Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. The drug is taken by mouth.
Side effects of rasagiline include insomnia and orthostatic hypotension, among others. Rasagiline acts as an inhibitor of the enzyme monoamine oxidase (MAO) and hence is a monoamine oxidase inhibitor (MAOI). More specifically, it is a selective inhibitor of monoamine oxidase B (MAO-B). The drug is thought to work by increasing levels of the monoamine neurotransmitter dopamine in the brain. Rasagiline shows pharmacological differences from the related drug selegiline, including having no amphetamine-like metabolites, monoamine-releasing activity, or monoaminergic activity enhancer actions, which may result in clinical differences between the medications.
Rasagiline was approved for medical use in the European Union in 2005 and in the United States in 2006. Generic versions of rasagiline are available.
Medical uses
Parkinson's disease Rasagiline is used to treat symptoms of Parkinson's disease both alone and in combination with other drugs. It has shown efficacy in both early and advanced Parkinson's, and appears to be especially useful in dealing with non-motor symptoms like fatigue.
Teva conducted clinical trials attempting to prove that rasagiline did not just treat symptoms, but was a disease-modifying drug—that it actually prevented the death of the dopaminergic neurons that characterize Parkinson's disease and slowed disease progression. They conducted two clinical trials, called TEMPO and ADAGIO, to try to prove this. The United States Food and Drug Administration (FDA) advisory committee rejected their claim in 2011, saying that the clinical trial results did not prove that rasagiline was neuroprotective. The main reason was that in one of the trials, the lower dose (1 mg) was effective at slowing progression, but the higher dose (2 mg) was not, contradicting standard dose-response pharmacology.,
MAO-B inhibitors like rasagiline may improve certain non-motor symptoms in Parkinson's disease. These may include depression, sleep disturbances, and pain (particularly related to motor fluctuations), but are unlikely to include cognitive or olfactory dysfunctions. The effects of MAO-B inhibitors like rasagiline on fatigue, autonomic dysfunctions, apathy, and impulse control disorders in people with Parkinson's disease remain unknown. Rasagiline has been reported to significantly improve quality of life in people with Parkinson's disease, but the effect sizes were trivial to small and may not be clinically meaningful. It showed a large effect size relative to placebo for depression in people with Parkinson's disease. In other studies, rasagiline appeared to reduce fatigue in people with Parkinson's disease. However, its effect sizes for this effect in a large trial were described as trivial.
Available forms Rasagiline is available in the form of 0.5 and 1mg oral tablets.
Contraindications Contraindications of rasagiline include concomitant use of serotonergic antidepressants (e.g., , , , , ), pethidine (meperidine), tramadol, methadone, propoxyphene, dextromethorphan (DXM), St. John's wort, cyclobenzaprine, and other monoamine oxidase inhibitors (MAOIs).https://www.accessdata.fda.gov/Drugsatfda_docs/Label/2014/021641s016s017lbl.Pdf This is due to possible risk of complications such as serotonin syndrome when such medications are combined with MAOIs like rasagiline. There should be a 14-day washout period between use of rasagiline and these medications. Consumption of food with very high amounts of tyramine such as certain aged cheeses should also be avoided while on rasagiline due to risk of hypertensive crisis. Rasagiline is contraindicated in people with moderate or severe hepatic impairment.
Side effects The FDA label contains warnings that rasagiline may cause severe hypertension or hypotension, may make people sleepy, may make motor control worse in some people, may cause hallucinations and psychotic-like behavior, may cause impulse control disorders, may increase the risk of melanoma, and upon withdrawal, may cause high fever or confusion.
Side effects when the drug is taken alone include flu-like symptoms, joint pain, depression, stomach upset, headache, dizziness, and insomnia. When taken with levodopa, side effects include increased movement problems, accidental injury, sudden drops in blood pressure, joint pain and swelling, dry mouth, rash, abnormal dreams and digestive problems including vomiting, loss of appetite, weight loss, abdominal pain, nausea, and constipation. When taken with Parkinson's drugs other than levodopa, side effects include peripheral edema, fall, joint pain, cough, and insomnia.
In a 2013 meta-analysis, none of the most frequently reported side effects of rasagiline occurred significantly more often than with placebo. It was concluded that rasagiline is well-tolerated.
Rasagiline has been found to produce orthostatic hypotension as a side effect. Rates of orthostatic hypotension in a selection of different clinical trials have been 1.2- to 5-fold higher than those of placebo, ranging from 3.1 to 44% with rasagiline and 0.6 to 33% with placebo. Orthostatic hypotension tends to be worst in the first 2months of treatment and then tends to decrease with time. Rasagiline can also cause hypotension while supine and unrelated to standing. In a clinical trial, the rate of hypotension was 3.2% with rasagiline versus 1.3% with placebo.
