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Zelapar

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Zelapar

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypertension

ZELAPAR should not be used at daily doses exceeding those recommended (2.5 mg/day) because of the risks associated with non-selective inhibition of MAO [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

The selectivity of ZELAPAR for MAO-B may not be absolute even at the recommended daily dose of 2.5 mg a day. The selectivity of MAO-B inhibitors, typically decreases and it is ultimately lost as the dose is increased beyond recommended doses. 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. Selectivity for MAO-B inhibition is gradually lost with increasing daily doses. An increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg ZELAPAR daily [see DRUG INTERACTIONS]. However, the precise dose at which ZELAPAR becomes a nonselective inhibitor of all MAO enzymes in individual patients is unknown.

Reports of hypertensive reactions have occurred in patients who ingested tyraminecontaining consumables (i.e., food or drink) while receiving swallowed selegiline at the recommended dose (a dose believed to be relatively selective for MAO-B).

The safe use of ZELAPAR at doses above 2.5 mg daily without dietary tyramine restrictions has not been established.

A pharmacodynamic study showed increased tyramine sensitivity for increasing blood pressure and decreased selectivity for MAO-B with dosing above the recommended level (2.5 mg daily) [see CLINICAL PHARMACOLOGY].

Uncontrolled hypertension has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine).

After starting ZELAPAR, monitor patients for new onset hypertension or exacerbation of hypertension that is not adequately controlled.

Serotonin Syndrome

Serotonin syndrome and hyperpyrexia have been reported with the combined treatment of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a non-selective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl), rasagiline (AZILECT), and Zydis selegiline (ZELAPAR).

Serotonin syndrome is a potentially serious condition, which can result in death. Typical clinical signs and symptoms include behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, hypotension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor).

In the post-marketing period, fatal and non-fatal cases of serotonin syndrome have been reported in patients treated with antidepressants concomitantly with ZELAPAR [see CONTRAINDICATIONS and DRUG INTERACTIONS].

Clinical studies of ZELAPAR did not allow concomitant use of any selective serotonin re-uptake inhibitor (e.g., fluoxetine-Prozac, fluvoxamine-Luvox, paroxetine-Paxil, sertraline, venlafaxine-Effexor, or nefazadone-Serzone) or any non-selective serotonin reuptake inhibiting antidepressant drug (except when taken at a low dose and only at night for the purpose of effective sleep) with ZELAPAR.

Because the mechanisms responsible for these reactions are not fully understood, avoid the combination of ZELAPAR with any antidepressant. At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. In patients taking antidepressants with a long half-life (e.g., fluoxetine and its active metabolite), allow at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) to elapse between discontinuation of fluoxetine and initiation of ZELAPAR [see DRUG INTERACTIONS].

Falling Asleep During Activities Of Daily Living And Somnolence

Patients with Parkinson's disease treated with ZELAPAR or other drugs increasing dopaminergic tone have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment.

It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment.

Somnolence may occur in patients receiving ZELAPAR. There was an increased risk for somnolence in geriatric patients ( > 65 years) vs non-geriatric patients treated with ZELAPAR. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with ZELAPAR. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with ZELAPAR.

Before initiating treatment with ZELAPAR, advise patients about the potential to develop drowsiness and specifically ask about factors that may increase this risk, such as concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), ZELAPAR should ordinarily be discontinued. If a decision is made to continue ZELAPAR, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Hypotension/Orthostatic Hypotension

Assessments of orthostatic (supine and 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 ZELAPAR treatment than with placebo treatment. Patients taking ZELAPAR were most likely to experience a decline in systolic and diastolic blood pressure at 8 weeks (2 weeks after initiating 2.5 mg ZELAPAR). At that time, the incidence of systolic orthostatic hypotension was about 21% in ZELAPAR-treated patients and 9% in placebo-treated patients. The incidence of diastolic orthostatic hypotension was about 12% in ZELAPAR-treated patients and about 4% in placebo-treated patients. Thus, it appears that there may be an increased risk for orthostatic hypotension in the period after increasing the daily dose of ZELAPAR® from 1.25 to 2.5 mg.

The incidence of orthostatic hypotension was higher in geriatric patients ( ≥ 65 years) than in non-geriatric patients. In the geriatric patients, orthostatic hypotension occurred in about 3% of ZELAPAR-treated patients compared to 0% of placebo-treated patients.

Dyskinesia

ZELAPAR may potentiate dopaminergic side effects of levodopa and may cause dyskinesia or exacerbate preexisting dyskinesia. In controlled trials, the incidence of dyskinesia was 6% in ZELAPAR-treated patients and 3% in placebo-treated patients.

Decreasing the dose of levodopa may lessen dyskinesia. The incidence of dyskinesia causing study discontinuation was greater on ZELAPAR than on placebo.

Hallucinations/Psychotic-Like Behavior

In controlled trials, hallucination was reported by 4% of ZELAPAR-treated patients and 2% in placebo-treated patients. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of ZELAPAR-treated patients, compared to no patient on placebo.

Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during ZELAPAR treatment or after starting or increasing the dose of ZELAPAR. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with ZELAPAR because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of ZELAPAR [see DRUG INTERACTIONS].

Impulse Control/Compulsive Behaviors

Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including ZELAPAR, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge eating, or other urges while being treated with ZELAPAR. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ZELAPAR.

Withdrawal Emergent Hyperpyrexia And Confusion

Although not reported with ZELAPAR 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.

Melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using ZELAPAR for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Irritation Of The Buccal Mucosa

In the controlled clinical trials, periodic examinations of the tongue and oral mucosa were performed. At the end of the study, the frequency of mild oropharyngeal abnormality (e.g., swallowing pain, mouth pain, discrete areas of focal reddening, multiple foci of reddening, edema, and/or ulceration) in patients without similar abnormality at baseline was 10% in ZELAPAR-treated patients compared to 3% in placebo-treated patients.

Risk For Phenylketonuric Patients

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

Effect On Renal Function

Small increments in serum BUN and creatinine have been observed in patients treated with high dose ZELAPAR (10 mg daily; 4 times the recommended dose).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Assessment of the carcinogenic potential of selegiline administered orally to mice and rats is ongoing.

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

Mutagenesis

Selegiline was negative in the in vitro bacterial reverse mutation (Ames) assay in and the in vivo micronucleus assay. In the in vitro chromosomal aberration assay in mammalian cells, selegiline was negative in the absence of metabolic activation but was clastogenic in the presence of metabolic activation.

Impairment of Fertility

When selegiline was administered orally to male (5, 10, and 40 mg/kg/day) and female (1, 5, and 25 mg/kg/day) rats prior to and during mating and continuing in females to gestation day 7, a decreased number of implantations was observed at the highest doses tested. In males, a reduction in sperm count and density was observed at the highest dose tested. The no-effect doses for reproductive impairment in rats (10 mg/kg/day in males and 5 mg/kg/day in females) are approximately 40 (males) and 20 (females) times the maximum recommended human dose of 2.5 mg/day on a mg/m² basis.

No fertility studies have been conducted with selegiline using the buccal route.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In animal studies, administration of selegiline during pregnancy was associated with developmental toxicity (decreased embryofetal and postnatal offspring growth and survival) at doses greater than those used clinically. ZELAPAR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In rats administered selegiline orally (5, 10, and 40 mg/kg/day) throughout the period of organogenesis, a decrease in fetal body weight was observed at the mid and high doses. The no-effect dose for embryofetal developmental toxicity in rats (5 mg/kg/day) is approximately 20 times the maximum recommended human dose (MRHD) of 2.5 mg/day on a mg/m² basis.

In rabbits administered selegiline orally (5, 30, and 60 mg/kg/day) throughout the period of organogenesis, embryolethality was observed at the highest dose tested and reduced fetal body weight was observed at the mid and high doses. The no-effect dose for embryofetal developmental toxicity in rabbits (5 mg/kg/day) is approximately 40 times the MRHD on a mg/m² basis.

In rats administered selegiline orally (0.3, 1, and 10 mg/kg/day) during gestation and lactation, decreases in offspring survival and body weights were observed at the highest dose tested. The no-effect dose for pre-and postnatal developmental toxicity (1 mg/kg/day) is approximately 4 times the MRHD on a mg/m² basis.

Nursing Mothers

Selegiline and metabolites were detected in rat milk at levels higher than those in maternal plasma. It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZELAPAR is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

The overall incidence of adverse reactions was increased in geriatric patients ( > 65 years) compared to non-geriatric patients ( < 65 years). Clinical studies did not include a sufficient number of geriatric subjects older than 75 years to determine whether they respond differently to ZELAPAR.

Analysis of adverse reaction incidence in each group was conducted to calculate and compare relative risk (ZELAPAR % / Placebo %) for each treatment. The relative risk was ≥ 2 fold higher for ZELAPAR treatment in the geriatric patients compared to the non-geriatric patients for hypertension, orthostatic/postural hypotension [see WARNINGS AND PRECAUTIONS]. The incidence of orthostatic hypotension by measurement of blood pressure was also higher in geriatric patients than in non-geriatric patients. In the geriatric patients, the treatment difference for incidence of orthostatic hypotension determined by supine and standing blood measurements was 3%.

Hepatic Impairment

Patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9) may require a dose reduction of ZELAPAR (from 2.5 to 1.25 mg daily) depending on the clinical response. ZELAPAR is not recommended in patients with severe hepatic impairment (Child-Pugh score > 9) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Renal Impairment

No dose adjustment of ZELAPAR is required in patients with mild to moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min). ZELAPAR is not recommended in patients with severe renal impairment and patients with end-stage renal disease [ESRD] (CLcr < 30 mL/min) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 9/29/2014
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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