WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Suicidal Thoughts And Behaviors In Adolescents And Young
Adults
In pooled analyses of placebo-controlled trials of
antidepressant drugs (SSRIs and other antidepressant classes) that included
approximately 77,000 adult patients and over 4,400 pediatric patients, the
incidence of suicidal thoughts and behaviors in pediatric and young adult
patients was greater in antidepressant-treated patients than in placebo-treated
patients. The drug-placebo differences in the number of cases of suicidal
thoughts and behaviors per 1000 patients treated are provided in Table 2.
No suicides occurred in any of the pediatric studies.
There were suicides in the adult studies, but the number was not sufficient to
reach any conclusion about antidepressant drug effect on suicide.
Table 2: Risk Differences of the Number of Cases of
Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of
Antidepressants in Pediatric and Adult Patients
Age Range (years) |
Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated |
Increases Compared to Placebo |
< 18 |
14 additional patients |
18-24 |
5 additional patients |
Decreases Compared to Placebo |
25-64 |
1 fewer patient |
≥ 65 |
6 fewer patients |
It is unknown whether the risk
of suicidal thoughts and behaviors in pediatric and young adult patients
extends to longer-term use, i.e., beyond four months. However, there is
substantial evidence from placebo-controlled maintenance trials in adults with
MDD that antidepressants delay the recurrence of depression.
Monitor all antidepressant-treated patients for clinical
worsening and emergence of suicidal thoughts and behaviors, especially during
the initial few months of drug therapy and at times of dosage changes. Counsel
family members or caregivers of patients to monitor for changes in behavior and
to alert the healthcare provider. Consider changing the therapeutic regimen,
including possibly discontinuing EMSAM, in patients whose depression is
persistently worse, or who are experiencing emergent suicidal thoughts or
behaviors.
Serotonin Syndrome
The development of a potentially life-threatening
serotonin syndrome has been reported with concomitant use of MAOIs, such as
EMSAM, with serotonergic drugs. These reactions have also been reported in
patients who have discontinued serotonergic drugs and then subsequently started
an MAOI [see CONTRAINDICATIONS].
Serotonin syndrome symptoms may include mental status
changes (e.g., agitation, hallucinations, delirium, and coma), autonomic
instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis,
flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity,
myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal
symptoms (e.g., nausea, vomiting, diarrhea).
Patients should be monitored for the emergence of
serotonin syndrome. Treatment with EMSAM and any concomitant serotonergic
agents should be discontinued immediately if the above events occur and
supportive treatment should be initiated.
Blood Pressure Elevation
Tyramine-Induced Hypertensive Crisis
EMSAM inhibits the catabolism of dietary amines, such as
tyramine, and has the potential to produce a hypertensive crisis following the
ingestion of tyramine-rich foods or beverages [see DRUG INTERACTIONS and
CLINICAL PHARMACOLOGY].
Hypertensive crises, which in some cases may be fatal,
are characterized by some or all of the following symptoms: occipital headache
which may radiate frontally, palpitation, neck stiffness or soreness, nausea,
vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin),
dilated pupils, and photophobia. Either tachycardia or bradycardia may be
present and can be associated with constricting chest pain. Intracranial
bleeding has been reported in association with the increase in blood pressure.
Patients should be instructed as to the signs and symptoms of severe
hypertension and advised to seek immediate medical attention if these signs or
symptoms are present.
If a hypertensive crisis occurs, EMSAM should be
discontinued immediately and therapy to lower blood pressure should be
instituted immediately. Fever should be managed by means of external cooling.
Patients must be closely monitored until symptoms have stabilized. To prevent a
hypertensive crisis, patients receiving treatment with EMSAM 9 mg per 24 hours
or EMSAM 12 mg per 24 hours should follow the advice regarding a low tyramine
diet described in Table 5 under Dietary Modifications Required for Patients
Taking EMSAM 9 mg per 24 hours and 12 mg per 24 hours [see DRUG INTERACTIONS].
Blood Pressure Elevation Related To Concomitant
Medication
Carbamazepine is contraindicated with EMSAM because
carbamazepine has been shown to significantly elevate selegiline levels, which
may increase the risk of a hypertensive crisis [see CONTRAINDICATIONS and
DRUG INTERACTIONS].
