Pharmacology Update
Rasagiline Tablets(Azilect®)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.
A second generation, selective, irreversible, monoamine oxidase type B inhibitor has been approved for the treatment of Parkinson's disease (PD). Rasagiline is manufactured by Teva Pharmaceutical Industries Ltd in Israel and marketed by Teva Neurosciences, Inc. and Eisai Inc. in the United States as "Azilect®."
Indications
Rasagiline is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease both as initial therapy and as adjunct therapy with levodopa.1
Dosage
The recommended dose for monotherapy is 1 mg daily. For adjunctive therapy, the recommended initial dose is 0.5 mg daily. The dose may be increased to 1 mg daily. The dose of levodopa may be reduced based on individual response such as dopaminergic side effects. In clinical trials, 9-17% of patients had levodopa dosage reduction with an average dose reduction of 9%-13%.1
Potential Advantages
Rasagiline is dosed once daily and titration is generally not necessary. Rasagiline is 5 to 10 times more potent than selegiline. In contrast to selegiline, rasagiline is not metabolized to L-amphetamine and L-methamphetamine.2
Potential Disadvantages
Rasagiline does not appear to be as effective as other anti-Parkinson drugs as monotherapy.2 Dyskinesia was reported in 18% of patients who had rasagiline added to levodopa and dopamine agonist compared to 10% for placebo (P = 0.03).3 Dietary restriction and avoidance of exogenous amines are recommended.1 A higher incidence of depression, hallucination, and postural hypotension has been reported in patients older than 65 or 70 years when combined with levodopa.4 Coadministration of tricyclic, SSRI, and SNRI antidepressants should be avoided and dosage reduction of rasagiline is recommended if coadministered with a CYP1A2 inhibitor (eg, ciprofloxacin).1
Comments
The efficacy of rasagiline has been demonstrated in one study in early PD not requiring dopaminergic therapy and 2 studies in patients with PD and motor fluctuations.3,5,6 As initial therapy, the TEMPO Study showed that patients randomized to rasagiline had a adjusted reduction in the United Parkinson's Disease Rating Scale (UPDRS) of -4.20 compared to placebo at 26 weeks, (n = 404).5 As adjunct therapy, rasagiline was added as adjunct to levodopa in patients with mean disease duration of 9-10 years.3,6 These patients were on a mean levodopa dose of 700-800 mg, and 60-70% were also on dopamine agonist. The mean "off" (poor or absent motor function) time was about 6 hours. The follow-up time was 18 weeks in one study (LARGO; n = 687) and 26 weeks in another (PRESTO; n = 472). The addition of 1 mg of rasagiline decreased "off" time by 0.94-1.18 hours. This improvement was similar to entacapone, which was an active arm in one study.3 As a continuation of the TEMPO Study, patients in the placebo group were given rasagiline for an additional 26 weeks and those on rasagiline continued for another 26 weeks.7 Patients treated with rasagiline for 12 months showed less functional decline than those with treatment delayed for 6 months. This along with animalmodels showing antioxidant and antiapoptotic properties suggest that rasagiline and/or its metabolite, aminoindane, may have neuroprotective effects. Further study is required to substantiate whether rasagiline affects disease progression. A multicenter study (ADI-AGO) was initiated in 2005 to investigate this possible effect. Rasagiline is generally well tolerated. The frequencies of worsening cognitive and behavioral symptoms appear to be low.8 Dyskinesia has been reported when rasagiline is added to levodopa and the elderly may be more likely to experience postural hypotension, depression, or hallucinations. The wholesale cost of rasagiline is $6.82 per day.
Clinical Implications
Parkinson's disease is a progressive neurodegenerative disease. Rasagiline is the newest anti-Parkinson drug and has demonstrated efficacy in early PD as well as an adjunct to levodopa in moderate-to-advanced disease. While rasagiline is conveniently dosed and well tolerated it may not be as effective as levodopa for early PD. As adjunct to levodopa, its effects may be similar to entacapone. Since comparative studies are not available and the potential neuroprotective effects need to be proven, the role of rasagiline remains to be established.
References
1. Azilect Product Information. Teva Neuroscience, Inc. August 2006.
2. Rascol O. Rasagiline in the pharmacotherapy of Parkinson's disease—a review. Expert Opin Pharmacother. 2005;6:2061-2075.
3. 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;62:241-248.
4. Goetz CG, et al. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004. Mov Disord. 2005;20:523-539.
5. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. 2002;59:1937-1943.
6. Rascol O, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet. 2005;365:947-954.
7. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol. 2004;61:561-566.
8. Parkinson Study Group. Rasagiline-associated motor improvement in PD occurs without worsening of cognitive and behavioral symptoms. J Neurol Sci. 2006;248:78-83.
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