Drug Monograph
Rasagiline
rasagiline mesylate — Brand name: Azilect
Pharmacokinetic Profile
Half-Life
3 h (mean, steady state)
Metabolism
Hepatic via CYP1A2 (major)
Protein Binding
88–94%
Bioavailability
~36%
Volume of Distribution
87 L (steady state)
Clinical Information
Drug Class
Selective, irreversible MAO-B inhibitor
Available Doses
0.5 mg, 1 mg tablets
Route
Oral
Renal Adjustment
None required (mild–moderate); not studied in severe
Hepatic Adjustment
Mild: max 0.5 mg/day; moderate–severe: contraindicated
Pregnancy
Category C — animal harm demonstrated
Lactation
Unknown if excreted; caution advised
Schedule / Legal Status
Prescription only (not controlled)
Generic Available
Yes
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Parkinson disease — early, untreated | Adults | Monotherapy (no concomitant dopaminergic therapy) | FDA Approved |
| Parkinson disease — motor fluctuations | Adults | Adjunctive to levodopa (with or without other PD drugs) | FDA Approved |
Rasagiline is the only MAO-B inhibitor with robust evidence supporting both initial monotherapy in early Parkinson disease and adjunctive use in patients with motor fluctuations on levodopa. Unlike selegiline, rasagiline does not metabolize to amphetamine or methamphetamine derivatives, and its once-daily dosing without food restrictions at standard doses offers a practical advantage. The TEMPO and ADAGIO trials provided evidence for early use, while the PRESTO and LARGO trials established its efficacy as adjunctive therapy for reducing off-time in levodopa-treated patients.
Off-Label Uses
Neuroprotection / disease modification in PD: The ADAGIO trial explored whether rasagiline 1 mg/day started early confers a disease-modifying benefit beyond symptomatic improvement. Results met criteria for a delayed-start design at 1 mg but not 2 mg, and the interpretation remains controversial. Rasagiline is not approved as a disease-modifying agent. Evidence quality: Moderate (conflicting dose-response)
Restless legs syndrome: Small open-label studies suggest possible benefit; controlled data are insufficient. Evidence quality: Low
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Early PD — initial monotherapy | 1 mg QD | 1 mg QD | 1 mg/day | No titration needed; can be given with or without food No dietary tyramine restrictions required at recommended dose |
| PD with motor fluctuations — adjunct to levodopa | 0.5 mg QD | 0.5–1 mg QD | 1 mg/day | May increase to 1 mg if tolerated but response insufficient; consider levodopa dose reduction of 10–13% for dopaminergic side effects |
| PD — adjunct without levodopa (with dopamine agonist) | 1 mg QD | 1 mg QD | 1 mg/day | Same dose as monotherapy; no food restrictions |
| Patient on CYP1A2 inhibitor (ciprofloxacin, fluvoxamine) | 0.5 mg QD | 0.5 mg QD | 0.5 mg/day | Ciprofloxacin doubles rasagiline exposure; do not exceed 0.5 mg while on CYP1A2 inhibitor Review concomitant medications at each visit |
| Mild hepatic impairment (Child-Pugh A) | 0.5 mg QD | 0.5 mg QD | 0.5 mg/day | Do not use in moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment |
Clinical Pearl: No Routine Tyramine Restriction
At the approved doses of 0.5–1 mg/day, rasagiline retains selective MAO-B inhibition and does not ordinarily require dietary tyramine restrictions. However, patients should still be advised to avoid foods with very high tyramine content (>150 mg per serving, such as Stilton cheese), as rare hypertensive episodes have been reported in postmarketing surveillance even at recommended doses. This represents a meaningful practical advantage over non-selective MAOIs.
