Preventing Rasagiline Drug Interactions

Rasagiline (Azilect) is a new selective,irreversible inhibitor of monoamineoxidase type B (MAO-B)that shows promise as an advance in thetreatment of Parkinson's disease. Rasagilineis in the same category as selegilinebut has some properties that differfrom selegiline, and thus the drug interactionsare not exactly the same.

Interactions with Other Drugs

Inhibition of MAO-B. Rasagiline inhibitionof MAO-B is not an important sourceof drug interactions per se, but since ithas not been ruled out that rasagilinemay inhibit MAO-A under some circumstances,a number of contraindicationsand warnings appear in the productinformation as described later on.Rasagiline metabolized by CYP1A2.

Because CYP1A2 is susceptible to bothinhibition and induction by other drugs,such drugs may increase or decreaserasagiline plasma concentrations.

Differences Between Rasagilineand Selegiline

Because rasagiline, like selegiline, isa selective MAO-B inhibitor that mightalso inhibit MAO-A, its interactionsbased on MAO inhibition are assumedto be essentially the same as for selegiline.The primary difference in druginteractions is that rasagiline is metabolizedprimarily by CYP1A2, whileselegiline is metabolized by more complexpathways involving CYP2B6 andCYP2C19.¹

Potential Adverse Outcomes

Serotonin syndrome. Several drugs arelisted in the product information as contraindicatedwith rasagiline due to therisk of serotonin syndrome. Meperidine iscontraindicated primarily because it hasresulted in severe and fatal interactionswith MAO-A inhibitors and in at least 1case with selegiline. Other drugs listed ascontraindicated with rasagiline based onsimilar theoretical considerations includetramadol, methadone, propoxyphene,dextromethorphan, St. John's wort, mirtazapine,and cyclobenzaprine. Althoughthere is little evidence to suggest thesecombinations are actually dangerous, thepotential adverse outcomes are sosevere that the "contraindication"designationis probably appropriate.

Serotonergic antidepressants such asselective serotonin reuptake inhibitors(SSRIs), selective serotonin/norepinephrinereuptake inhibitors, and tricyclic antidepressants(TCAs) are not listed in therasagiline product information as "contraindicated,"but concomitant use of rasagilinewith these agents "is not recommended."Hundreds of patients in rasagilineclinical trials received concomitantSSRIs or TCAs, apparently without adverseinteractions, but the regulators correctlymention that this does not rule outthe possibility of a rare, serious adverseoutcome from these combinations.

Hypertensive crisis. Since nonselectiveMAO inhibitors can cause acute hypertensivereactions if the patient ingestshigh-tyramine foods, and since one cannotrule out that rasagiline will be a nonselectiveMAO inhibitor in some patients,patients should be warned to avoid foodsrich in tyramine. For the same reasons,patients should avoid OTC sympathomimeticssuch as pseudoephedrine,phenylpropanolamine, ephedrine, andphenylephrine.

Altered rasagiline response. Rasagilineis metabolized primarily by CYP1A2, soinhibitors of this isozyme would beexpected to increase rasagiline plasmaconcentrations. Ciprofloxacin purportedlycan double rasagiline plasma concentrations,² and one would expect otherCYP1A2 inhibitors such as atazanavir,cimetidine, enoxacin, mexiletine, tacrine,and zileuton to increase rasagiline levelsas well. Of these drugs, fluvoxamine andenoxacin markedly inhibit CYP1A2 andtheir use with rasagiline should probablybe contraindicated.

One should also expect reduced rasagilineeffect in patients receiving CYP1A2inducers such as barbiturates, carbamazepine,and rifampin. Smoking is aparticularly potent stimulant to CYP1A2activity, so one would expect smokers tohave substantial reductions in rasagilineplasma concentrations. One should bealert for the need to increase rasagilinedosage in patients on CYP1A2 inducers.

Conclusion

Although most rasagiline drug interactionsare based on theoretical considerationsrather than actual clinical data, thepotential severity of many of the adverseoutcomes dictates a conservative approachwhen giving rasagiline concomitantlywith these drugs. Many of thepotentially interacting drugs are not lifesavingand have alternatives (eg, OTCnasal decongestants, dextromethorphan,meperidine). For other drugs suchas antidepressants that may be importantfor the patient, one should weigh thebenefits versus the (usually small) risk ofusing them with rasagiline.

Drs. Horn and Hansten are both professorsof pharmacy at the Universityof Washington School of Pharmacy.For an electronic version of this article,including references if any, visitwww.hanstenandhorn.com.

References

1. Chen JJ, Ly A-V. Rasagiline: a second-generation monoamine oxidase type-B inhibitor for thetreatment of Parkinson's disease. Am J Health Syst Pharm. 2006;63:915-928.

2. Azilect Product Information. Kansas City, Mo: Teva Neuroscience Inc; 2006.