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2006 dec 4/18 (1249/1250): rasagiline (azilect) for parkinson's disease

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December 4/18, 2006
Happy New Year
motor symptoms. Inhibiting MAO-B in the striatum This is the last issue of The Medical Letter for 2006. (most of MAO in the brain is type B) increases extra- The first issue of 2007 will be dated January 1st. cellular levels of dopamine and decreases motor dys-function.
NEUROPROTECTIVE EFFECTS — Loss of dopamin-
Rasagiline (Azilect) for Parkinson’s
ergic neurons in PD may be caused by gradual celldeath resulting from genetic and environmental factors such as oxidative stress, mitochondrial dysfunction,inflammation, excitotoxicity and protein aggregation. In Rasagiline (Azilect – Teva), a monoamine oxidase-type experimental models, the MAO-B inhibitors selegiline B (MAO-B) inhibitor, was recently approved by the FDA and rasagiline have demonstrated neuroprotective and for once-daily oral treatment of Parkinson’s disease anti-apoptotic effects on dopamine neurons. Selegiline (PD). It can be taken alone for treatment of early dis- is metabolized, however, to amphetamine derivatives ease or with levodopa/carbidopa (Sinemet, and others) for advanced disease. Selegiline (Eldepryl, and others),the first MAO-B inhibitor marketed in the US, has beenavailable since 1988; a new lower-dose disintegrating PHARMACOLOGY
tablet (Zelapar) was recently approved.
DRUGS FOR PARKINSON’S DISEASE — PD is
characterized by loss of dopamine-containing neu- rons in the substantia nigra. Levodopa/carbidopa is
considered the most effective treatment, but after 2 Hepatic by CYP1A2 to a non-amphetamine metabolite to 5 years, most patients develop motor complica- tions including dyskinesias and fluctuations in thera-
peutic response. Dopamine agonists such as
Rasagiline can be taken with or without food, but when pramipexole (Mirapex) or ropinirole (Requip) are taken with a high-fat meal, its peak plasma concentra- often used, therefore, as initial treatment to delay the tion (Cmax) decreases by 60% and the area under the use of levodopa and the associated motor complica- curve (AUC) decreases by 20%. In patients with mild tions. In more advanced disease, levodopa can be hepatic impairment, AUC is increased 2-fold and Cmax combined with a dopamine agonist or with enta-
is increased 1.4-fold compared to healthy subjects.5 capone (Comtan),1 which prolongs the effects of lev-
odopa. Amantadine (Symmetrel, and others) has
Even though the half-life of rasagiline is only about 3 some dopaminergic activity and has been used in hours, it irreversibly inhibits MAO-B and therefore early and late disease, especially in younger remains effective until new MAO-B is synthesized.5 patients. Selegiline is approved only for use with lev-
CLINICAL STUDIES — Early Parkinson’s Disease –
odopa, but it has also been used as initial monother- A 26-week, randomized, double-blind trial in 404 patients who had had PD for about one year and had not required levodopa treatment compared rasagiline 1 MECHANISM OF ACTION — As PD progresses,
or 2 mg once daily to placebo. Patients were not dopamine levels decrease, causing an increase in allowed to take dopamine agonists, selegiline or FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS
SOME DRUGS FOR PARKINSON’S DISEASE
FORMULATIONS
DAILY DOSAGE COST1
MAO-B Inhibitors
Rasagiline – Azilect (Teva)
Dopamine Agonists
Bromocriptine – generic
Other Drugs
Amantadine – generic
* Oral disintegrating tablets1. Cost for 30 days’ treatment with the lowest recommended dosage according to most recent data (October 31, 2006) from retail pharmacies nationwide available from Wolters Kluwer Health.
amantadine; about 15% of patients were taking anti- In another double-blind trial, 687 patients with PD cholinergics. Both doses of rasagiline were superior already taking levodopa were randomized to either to placebo in their effect on overall Unified adjunctive rasagiline (1 mg once daily), entacapone Parkinson’s Disease Rating Scales (UPDRS) includ- (200 mg with each levodopa dose) as an active com- ing mental and motor function and activities of daily parator, or placebo for 18 weeks. Daily “off” time living. After 26 weeks, scores had increased from decreased by 0.40 hours with placebo, 1.18 hours with baseline (worsening of the disease) by 0.1 unit with 1 rasagiline and 1.20 hours with entacapone. Rating mg, 0.7 unit with 2 mg and 3.9 units with placebo.