Pharmacology
Mechanism of Action
Rasagiline is a potent, selective, irreversible inhibitor of monoamine oxidase type B (MAO-B). By covalently binding to the flavin adenine dinucleotide (FAD) cofactor within MAO-B, rasagiline permanently inactivates the enzyme, preventing the oxidative deamination of dopamine in the striatum. This results in higher synaptic dopamine concentrations and prolonged dopaminergic signalling. Unlike selegiline, rasagiline is not metabolized to amphetamine derivatives; its primary metabolite, 1-aminoindan (1-AI), lacks MAO inhibitory activity but may possess modest neuroprotective properties through anti-apoptotic mechanisms independent of MAO-B inhibition. Selectivity for MAO-B diminishes in a dose-dependent manner at supra-therapeutic doses. Because binding is irreversible, functional recovery of enzyme activity depends on de novo MAO-B protein synthesis rather than drug clearance.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid; Tmax ~1 h; absolute bioavailability ~36%. Food decreases Cmax by ~60% and AUC by ~20% | AUC reduction with food is not clinically significant; can be given with or without meals. Dose-proportional PK over 1–10 mg range |
| Distribution | Vd 87 L at steady state; protein binding 88–94% (61–63% to albumin); tissue binding exceeds plasma protein binding | Moderate volume of distribution; good CNS penetration with preferential accumulation in MAO-B-rich brain regions |
| Metabolism | Hepatic via CYP1A2 (major); N-dealkylation → 1-aminoindan (1-AI); hydroxylation → 3-OH-PAI, 3-OH-AI | CYP1A2 dependence is the key drug interaction concern; ciprofloxacin doubles rasagiline AUC. Unlike selegiline, no amphetamine metabolites are formed |
| Elimination | Primarily renal as metabolites (<1% unchanged); glucuronide conjugation of hydroxylated metabolites; t½ ~3 h | Short plasma half-life is pharmacologically irrelevant because MAO-B inhibition is irreversible; clinical effect persists until new enzyme is synthesized. No dose adjustment in mild–moderate renal impairment |
Side Effects
≥10%
Very Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dyskinesia (adjunct to levodopa) | 18% vs 10% placebo | Dopaminergic potentiation; reduce levodopa dose by 10–13%. Most common reason for levodopa adjustment in trials |
| Headache (monotherapy) | 14% vs 12% placebo | Small excess over placebo; usually self-limiting and does not require treatment discontinuation |
1–10%
Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Postural hypotension (adjunct to levodopa) | 6–9% vs 3% placebo | Dose-related (6% at 0.5 mg, 9% at 1 mg); greatest risk in first 2 months; tends to decrease over time |
| Arthralgia (monotherapy) | 7% vs 4% placebo | Also common in adjunct therapy; not clearly dose-related |
| Dyspepsia (monotherapy) | 7% vs 4% placebo | Mild; rarely requires treatment modification |
| Depression (monotherapy) | 5% vs 2% placebo | Distinguish from PD-related depression; may necessitate antidepressant (note MAOI interaction constraints) |
| Fall (monotherapy / adjunct) | 5% vs 3% placebo | Multifactorial in PD; assess for orthostatic hypotension, gait impairment, and home safety |
| Flu syndrome (monotherapy) | 5% vs 1% placebo | Non-specific; reported predominantly in the monotherapy trial |
| Weight loss (adjunct to levodopa) | ~4% vs ~1% placebo | Monitor nutritional status; may compound PD-related weight loss |
| Nausea (adjunct to levodopa) | ~4% vs ~1% placebo | Dopaminergic effect; may improve with levodopa dose reduction |
| Constipation (adjunct to levodopa) | ~4% vs ~2% placebo | Common in PD; increase fluids and dietary fibre |
| Dry mouth (adjunct to levodopa) | ~4% vs ~2% placebo | Manage with oral hygiene measures |
| Orthostatic hypotension (adjunct without levodopa) | 3.1% vs 0.6% placebo | Post-treatment hypotension risk (SBP <90 or DBP <50 with >30/20 mmHg drop): 3.2% vs 1.3% placebo |
Serious
Serious Adverse Effects (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hypertensive crisis (tyramine reaction) | Rare at recommended doses | Minutes to hours after very high tyramine ingestion | Discontinue rasagiline; emergent BP reduction; ED evaluation. Counsel patients to avoid foods with >150 mg tyramine per serving |
| Serotonin syndrome | Rare (reported with concomitant serotonergic drugs) | Hours to days after co-administration | Stop all serotonergic agents; supportive care; cyproheptadine may be considered |
| Hallucinations / psychotic-like behavior | 1.3% monotherapy; 4–5% adjunct to levodopa | Variable; weeks to months | Reduce dopaminergic therapy; consider low-dose quetiapine or pimavanserin; do not use in patients with major psychotic disorder |
| Falling asleep during daily activities | Uncommon | Variable; may occur without warning drowsiness | Discontinue rasagiline if occurs; counsel against driving until resolved |
| Impulse control disorders | Uncommon (class effect) | Weeks to months | Dose reduction or discontinuation; screen patients and caregivers at each visit |
| Melanoma | 2–6-fold increased risk in PD (disease-related, not drug-specific) | Any time | Periodic dermatologic screening recommended for all PD patients |
| Withdrawal-emergent hyperpyrexia and confusion | Very rare | Days after abrupt discontinuation | Do not stop abruptly; taper when discontinuing; resembles NMS |
Discontinuation
Discontinuation Rates
Monotherapy (Study 1)
5% vs 2% placebo
Top reason: Hallucinations (only AE causing >1 patient to discontinue)
Adjunct to Levodopa (Study 3)
7–9% vs 6% placebo
Top reasons: Diarrhea, weight loss, hallucination, rash
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Hallucinations (monotherapy) | 1.3% vs 0% placebo | Only adverse event causing >1 discontinuation in Study 1 |
| Nausea (adjunct without levodopa) | Leading cause | Along with dizziness; Study 2 discontinuation 8% vs 4% placebo |
Managing Dyskinesia When Adding Rasagiline to Levodopa
Dyskinesia is the most clinically significant adverse effect when rasagiline is used adjunctively with levodopa, affecting 18% of patients vs 10% on placebo. In clinical trials, levodopa dose reduction was required in 16–17% of rasagiline-treated patients (vs 8% placebo), with an average reduction of 9–13%. The standard approach is to proactively reduce levodopa by approximately 10% when adding rasagiline and titrate based on motor response and dyskinesia burden.