The use of EMSAM with adrenergic drugs or buspirone may
produce substantial increases in blood pressure. Therefore, monitor blood
pressure if EMSAM is used with any of the following drugs: buspirone,
amphetamines, or cold products or weight-reducing preparations that contain
sympathomimetic amines (e.g., pseudoephedrine, phenylephrine,
phenylpropanolamine, and ephedrine).
Activation Of Mania/Hypomania
In patients with bipolar disorder, treating a depressive
episode with EMSAM or another antidepressant may precipitate a mixed/manic
episode. During Phase III trials, a manic reaction occurred in 8 out of 2,036
(0.4%) patients treated with EMSAM. Prior to initiating treatment with EMSAM,
screen patients for any personal or family history of bipolar disorder, mania,
or hypomania.
External Heat
The effect of direct heat applied to EMSAM on the
bioavailability of selegiline has not been studied. However, in theory, heat
may result in an increase in the amount of selegiline absorbed from EMSAM and
produce elevated serum levels of selegiline. Patients should be advised to
avoid exposing the EMSAM application site to external sources of direct heat,
such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated
water beds, and prolonged direct sunlight.
Patient Counseling Information
See FDA-approved patient
labeling (Medication Guide and Instructions for Use).
Advise patients and their
caregivers about the benefits and risks associated with treatment with EMSAM
and counsel them in its appropriate use. Advise patients and their caregivers
to read the Medication Guide and assist them in understanding its contents. The
complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of
the following issues and asked to alert their prescriber if these occur while
taking EMSAM.
Suicide Risk: Advise patients and
caregivers to look for the emergence of suicidal ideation and behavior,
especially early during treatment and when the dose is adjusted up or down [see
BOXED WARNING and WARNINGS AND PRECAUTIONS].
Tyramine Reactions: Patients should be
advised that tyramine-rich foods and beverages should be avoided while on EMSAM
9 mg per 24 hours or EMSAM 12 mg per 24 hours, and for 2 weeks following
discontinuation of EMSAM at these doses because of the risk of a tyramine
reaction [see WARNINGS AND PRECAUTIONS,
DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY]. Patients should also be advised to avoid
tyramine-containing nutritional supplements. Patients should be instructed to
immediately report the occurrence of the following acute symptoms:
severe headache, neck stiffness, heart racing or palpitations, or other sudden
or unusual symptoms.
Concomitant Medication: Advise patients to inform
their physicians if they are taking, or plan to take, any prescription or
over-the-counter medications, including herbals, because of a potential for
dangerous interactions. Instruct patients not to take EMSAM with medication
that is contraindicated or within two weeks of stopping such medication (5
weeks for fluoxetine). Contraindicated medication should not be started within
two weeks of stopping EMSAM [see CONTRAINDICATIONS].
Psychomotor Performance: EMSAM has not been shown
to impair psychomotor performance; however, any psychoactive drug may
potentially impair judgment, thinking, or motor skills. Patients should be
cautioned about operating hazardous machinery, including automobiles, until
they are reasonably certain that EMSAM therapy does not impair their ability to
engage in such activities.
Alcohol: Patients should be told that, although
EMSAM has not been shown to increase the impairment of mental and motor skills
caused by alcohol, the concomitant use of EMSAM and alcohol in depressed
patients is not recommended.
Pediatrics: Advise patients that EMSAM must not be
used in children less than 12 years of age because of an increased risk of
severe increases in blood pressure. Also, patients should be advised that EMSAM
is not recommended for use in pediatric patients ages 12 to 17 years [see
Use in Specific Populations].
Pregnancy: Advise the pregnant woman about the
potential risk to the fetus [see Use in Specific Populations].
Lactation: Advise a woman that breastfeeding is
not recommended during treatment with EMSAM treatment and for 5 days after the
final dose [see Use in Specific Populations].