Rarely, rasagiline has been reported to induce impulse control disorders,Galvez-Jimenez, N. (2008, July). Rasagiline-and selegiline-induced hypersexuality and other impulse control disorders (ICB) in Parkinson's disease (PD): Report of 3 cases. In MOVEMENT DISORDERS (Vol. 23, No. 9, pp. 1347-1347). COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA: WILEY-BLACKWELL.Senol, M., & Kendirli, M. (2018, October). Rasagiline as Adjunctive Therapy Induced Impulse Control Disorders in Parkinson's Disease. In MOVEMENT DISORDERS (Vol. 33, pp. S832-S832). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY. obsessive–compulsive symptoms, hypersexuality, and spontaneous orgasm or ejaculation. Other rare adverse effects associated with rasagiline include pleurothotonus (Pisa syndrome), livedo reticularis, tendon rupture, and hypoglycemia.
Serotonin syndrome has been reported rarely with rasagiline both alone and in combination with selective serotonin reuptake inhibitors (SSRIs) like escitalopram, paroxetine, and sertraline and other MAOIs like linezolid.
A withdrawal syndrome associated with rasagiline has been reported.
Overdose Rasagiline has been studied at single doses of up to 20mg and at repeated doses of up to 10mg/day and was well-tolerated at these doses. However, in a dose-escalation study with concomitant levodopa therapy, a dosage of 10mg/day rasagiline was associated with cardiovascular side effects including hypertension and orthostatic hypotension in some people. The symptoms of rasagiline overdose may be similar to the case of non-selective MAOIs. Onset of symptoms may be delayed by 12hours and may not peak for 24hours. A variety of different symptoms may occur and the central nervous system and cardiovascular system are prominently involved. Death may result and immediate hospitalization is warranted. Serotonin syndrome has occurred with rasagiline overdose and body temperature should be monitored closely. There is no specific antidote for overdose and treatment is supportive and based on symptoms.
Interactions Rasagiline is contraindicated with known serotonergic agents like selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), triazolopyridines or serotonin antagonists and reuptake inhibitors (SARIs) like trazodone, and other monoamine oxidase inhibitors (MAOIs), as well as meperidine (pethidine), tramadol, methadone, propoxyphene, dextromethorphan, St. John's wort, and cyclobenzaprine, due to potential risk of serotonin syndrome. However, the risk appears to be low, based on a large study of 1,504people which looked for serotonin syndrome in people with Parkinson's disease who were treated with rasagiline plus antidepressants, rasagiline without antidepressants, or antidepressants plus Parkinson's drugs other than either rasagiline or selegiline, and in which no cases were identified.
There is a risk of psychosis or bizarre behavior if rasagiline is used with dextromethorphan.
There is a risk of non-selective MAO inhibition and hypertensive crisis if rasagiline is used with other MAOIs.
Rasagiline may have a risk of hypertensive crisis in combination with sympathomimetic agents such as amphetamines, ephedrine, epinephrine, isometheptene, and pseudoephedrine. However, based on widespread clinical experience with the related selective MAO-B inhibitor selegiline, occasional use of over-the-counter sympathomimetics like pseudoephedrine appears to pose minimal risk of hypertensive crisis. In any case, the combination of sympathomimetics with MAO-B inhibitors like rasagiline and selegiline should be undertaken with caution.
Pharmacology
Pharmacodynamics
Monoamine oxidase inhibitor Parkinson's disease is characterized by the death of cells that produce dopamine, a neurotransmitter. An enzyme called monoamine oxidase (MAO) breaks down neurotransmitters. MAO has two forms, MAO-A and MAO-B. MAO-B is involved in the metabolism of dopamine. Rasagiline prevents the breakdown of dopamine by irreversibly binding to MAO-B. Dopamine is therefore more available, somewhat compensating for the diminished quantities made in the brains of people with Parkinson's disease.
Rasagiline acts as a selective and potent irreversible inhibitor of the monoamine oxidases (MAO) enzymes monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A). It is selective for inhibition of MAO-B over MAO-A, but can also inhibit MAO-A at high doses or concentrations. MAO-B is involved in the metabolism of the monoamine neurotransmitter dopamine in the body and brain. By inhibiting MAO-B, rasagiline is thought to increase dopamine levels. In the case of Parkinson's disease, increased dopamine levels in the striatum are thought to be responsible for rasagiline's therapeutic effectiveness in treating the condition.
Rasagiline inhibits platelet MAO-B activity with single doses by 35% one-hour after 1mg, 55% after 2mg, 79% after 5mg, and 99% after 10mg in healthy young people. With all dose levels, maximum inhibition is maintained for at least 48hours after the dose. With repeated doses, rasagiline reaches greater than 99% platelet MAO-B inhibition after 6days of 2mg/day, 3days of 5mg/day, and 2 days of 10mg/day. Similarly, repeated administration of 0.5, 1, and 2mg/day rasagiline resulted in complete MAO-B inhibition. Clinically relevant inhibition of MAO-B is thought to require 80% inhibition and above. Following the last dose, platelet MAO-B levels remain significantly inhibited for 7days and return to baseline after 2weeks. In people with Parkinson's disease, rasagiline at a dose of 1mg/day achieved near-complete inhibition of platelet MAO-B after 3days of dosing. The recommended dosing schedule of rasagiline in Parkinson's disease (1mg/day) has been described as somewhat questionable and potentially excessive from a pharmacological standpoint.