Drug Interactions
Rasagiline’s interaction profile centers on two axes: serotonergic co-prescribing risk (shared with all MAOIs) and CYP1A2-mediated metabolic interactions (unique to rasagiline among MAO-B inhibitors). At recommended doses, MAO-B selectivity is maintained and tyramine sensitivity is only mildly increased, so routine dietary restrictions are not required.
MajorMeperidine / Tramadol / Methadone / Propoxyphene
MechanismSerotonergic potentiation and unknown additive mechanisms
EffectSerotonin syndrome; severe agitation, hyperpyrexia, rigidity; fatalities reported with meperidine + MAOIs
ManagementAbsolutely contraindicated; 14-day washout after stopping rasagiline before initiating these agents
FDA PIMajorSSRIs / SNRIs / TCAs (e.g., fluoxetine, sertraline, venlafaxine, amitriptyline)
MechanismAdditive serotonergic activity with MAO inhibition
EffectRisk of serotonin syndrome (hyperthermia, rigidity, myoclonus, autonomic instability)
ManagementNot recommended; 14-day washout after stopping rasagiline; ≥5 weeks after stopping fluoxetine before starting rasagiline
FDA PIMajorDextromethorphan
MechanismSerotonergic activity combined with MAO inhibition
EffectEpisodes of psychosis and bizarre behavior reported
ManagementContraindicated; counsel patients to check OTC cough products
FDA PIMajorOther MAOIs (selegiline, phenelzine, tranylcypromine, linezolid)
MechanismDual MAO inhibition leading to non-selective blockade
EffectHypertensive crisis and serotonin syndrome risk
ManagementContraindicated; 14-day washout required between agents
FDA PIModerateCiprofloxacin / CYP1A2 Inhibitors (fluvoxamine, cimetidine)
MechanismCYP1A2 inhibition reduces rasagiline metabolism, increasing plasma levels up to 2-fold
EffectIncreased risk of adverse events including hypertension
ManagementReduce rasagiline to maximum 0.5 mg/day while CYP1A2 inhibitor is co-administered; monitor BP
FDA PI / PK StudyModerateSympathomimetic Amines (pseudoephedrine, phenylephrine, ephedrine)
MechanismEnhanced catecholaminergic effect with MAO-B inhibition
EffectPotential for hypertensive reaction; risk is lower than with non-selective MAOIs
ManagementUse with caution; avoid decongestant-containing OTC products; monitor blood pressure
FDA PIMinorLevodopa / Carbidopa
MechanismRasagiline inhibits dopamine catabolism, potentiating levodopa effect
EffectEnhanced dopaminergic effects: dyskinesia (18% vs 10%), postural hypotension, hallucinations
ManagementIntended therapeutic interaction; start rasagiline at 0.5 mg; reduce levodopa by ~10% if dopaminergic side effects emerge
FDA PIMajorSt. John’s Wort / Cyclobenzaprine
MechanismSt. John’s Wort: serotonergic; Cyclobenzaprine: structurally related to TCAs
EffectSerotonin syndrome risk
ManagementContraindicated with rasagiline
FDA PIMonitoring
- Blood PressureEvery visit (first 2 months); then periodically
RoutineCheck supine and standing BP. Orthostatic hypotension is most common in the first 2 months and tends to decrease. Also monitor for hypertension, especially if patient consumes very high-tyramine foods or takes sympathomimetics. - Motor StatusEvery visit
RoutineAssess wearing-off time, dyskinesia severity, and overall motor response. When used adjunctively, evaluate need for levodopa dose adjustment at each visit. - Mental StatusEvery visit
RoutineScreen for hallucinations, psychotic-like behavior, depression, and impulse control disorders. Include caregiver input. Rasagiline should not be used in patients with major psychotic disorders. - Hepatic FunctionBaseline
Trigger-basedAssess liver function before initiating therapy, as rasagiline is contraindicated in moderate–severe hepatic impairment and requires dose reduction in mild impairment. - Skin ExaminationPeriodically
RoutinePD patients carry 2–6-fold increased melanoma risk. Conduct periodic dermatologic screening, ideally by a dermatologist. - Somnolence / Sleep EpisodesEvery visit
Trigger-basedAsk specifically about daytime sleepiness and sudden sleep onset. Consider sedating co-medications and CYP1A2 inhibitors that increase rasagiline levels as risk factors. - CYP1A2 InhibitorsEvery visit
Trigger-basedReview medication list for new CYP1A2 inhibitors (ciprofloxacin, fluvoxamine, cimetidine). Reduce rasagiline to 0.5 mg if any are added.