How To Use EMSAM
Detailed Instructions are provided in the Medication
Guide. Prescribers should instruct patients on the following:
- EMSAM should be applied to dry, intact skin on the upper
torso (below the neck and above the waist), upper thigh or the outer surface of
the upper arm. A new application site should be selected with each new
transdermal system to avoid re-application to the same site on consecutive days.
Transdermal systems should be applied at approximately the same time each day.
- Apply the transdermal system to an area of skin that is
not hairy, oily, irritated, broken, scarred or calloused. Do not place the
transdermal system where your clothing is tight, which could cause the
transdermal system to rub off.
- After you have selected the site for your transdermal
system, wash the area gently and thoroughly with soap and warm water. Rinse
until all soap is removed. Dry the area with a clean dry towel.
- Just before you apply the transdermal system, remove it
from the pouch by tearing at the notches (do not use scissors). Remove half of
the release liner and throw it away. Try not to touch the exposed side (sticky
side) of the transdermal system, because the medicine could come off on your
fingers.
- Press the sticky side of the transdermal system firmly
against the skin site that was just washed and dried. Remove the second half of
the release liner and press the remaining sticky side firmly against your skin.
Make sure that the transdermal system is flat against the skin (there should be
no bumps or folds in the transdermal system) and is sticking securely. Be sure
the edges are stuck to the skin surface.
- After you have applied the transdermal system, wash your
hands thoroughly with soap and water to remove any medicine that may have
gotten on them. Do not touch your eyes until after you have washed your hands.
- After 24 hours, remove your transdermal system slowly and
carefully to avoid damaging your skin.
- If the transdermal system is too sticky on your skin, and
you need something to help you remove it:
- Gently wash the area with warm water and mild soap.
- A small amount of oil-based product (petroleum jelly,
olive oil, or mineral oil) may be needed to help remove the transdermal system.
Gently apply and spread the oil underneath the transdermal system edges.
- Apply an oil-based product or lotion to your skin if any
adhesive (glue) remains after you remove your transdermal system. This will
gently loosen and remove any adhesive that is left over.
- Fold the used EMSAM transdermal system in half and press
it together firmly so that the sticky side sticks to itself.
- Safely throw away the folded transdermal system in a
container with a lid right away so that children and pets cannot reach it.
- Safely throw away any unused EMSAM transdermal systems
that are left over from the prescription as soon as they are no longer needed.
- Wash your hands with soap and water.
- If your transdermal system falls off, apply a new
transdermal system to a new site and resume your previous schedule.
- Only one EMSAM transdermal system should be worn at a
time.
- Do not cut the EMSAM transdermal system into smaller
portions.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
In a dermal carcinogenicity study in CD-1 mice,
selegiline (the drug substance of EMSAM) was administered daily for 2 years at
the same skin site at dose levels of 20, 70, and 200 mg per kg per day
(dissolved in acetone). The incidence of systemic tumors was not increased and
the high dose provided systemic exposures to selegiline and its three
metabolites in mice that were greater than 40 times the exposures in humans at
the maximum recommended human dose (MRHD). The incidence of squamous cell
carcinoma was slightly increased on treated skin of mice administered the high
dose. This finding was associated with an increased incidence of epithelial
hyperplasia, dyskeratosis/hyperkeratosis and inflammation.
In an oral carcinogenicity study in rats, selegiline
given in the diet for 104 weeks was not carcinogenic up to the highest
evaluable dose tested (3.5 mg per kg per day), which exposed rats to systemic
levels of selegiline and its three metabolites that were comparable to those in
humans at the MRHD.
Mutagenesis
Selegiline induced mutations and chromosomal damage when
tested in the in vitro mouse lymphoma assay with and without metabolic
activation. Selegiline was negative in the Ames assay, the in vitro mammalian
chromosome aberration assay in human lymphocytes, and the in vivo oral mouse
micronucleus assay.
Impairment Of Fertility
A mating and fertility study was conducted in male and
female rats at transdermal doses of 10, 30, and 75 mg per kg per day of
selegiline (8, 24, and 60 times the maximum recommended human dose of EMSAM [12
mg per 24 hours] on a mg per m² basis). Slight decreases in sperm concentration
and total sperm count were observed at the high dose; however, no significant
adverse effects on fertility or reproductive performance were observed.
