WARNINGS
Selegiline should not be used at daily doses exceeding
those recommended (10 mg/day) because of the risks associated
with non-selective inhibition of MAO. (See CLINICAL PHARMACOLOGY.)
The selectivity of selegiline for MAO B may not be absolute
even at the recommended daily dose of 10 mg a day and
selectivity is further diminished with increasing daily
doses. The precise dose at which selegiline becomes a
non-selective inhibitor of all MAO is unknown, but may
be in the range of 30 to 40 mg a day.
Severe CNS toxicity associated with hyperpyrexia and
death have been reported with the combination of tricyclic
antidepressants and non-selective MAOIs (Phenelzine, Tranylcypromine).
A similar reaction has been reported for a patient on
amitriptyline and selegiline. Another patient receiving
protriptyline and selegiline developed tremors, agitation,
and restlessness followed by unresponsiveness and death
two weeks after selegiline was added. Related adverse
events including hypertension, syncope, asystole, diaphoresis,
seizures, changes in behavioral and mental status, and
muscular rigidity have also been reported in some patients
receiving selegiline and various tricyclic antidepressants.
Serious, sometimes fatal, reactions with signs and symptoms
that may include hyperthermia, rigidity, myoclonus, autonomic
instability with rapid fluctuations of the vital signs,
and mental status changes that include extreme agitation
progressing to delirium and coma have been reported with
patients receiving a combination of fluoxetine hydrochloride
and non-selective MAOIs. Similar signs have been reported
in some patients on the combination of selegiline (10
mg a day) and selective serotonin reuptake inhibitors
including fluoxetine, sertraline, and paroxetine.
Since the mechanisms of these reactions are not fully
understood, it seems prudent, in general, to avoid the
combination of selegiline and tricyclic antidepressants
as well as selegiline and selective serotonin reuptake
inhibitors. At least 14 days should elapse between discontinuation
of selegiline and initiation of treatment with a tricyclic
antidepressant or selective 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 selegiline.
PRECAUTIONS
General
Some patients given selegiline 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 by approximately
10 to 30%.
The decision to prescribe selegiline 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
selegiline. Consequently, the full spectrum of possible
responses to selegiline may not have been observed in
pre-marketing evaluation of the drug. It is advisable,
therefore, to observe patients closely for atypical responses.
Information for the Patient
See PATIENT INFORMATION section.
Laboratory Tests
No specific laboratory tests are deemed essential for
the management of patients on selegiline hydrochloride.
Periodic routine evaluation of all patients, however,
is appropriate.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
Assessement of the carcinogenic potential of selegiline
in mice and rats is ongoing.
Selegiline did not induce mutations or chromosomal damage
when tested in the bacterial mutation assay in Salmonella
typhimurium and an in vivo chromosomal aberration assay.
While these studies provide some resurrance 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 assays have been performed.
The effect of selegiline on fertility has not been adequately
assessed.
Pregnancy
Teratogenic Effects: Pregnancy Category C: No teratogenic
effects were observed in a study of embryo-fetal development
in Sprague-Dawley rats at oral doses of 4, 12, and 36
mg/kg or 4, 12, and 35 times the human therapeutic dose
on a mg/m2 basis. 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 or
10, 48, and 95 times the human therapeutic dose on a mg/m2basis;
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, increases
in 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- postnatal development
study in Sprague-Dawley rats oral doses of 4, 16, and
64 mg/kg or 4, 15, and 62 times the human therapeutic
dose on a mg/m2 basis, an increase in the numbers if stillbirths
and decrease in the number of pigs 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 pigs 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.
There are no adequate and well-controlled studies in
pregnant women. Selegiline should be used during pregnancy
only if the potential benefit justifies the potential
risk to the fetus.
Nursing Mothers
It is not known whether selegiline hydrochloride is excreted
in human milk. Because many drugs are excreted in human
milk, consideration should be given to discontinuing the
use of all but absolutely essential drug treatments in
nursing women.
Pediatric Use
The effects of selegiline hydrochloride in pediatric
patients have not been evaluated.
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