range (2.5 mg twice daily) due to increased sensitivity, orthostatic hypotension risk, and potential for confusion.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Other MAOIs and sympathomimetics can cause hypertensive crisis Can cause hypertensive crisis if tyramine-rich foods are consumed in high doses.

Breastfeeding

Selegiline is excreted into human breast milk; the milk-to-plasma (M/P) ratio is unknown. A study in lactating women receiving 10 mg/day found measurable levels in milk. The effect on the nursing infant is unknown. Due to potential for serious adverse reactions (e.g., hypertensive crisis, MAO inhibition effects), breastfeeding is not recommended during selegiline therapy.

Teratogenic Risk

Selegiline hydrochloride is classified as FDA Pregnancy Category C. Animal studies have shown increased incidences of fetal loss and skeletal variations at doses >5 mg/kg/day (approximately 50 times the human therapeutic dose). There are no adequate and well-controlled studies in pregnant women. Risk cannot be ruled out. First-trimester exposure: theoretical risk due to monoamine oxidase inhibition may affect early embryonic development; limited data. Second and third trimesters: potential for hypertensive crises in the mother, which could affect uteroplacental perfusion. There is a risk of neonatal withdrawal if used near term.

Warnings & precautions

■ FDA Black Box Warning

MAO inhibitors, including selegiline, may increase the risk of hypertensive crisis when used with tyramine-rich foods, certain drugs (e.g., sympathomimetics, serotonergic agents), or in patients with pheochromocytoma.

Side Effect Profile

Common Effects	Nausea
Serious Effects

Absolute Contraindications

Concurrent use with other MAOIs, SSRIs, SNRIs, bupropion, or opioids; pheochromocytoma; severe hepatic impairment; tyramine-rich foods; concurrent therapy with levodopa/carbidopa (oral selegiline only).

Clinical Precautions

Precautions

Risk of hypertensive crisis; serotonin syndrome with serotonergic drugs; may cause dizziness, orthostatic hypotension; avoid abrupt discontinuation; use cautiously in patients with hepatic or renal impairment.

Clinical Tips & Counseling

Drug interactions

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