Use In Specific Populations
Pregnancy
Risk Summary
The available data on EMSAM use in pregnant women are not
sufficient to inform a drug-associated risk of adverse pregnancy-related
outcomes. In animal embryo-fetal development studies, transdermal
administration of selegiline to rats and rabbits at doses up to 60 and 64 times
the maximum recommended human dose (MRHD) respectively, produced slight
increases in malformations in both rats and rabbits, and decreased fetal
weight, delayed ossification, and embryo-fetal post-implantation loss in rats.
Most of these effects were seen at the high dose in both rats and rabbits.
These effects were not seen at 8 times and 16 times the MRHD in rats and
rabbits, respectively. In a pre-natal and post-natal development study,
transdermal administration of selegiline in rats at doses 8, 24, and 60 times
MRHD produced a decrease in pup weight and survival at the medium and high doses,
an increase in the number of stillborn pups at the high dose, and delayed
neurobehavioral and sexual development in pups at all doses. A persistent
effect on reproductive performance of pups born to mothers treated at the high
dose was evident (see Data). When treating a pregnant woman with EMSAM,
the physician should carefully consider both the potential risks of taking an
MAOI, particularly the risk of hypertensive crisis during pregnancy, along with
the established benefits of treating depression with an antidepressant.
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,
respectively.
Clinical Considerations
Disease-Associated Maternal And Embryo/Fetal Risk
A prospective longitudinal study was conducted of 201
pregnant women with a history of major depression, who were either on
antidepressants or had received antidepressants less than 12 weeks prior to
their last menstrual period, and were in remission. Women who discontinued
antidepressant medication during pregnancy showed a significant increase in
relapse of their major depression compared to those women who remained on
antidepressant medication throughout pregnancy.
Data
Animal Data
In an embryofetal development study, rats were treated
with transdermal selegiline during the period of organogenesis at doses of 10,
30, and 75 mg/kg/day (8, 24, and 60 times the MRHD of EMSAM [12 mg/24 hours] on
a mg/m² basis). At the highest dose there was a decrease in fetal weight and
slight increases in malformations, delayed ossification (also seen at the mid
dose), and embryofetal post-implantation loss. Concentrations of selegiline and
its metabolites in fetal plasma were generally similar to those in maternal
plasma.
In an embryofetal development study, rabbits were treated
with transdermal selegiline during the period of organogenesis at doses of 2.5,
10, and 40 mg/kg/day (4, 16, and 64 times the MRHD on a mg/m² basis). A slight
increase in visceral malformations was seen at the high dose.
In a prenatal and postnatal development study, rats were
treated with transdermal selegiline at doses of 10, 30, and 75 mg/kg/day (8,
24, and 60 times the MRHD on a mg/m² basis) on days 6 to 21 of gestation and
days 1 to 21 of the lactation period. An increase in post-implantation loss was
seen at the mid and high doses, and an increase in stillborn pups was seen at
the high dose. Decreases in pup weight (throughout lactation and postweaning
periods) and survival (throughout lactation period), delayed pup physical
development, and pup epididymal and testicular hypoplasia, were seen at the mid
and high doses. Delayed neurobehavioral and sexual development was seen at all
doses. Adverse effects on pup reproductive performance, as evidenced by
decreases in implantations and litter size, were seen at the high dose. These
findings suggest persistent effects on the offspring of treated dams. A
no-effect dose was not established in this study for developmental toxicity.
Lactation
Risk Summary
There is no information regarding the presence of
selegiline in human milk, or on its effects on milk production or the breastfed
infant. Selegiline and its metabolites are present in the milk of lactating
rats (see Data).
Because of the potential for serious adverse reactions in
breastfed infants from EMSAM, including the potential for hypertensive crisis,
advise a woman that breastfeeding is not recommended during treatment with
EMSAM and for 5 days after the final dose.
Data
In a prenatal and postnatal development study where rats
were treated with transdermal selegiline at doses approximately 8, 24, and 60
times the MRHD on days 6 to 21 of gestation and days 1 to 21 of the lactation
period, concentrations of selegiline and its metabolites in milk were
approximately 15 and 5 times, respectively, the concentrations in maternal
plasma.
