The selectivity of ZELAPARÃ? for MAO-B may not be absolute even at the recommended daily dose of 2.5 mg a day. Even for "selective" MAO-B inhibitors, the selectivity for inhibiting MAO-B typically diminishes and is ultimately lost as the dose is increased beyond particular dose levels. Rare cases of hypertensive reactions associated with ingestion of tyramine containing foods have been reported even in patients taking the recommended daily dose of swallowed selegiline, a dose which is generally believed to be selective for MAO-B. Obviously, any selectivity is further diminished with increasing daily doses. An increase in tyramine sensitivity for blood pressure responses appears to occur beginning at a 5 mg daily dose. However, the precise dose at which ZELAPARÃ? becomes a non-selective inhibitor of all MAO is unknown.

Severe CNS toxicity associated with hyperpyrexia and death has been reported with the combination of tricyclic antidepressants and non-selective MAOIs (NARDIL^Ã?, PARNATE^Ã?) or a selective MAO-B inhibitor, swallowed selegiline (Eldepryl). These adverse events have included behavioral and mental status changes, diaphoresis, muscular rigidity, hypertension, syncope, and death.

Serious, sometimes fatal, reactions with signs and symptoms including hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuations, and mental status changes progressing to extreme agitation, delirium, and coma have been reported in patients receiving a combination of selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (PROZAC^Ã?), fluvoxamine (LUVOX^Ã?), sertraline (ZOLOFT^Ã?), and paroxetine (PAXIL^Ã?) and non-selective MAOIs or the selective MAO-B inhibitor selegiline. Similar reactions have been reported with serotonin-norepinephrine reuptake inhibitors (SNRIs) including venlafaxine and non-selective MAOIs or the selective MAO-B inhibitor selegiline.

Since the mechanisms of these reactions are not fully understood, it seems prudent, in general, to avoid these combinations of ZELAPARÃ? and tricyclic antidepressants as well as ZELAPARÃ? and serotonin reuptake inhibitors. At least 14 days should elapse between discontinuation of ZELAPARÃ? and initiation of treatment with a tricyclic antidepressant or serotonin reuptake inhibitors. Because of the long half-lives of fluoxetine and its active metabolite, at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of treatment with ZELAPARÃ?.

Although the incidence of orthostatic/postural hypotension reported as an adverse event was not higher in all patients treated in two clinical controlled trials, the incidence of adverse orthostatic hypotension was higher in geriatric patients (≥ 65 year old) than in non-geriatric patients. In the geriatric patients, this adverse event of orthostatic hypotension occurred in about 3% of ZELAPARÃ?-treated patients compared to none (0%) of placebo-treated geriatric patients. Of potential relevance, the risk of dizziness was also greater in geriatric patients. In non-geriatric patients, the incidence of adverse orthostatic hypotension was not more frequent with ZELAPARÃ? than with placebo treatment.

Assessments of orthostatic (supine vs. standing) blood pressures at different times throughout the 12 week study period in two controlled trials showed that the frequency of orthostatic hypotension (> 20 mm Hg decrease in systolic blood pressure and/or > 10 mm Hg decrease in diastolic blood pressure) was greater with ZELAPARÃ? treatment than with placebo treatment. Of particular note, the treatment difference incidence (i.e. ZELAPARÃ? % - placebo %) of systolic and diastolic orthostatic decrements was most striking at 8 weeks (2 weeks after initiating 2.5 mg ZELAPARÃ?). At that time, the incidence of systolic orthostatic hypotension was about 21% in the ZELAPARÃ? patients and about 9% in the placebo patients. The incidence of diastolic orthostatic hypotension was about 12% in the ZELAPARÃ? group and about 4% in the placebo group. Thus, it appears that there may be an increased risk for orthostatic hypotension in the period after increasing the daily dose of ZELAPARÃ? from 1.25 to 2.5 mg.

Some epidemiological studies have shown that patients with Parkinsons disease have a higher risk (perhaps 2- to 4-fold higher) of developing melanoma than the general population, although it is unclear whether the observed increased risk was due to Parkinsons disease itself or to drugs used to treat Parkinsons disease. Selegiline is one of the drugs used to treat Parkinsons disease. Although ZELAPARÃ? has not been associated with an increased risk of melanoma specifically, its potential role as a risk factor has not been systematically studied. Patients using ZELAPARÃ? should be made aware of these results and should undergo periodic dermatologic screening.

Some patients given ZELAPARÃ? may experience an exacerbation of levodopa associated side effects, presumably due to the increased amounts of dopamine reacting with super sensitive, post-synaptic receptors. These effects may often be mitigated by reducing the dose of levodopa/carbidopa. For example, in the study demonstrating the efficacy of ZELAPARÃ?, there was an average 24% reduction in levodopa/carbidopa dosage in the 17% of patients who experienced a dose reduction during ZELAPARÃ?treatment.

