Pharmacy & Therapeutics - April 2008 - (Page 214) DRUG FORECAST population and their responsiveness to the system. levothyroxine (Synthroid, Abbott), olanzapine (Zyprexa, Lilly), and warfarin (Coumadin, Bristol-Myers Squibb) have been the subject of several studies, none of which has confirmed an altered pharmacokinetic profile of either selegiline or the test agent. However, the potential for drug–drug interactions has been identified with carbamazepine (Tegretol, Novartis) and some sympathomimetic agents. As with other MAOIs, these agents are contraindicated in patients using the STS (Table 1).26 Carbamazepine can cause a decrease in drug exposure, although slightly increased levels of selegiline and its metabolites were seen following a single application of the STS at 6 mg/24 hours in subjects who had received carbamazepine 400 mg/day for 14 days.26 The clinical relevance of these findings is unknown. For the sympathomimetic agents, pharmacokinetic studies have shown that giving the STS at a dose of 6 mg/24 hours with phenylpropanolamine (PPA) 25 mg every four hours for 24 hours does not affect the pharmacokinetics of PPA. However, there was a higher incidence of significant blood pressure elevations with the STS plus PPA than with PPA alone, suggesting a possible pharmacodynamic interaction.26 Giving the STS at a dose of 6 mg/24 hours for 10 days with pseudoephedrine (60 mg three times daily) did not affect the pharmacokinetic properties of pseudoephedrine.26 As with other MAOIs, the STS should not be administered with cold products or weight-reducing preparations that contain vasoconstrictors, including amphetamine and other sympathomimetic agents (see Table 1). Other medications are also contraindicated with the STS, such as: • selective serotonin reuptake inhibitors (SSRIs). • selective norepinephrine reuptake inhibitors (SNRIs). • tricyclic antidepressants. • St. John’s wort. • meperidine (Demerol, Sanofi-Synthelabo). • analgesic agents: tramadol (Ultram, PriCara), methadone (Dolophine, Roxane), and propoxyphene (Darvon, aaiPharma/Xanodyne). • cold or cough preparations containing dextromethorphan. Oral selegiline and other MAOIs should not be used concomitantly with the STS (see Table 1). Contraindications with other anti depressants are largely related to CNS toxicity (“serotonin syndrome”), which has been reported in case studies.29 Serotonin toxicity is characterized by neuromuscular excitation (hyperreflexia, myoclonus, rigidity), autonomic stimulation (hyper thermia, tachycardia, tremor, flushing), and an altered mental state (anxiety, agitation, confusion). Serotonin toxicity can be mild, with features that might not be a concern to the patient; moderate, with toxicity causing significant but not life-threatening distress; or severe, consisting of a medical emergency characterized by rapid onset of severe hyperthermia, muscle rigidity, and multiple organ failure.29 An increase in CNS toxicity has been observed in case reports of patients who received an MAOI with or shortly after the administration of SSRIs.30–37 Two case reports in individual patients have described similar reactions with oral selegiline and SSRIs.38,39 However, in patients with Parkinson’s disease, oral selegiline at the approved dose of 5 mg twice daily was well tolerated when it was administered with sertraline (Zoloft, Pfizer), paroxetine (Paxil, GlaxoSmithKline), or fluoxetine (Prozac, Lilly).40–42 In general, the quality of the evidence is poor and further studies are required to examine drug interactions with anti depressant medications. Owing to their irreversible inhibition of MAO, the physiological effects of MAOIs may persist for up to three weeks after they are discontinued.43 As such, a 14-day washout period is recommended before alternative antidepressant therapy is initiated in order to prevent potentially serious pharmacodynamic interactions. Similar precautions should be taken when patients are switched from one MAOI to another, although more rapid switches (from one to eight days) have been safely performed.44,45 The practice of avoiding the narcotic analgesic meperidine in patients receiving MAOIs is based on data from case reports with nonselective MAOIs46–52 and from one case report with oral selegiline and meperidine (pethidine).51 For those patients receiving MAOIs, morphine is considered the narcotic analgesic of PRACTICAL CONSIDERATIONS Dosage STS patches are available in three doses: 6, 9, and 12 mg every 24 hours. No dietary modifications are required at the recommended starting and target doses for the 6-mg/24 hour regimen. Higher STS doses of 9 and 12 mg/24 hours are also effective, but studies were not designed to evaluate improved efficacy at higher doses. Based on the more limited data available for the doses of 9 and 12 mg/24 hours, food effects cannot be ruled out; therefore, patients receiving these doses should follow dietary modifications that include the avoidance of tyramine-rich food and beverages during treatment and for up to two weeks after therapy has been completed. Dietary modifications should also be followed for two weeks after a dose reduction to 6 mg/24 hours.26 No dose adjustment is necessary for patients with mild-to-moderate renal or hepatic impairment. The recommended daily dose for elderly patients (65 years of age and older) is 6 mg/24 hours; careful monitoring of these patients is necessary if the dose is increased further.26 Applying the Patch The STS patch should be applied every 24 hours, and it should be changed at the same time each day. Patients should remove the old patch before applying a new one. The patch is applied to dr y, smooth skin on the patient’s upper chest or back (below the neck and above the waist), the upper thigh, or to the outer surface of the upper arm. A new site should be chosen each time the patch is changed. The application site should be free of hairy, oily, irritated, or broken tissue, and the patch should not be placed where the patient’s clothing is tight, because this can cause the patch to be rubbed off. DRUG–DRUG INTERACTIONS AND CONTRAINDICATIONS Despite the widespread use of MAOIs over the past 50 years, their pharmacokinetic interactions have yet to be fully elucidated.27,28 The potential for interactions between the STS and alcohol, alprazolam (Xanax, Pfizer), ibuprofen, 214 P&T® • April 2008 • Vol. 33 No. 4
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