Included as part of the PRECAUTIONS section.
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
Uncontrolled hypertension has been reported when taking
the recommended dose of swallowed selegiline and a sympathomimetic medication
After starting ZELAPAR, monitor patients for new onset
hypertension or exacerbation of hypertension that is not adequately controlled.
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
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
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
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.
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
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.
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.
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.
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
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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.
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
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 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.
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
Safety and effectiveness in pediatric patients have not
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
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%.
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].
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].