The decision to prescribe ZELAPARÃ? should take into consideration that the MAO system of enzymes is complex and incompletely understood and there is only a limited amount of carefully documented clinical experience with ZELAPARÃ?. Consequently, the full spectrum of possible responses to ZELAPARÃ? may not have been observed in pre-marketing evaluation of the drug. It is advisable, therefore, to observe patients closely for atypical responses.

It is important to note that each ZELAPARÃ? tablet contains 1.25 mg phenylalanine (a component of aspartame). Patients taking the 2.5 mg dose of ZELAPARÃ? will receive 2.5 mg phenylalanine.

In the controlled clinical trials, periodic examinations of the tongue and oral mucosa were performed. There was an increased frequency of mild oropharyngeal abnormality (e.g. swallowing pain, mouth pain, discrete areas of focal reddening, multiple foci of reddening, edema, and/or ulceration) at the end of the study in patients who did not have any abnormality at baseline and who received treatment with ZELAPARÃ? (10%) compared to patients who received placebo (3%). Separate analyses of each oropharyngeal abnormality were also assessed. ZELAPARÃ? patients (3%) showed an increased frequency of the development of mild discrete areas of focal reddening compared to placebo (0%) patients. ZELAPARÃ? patients (2%) also showed an increased frequency of the development of mild ulceration compared to placebo (1%) patients.

ZELAPARÃ? may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia. Decreasing the dose of levodopa may ameliorate this side effect.

Small increments in serum BUN and creatinine have been observed in patients treated with ZELAPARÃ? 10 mg daily (4 times the recommended dose). Similar changes were not observed in patients treated with 1.25 or 2.5 mg daily.

The effect of ZELAPARÃ? has not been studied in renally-impaired patients. ZELAPARÃ? should therefore be used with caution in patients with a history of, suspected, or known renal impairment. If such patients experience adverse reactions that seem more frequent or severe than might ordinarily be expected, consideration should be given to discontinuing ZELAPARÃ?.

The effect of ZELAPARÃ? has not been studied in hepatically-impaired patients. ZELAPARÃ? should therefore be used with caution in patients with a history of, suspected, or known hepatic impairment, particularly if the patient has an increased prothrombin time or increased serum bilirubin or decreased serum albumin. If such patients experience adverse reactions that seem more frequent or severe than might ordinarily be expected, consideration should be given to discontinuing ZELAPARÃ?.

Although not reported with ZELAPARÃ? in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.

When used as an adjunct to levodopa, hallucinations were reported as an adverse event in approximately 4% of patients treated with ZELAPARÃ? and 2% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of patients treated with ZELAPARÃ? and none of the placebo treated patients.

Patients should be cautioned of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop.

No specific laboratory tests are deemed essential for the management of patients on ZELAPARÃ?. Periodic routine evaluation of all patients, however, is appropriate.

Carcinogenicity studies of selegiline have not been conducted using the buccal route.

Selegiline did not induce mutations or chromosomal damage when tested in the bacterial mutation assay in Salmonella typhimurium and in an oral in vivo chromosomal aberration assay. While these studies provide some reassurance that selegiline is not mutagenic or clastogenic, they are not definitive because of methodological limitations. No definitive in vitro chromosomal aberration or in vitro mammalian gene mutation studies have been performed.

The effect of selegiline on fertility has not been adequately assessed.

No teratogenic effects were observed in a study of embryo-fetal development in SpragueDawley rats at oral doses of 4, 12, and 36 mg/kg.

No teratogenic effects were observed in a study of embryo-fetal development in New Zealand White rabbits at oral doses of 5, 25, and 50 mg/kg; however, in this study, the number of litters produced at the two higher doses was less than recommended for assessing teratogenic potential.

In the rat study, there was a decrease in fetal body weight at the highest dose tested. In the rabbit study, increases in the total resorptions and percent post-implantation loss, and a decrease in the number of live fetuses per dam occurred at the highest dose tested.

In a peri- and post-natal development study in SpragueDawley rats (oral doses of 4, 16, and 64 mg/kg), an increase in the number of stillbirths and decreases in the number of pups per dam, pup survival, and pup body weight (at birth and throughout the lactation period) were observed at the two highest doses. At the highest dose tested, no pups born alive survived to Day 4 postpartum. Postnatal development at the highest dose tested in dams could not be evaluated because of the lack of surviving pups. The reproductive performance of the untreated offspring was not assessed.

No reproductive and developmental toxicology studies have been conducted using the buccal route.

There are no adequate and well-controlled studies in pregnant women. ZELAPARÃ? should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether selegiline is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ZELAPARÃ?, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in patients under 16 years of age have not been established.

The majority of patients (128/194; 66%) who received ZELAPARÃ? in the double-blind placebo-controlled studies were 65 years of age and older (i.e. geriatric patients). There was no appreciable difference in treatment response of ZELAPARÃ? in geriatric vs. non-geriatric patients. However, the overall frequency of adverse events and of certain types of adverse events was increased in geriatric patients compared to non-geriatric patients. (See INCIDENCE IN CONTROLLED CLINICAL TRIALS UNDER ADVERSE REACTIONS.)

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