scales of activities of daily living and motor function dur- The percentages of patients requiring additive ther- ing “on” time also improved more with the active treat- apy with levodopa were 11.2% with 1 mg and 16.7% ADVERSE EFFECTS — In clinical trials in patients
In a 6-month continuation of the study, patients on with early PD, rasagiline taken alone was generally
active treatment continued to take either 1 or 2 mg, well tolerated. Adverse effects that were more com- while patients initially in the placebo group were mon with the 1-mg dose than with placebo included switched to 2 mg once daily (delayed-start group).
flu syndrome, arthralgia, depression, dyspepsia, and Patients treated for one year with rasagiline (early- start group) had smaller increases in UPDRS scoresfrom baseline than the delayed-start group.7 After In patients with advanced PD taking rasagiline with
more than 5 years’ follow-up, patients in the early- levodopa, adverse effects that were more common
start group were more improved than those in the with rasagiline 1 mg than with placebo included dyski- nesia, accidental injury, postural hypotension and gas-trointestinal effects (weight loss, vomiting, anorexia, Advanced Parkinson’s Disease – A 26-week dou-
abdominal pain, nausea and constipation).
ble-blind trial in 472 patients with PD for about 9 years(taking levodopa for about 8 years) compared adjunc- An increased incidence of melanoma compared to the tive treatment with rasagiline 0.5 or 1 mg once daily to general population was reported in patients taking placebo. Most patients were also taking dopamine rasagiline during clinical trials. Some studies have sug- agonists, amantadine, entacapone or anticholinergics gested an increased risk of malignant melanoma with to control motor dysfunction. Total daily “off” time PD itself.11,12 Periodic monitoring for melanoma is rec- decreased by 0.91 hours with placebo, 1.41 hours with 0.5 mg, and 1.85 hours with 1 mg. Rating scales ofactivities of daily living and other motor functions also DRUG INTERACTIONS — Rasagiline is metabolized
by CYP1A2; plasma concentrations may increase up to 2-fold when taken with inhibitors of CYP1A2, includ- The Medical Letter • Volume 48 • Issue 1249/1250 • December 4/18, 2006 SOME DRUGS THAT SHOULD NOT BE
TAKEN WITH RASAGILINE*
Analgesics: meperidine (Demerol, and others), methadone
(Dolophine, and others), propoxyphene (Darvon, and others), Antidepressants: mirtazapine (Remeron, and others), SSRIs1 or
R Hauser et al. Early treatment with rasagiline is more benefi- cial than delayed treatment start in the long-term management Other MAO inhibitors, including linezolid (Zyvox)
of Parkinson’s disease. Mov Disord 2005; 20 suppl 10:S75, Sympathomimetic amines: amphetamines, ephedrine, phenyl-
ephrine, pseudoephedrine (Sudafed, and others) Other drugs: cyclobenzaprine (Flexeril, and others),
dextromethorphan, St. John’s wort, general anesthesia (for * Or within 14 days of rasagiline administration 1. Fluoxetine must be stopped 5 weeks before treatment with rasagiline.
ing ciprofloxacin (Cipro, and others) and fluvoxamine Even though rasagiline is an MAO-B inhibitor, its selectivity in humans has not been fully character- ized. Consequently, patients should avoid foods rich in tyramine during treatment and for 14 days after rasagiline is discontinued to avoid a possible hyper- DOSAGE — The recommended dose of rasagiline for
initial treatment of PD is 1 mg once daily. Patients with
mild hepatic impairment should take 0.5 mg daily; the
drug is not recommended for patients with moderate
or severe hepatic impairment. Patients taking
ciprofloxacin, fluvoxamine or other drugs that inhibit
CYP1A2 should take 0.5 mg once daily.
The recommended initial dose for patients already tak-ing levodopa is 0.5 mg once daily, which can beincreased to 1 mg as needed. Dyskinesia and otherdopaminergic adverse effects were increased inpatients taking rasagiline combined with levodopa inclinical trials; the dose of levodopa may, therefore, needto be decreased. CONCLUSION — Rasagiline (Azilect), the second
MAO-B inhibitor approved for treatment of
Parkinson’s disease, appears to be modestly helpful
for treatment of early and advanced disease. No
studies are available comparing rasagiline with
selegiline, which costs less.
The Medical Letter • Volume 48 • Issue 1249/1250 • December 4/18, 2006 Coming Soon in The Medical Letter:
Oral Oxymorphone (Opana) for Pain
Sitagliptin (Januvia) for Diabetes
Telbivudine (Tyzeka) for Hepatitis B
Coming Soon in Treatment Guidelines:
Common Eye Disorders – January 2007
Cognitive Loss and Dementia – February 2007
Tuberculosis – March 2007
Mark Abramowicz, M.D.
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The Medical Letter • Volume 48 • Issue 1249/1250 • December 4/18, 2006

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