Contraindications & Cautions
Absolute Contraindications
- Concomitant meperidine, tramadol, methadone, or propoxyphene — serotonin syndrome risk; 14-day washout required
- Concomitant MAOIs (including selegiline, phenelzine, tranylcypromine, linezolid) — non-selective MAO inhibition and hypertensive crisis
- Concomitant dextromethorphan — psychosis, bizarre behavior reported
- Concomitant St. John’s Wort or cyclobenzaprine — serotonin syndrome risk
- Moderate or severe hepatic impairment (Child-Pugh B or C) — rasagiline undergoes extensive hepatic metabolism via CYP1A2
Relative Contraindications (Specialist Input Recommended)
- Major psychotic disorder — risk of exacerbating psychosis; antipsychotics may also reduce rasagiline efficacy
- Concomitant SSRIs, SNRIs, or TCAs — not recommended due to serotonin syndrome risk, though small numbers of patients were exposed in clinical trials without reported events
Use with Caution
- Patients taking CYP1A2 inhibitors — reduce dose to 0.5 mg/day
- Mild hepatic impairment — limit to 0.5 mg/day
- Elderly patients — no specific dose adjustment, but no significant safety profile differences noted
- Patients at risk for hypotension — including those on antihypertensives or with orthostatic symptoms
FDA Class-Wide Regulatory Warning
MAO Inhibitor Interactions — Hypertensive Crisis and Serotonin Syndrome
Rasagiline is a selective MAO-B inhibitor at recommended doses, but selectivity diminishes at higher doses. Rare postmarketing reports of hypertensive crisis associated with tyramine-rich food ingestion have occurred even at approved doses. Concomitant use with serotonergic drugs carries risk of serotonin syndrome, which can be fatal. Prescribers must review all concomitant medications, including OTC products, at every visit. At least 14 days should elapse between discontinuation of rasagiline and initiation of prohibited medications.
Patient Counselling
Purpose of Therapy
Explain that rasagiline helps manage Parkinson disease symptoms by preventing the breakdown of dopamine in the brain. In early PD, it can be used alone to improve motor function. In later-stage PD with wearing-off, it is added to levodopa to extend its duration of effect and reduce off-time.
How to Take
Take one tablet by mouth once daily, at any time of day, with or without food. No special dietary restrictions are needed at the standard dose, though it is wise to avoid foods with extremely high tyramine content (such as aged Stilton cheese or large quantities of fermented foods).
Drug Interactions & OTC Products
Tell patientMany common medications interact dangerously with rasagiline, including cough medicines containing dextromethorphan, all antidepressants, and certain pain medications (meperidine, tramadol). Always tell every healthcare provider you take rasagiline, and ask a pharmacist before buying any OTC cold, cough, or pain product.
Call prescriberIf you accidentally take a prohibited medication and develop agitation, muscle stiffness, fever, rapid heartbeat, or confusion — seek emergency care immediately.
Dizziness & Blood Pressure Changes
Tell patientRasagiline can cause blood pressure to drop when standing, particularly in the first two months. Rise slowly from sitting or lying positions and stay well hydrated.
Call prescriberIf you experience fainting, persistent dizziness, or a fall related to lightheadedness.
Involuntary Movements (Dyskinesia)
Tell patientIf taking rasagiline with levodopa, you may notice increased involuntary movements. This usually means the levodopa dose needs to be reduced — do not adjust doses on your own.
Call prescriberIf involuntary movements become bothersome or interfere with daily activities.
Drowsiness & Sleep Attacks
Tell patientSome patients fall asleep suddenly during normal activities, including driving. This can happen without feeling drowsy beforehand. Avoid driving or operating machinery if you experience any unusual sleepiness.
Call prescriberImmediately if you fall asleep during activities such as driving, eating, or talking.
Skin Checks
Tell patientPatients with Parkinson disease have a higher-than-average risk of melanoma. Have your skin checked regularly by a dermatologist, and report any new or changing moles promptly.
Call prescriberIf you notice any unusual red, brown, or black spots on your skin.
Sources
Regulatory (PI / SmPC)
- Azilect (rasagiline mesylate) tablets — FDA-approved prescribing information. Revised 2014. accessdata.fda.govPrimary source for dosing, adverse event incidence tables (Studies 1–4), PK data, and contraindications.
- Rasagiline tablets — FDA-approved prescribing information (generic label). Revised 2016. accessdata.fda.govConfirms dosing, monotherapy adverse event table (Table 1), and CYP1A2 interaction data.
Key Clinical Trials
- Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol. 2002;59(12):1937–1943. doi:10.1001/archneur.59.12.1937Pivotal 26-week monotherapy trial demonstrating rasagiline 1–2 mg/day improved UPDRS scores vs placebo in early PD.
- Olanow CW, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease (ADAGIO). N Engl J Med. 2009;361(13):1268–1278. doi:10.1056/NEJMoa0809335Delayed-start trial exploring disease modification; 1 mg met all primary endpoints but 2 mg did not, leaving neuroprotection question unresolved.
- Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol. 2005;62(2):241–248. doi:10.1001/archneur.62.2.241North American adjunct trial showing rasagiline reduced daily off-time by ~0.94 h vs placebo (Study 3 in FDA labeling).
- Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO study). Lancet. 2005;365(9463):947–954. doi:10.1016/S0140-6736(05)71083-7European adjunct trial confirming off-time reduction and demonstrating non-inferiority to entacapone (Study 4 in FDA labeling).
Guidelines
- Pringsheim T, Day GS, Smith DB, et al. Practice guideline recommendations summary: treatment of motor symptoms of Parkinson disease. Neurology. 2024;103(6):e209739. doi:10.1212/WNL.0000000000209739AAN guideline update recommending MAO-B inhibitors (including rasagiline) for early PD monotherapy and as adjunct to levodopa.
- Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and Movement Disorder Society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord. 2018;33(8):1248–1266. doi:10.1002/mds.27372MDS review classifying rasagiline as clinically useful for early PD and for reducing off-time as adjunct therapy.
Mechanistic / Basic Science
- Youdim MBH, Weinstock M. Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation. Neurotoxicology. 2004;25(1–2):243–250. doi:10.1016/S0161-813X(03)00103-7Explains the pharmacological basis for rasagiline’s MAO-B selectivity and reduced tyramine sensitivity compared to non-selective MAOIs.
- Weinreb O, Amit T, Bar-Am O, Youdim MBH. Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol. 2010;92(3):330–344. doi:10.1016/j.pneurobio.2010.06.008Reviews anti-apoptotic and neuroprotective mechanisms of rasagiline and its metabolite 1-aminoindan independent of MAO-B inhibition.
Pharmacokinetics / Special Populations
- Chen JJ, Swope DM. Clinical pharmacology of rasagiline: a novel, second-generation propargylamine for the treatment of Parkinson disease. J Clin Pharmacol. 2005;45(8):878–894. doi:10.1177/0091270005277935Comprehensive PK review covering bioavailability (36%), CYP1A2 dependence, food effects, and special populations.
- Loettgen J, Grunwald F, Keck P, et al. Safety and effectiveness of rasagiline in Chinese patients with Parkinson’s disease: a prospective, multicenter, non-interventional post-marketing study. Drug Saf. 2023;46(6):553–563. doi:10.1007/s40264-023-01288-2Post-marketing safety study (N=734) confirming consistent safety profile across monotherapy and adjunct therapy in a real-world setting.
- Leegwater-Kim J, Bortan E. The role of rasagiline in the treatment of Parkinson’s disease. Clin Interv Aging. 2010;5:149–156. doi:10.2147/CIA.S4145Practical clinical review summarizing pharmacokinetics, efficacy trials, and tolerability profile for clinicians.