Pediatric Use
Use of EMSAM in patients less than 12 years of age is
contraindicated because of the potential for a hypertensive crisis [see CONTRAINDICATIONS].
Limited pharmacokinetic data with doses lower than in the
commercially available formulations suggest that children under age 12 may be
exposed to increased levels of selegiline compared to adolescents and adults,
administered with and without dietary modifications, therefore, there may be an
increased risk of hypertensive crisis, even at the lowest dose of EMSAM.
Efficacy has not been established in pediatric patients
ages 12 to 17 years with MDD and EMSAM is not recommended for use in this age
range [see CLINICAL PHARMACOLOGY].
A multi-center, randomized, double-blind,
placebo-controlled, flexible-dose trial in 308 adolescents (ages 12 to 17
years) with MDD failed to demonstrate the efficacy of EMSAM. Diagnosis of major
depressive disorder (single episode or recurrent, moderate to severe) was based
on according DSM-IV criteria and Kiddie Schedule for Affective Disorders and
Schizophrenia for School Aged Children (K-SADS). Enrolled patients had a
Children's Depression Rating Scale-Revised of ≥ 45 at the screening
visit. Trial participants were randomized 1:1 to either EMSAM or matching
placebo without forced titration for a period of 12 weeks. Active treatment
consisted of EMSAM transdermal system at a dose of 6 mg per 24 hours, 9 mg per
24 hours, or 12 mg per 24 hours. The primary efficacy endpoint was the
difference in total score on the Children's Depression Rating Scale-Revised
(CDRS-R) from baseline to the end of study (EOS) (Week 12). There was no
observed difference in effect on CDRS-R Total Score at Week 12 (EOS) between
treatments. The mean reduction in CDRS-R Total Score was 21.4 in the EMSAM-treated
subjects and 21.5 in those receiving placebo treatment. Safety endpoints
included physical examination, 12-lead electrocardiogram, respiration rate,
temperature, supine and standing blood pressure and heart rate, application
site assessments, and adverse events. Overall, safety findings were similar to
those observed in EMSAM trials conducted in adults. Treatment-emergent adverse
events reported by at least 5% of EMSAM-treated patients at a rate at least
twice the placebo rate were insomnia (6%, 3%) and upper respiratory tract
infection (7%, 3%).
Geriatric Use
The recommended dose of EMSAM for elderly patients (65
years and older) is 6 mg per 24 hours daily. The effect of age on the
pharmacokinetics or metabolism of selegiline after administration of EMSAM has
not been systematically evaluated. One hundred ninety-eight (198) elderly (65
years of age and older) patients participated in clinical studies with EMSAM 6
mg per 24 hours to 12 mg per 24 hours. There were no overall differences in
effectiveness between elderly and younger patients. In short-term,
placebo-controlled depression trials, patients age 50 and older appeared to be
at higher risk for rash (4.4% EMSAM vs. 0% placebo) than younger patients (3.4%
EMSAM vs. 2.4% placebo).
Gender
No adjustment of EMSAM dosage based on gender is needed.
No gender differences have been observed in the pharmacokinetics or metabolism
of selegiline during administration of EMSAM.
Reduced Hepatic Function
No adjustment of EMSAM dosage is required in patients
with mild liver impairment (Child-Pugh 5-6 points) or moderate liver impairment
(Child-Pugh 7-9 points). After a single administration of EMSAM 6 mg per 24
hours in eight patients with mild or moderate liver impairment, no differences
in either the metabolism or pharmacokinetic behavior of selegiline or its
metabolites were observed as compared with data of normal subjects. EMSAM has
not been studied in patients with severe liver impairment (Child-Pugh 10-15
points).
Reduced Renal Function
No adjustment of EMSAM dosage is required in patients
with mild renal impairment (eGFR 6089 mL/min/1.73 m²), moderate renal
impairment (eGFR 30-59 mL/min/1.73 m²), or severe renal impairment (eGFR 15-29
mL/min/1.73 m²). Data from a single dose study examining the pharmacokinetics
of EMSAM 6 mg per 24 hours in 12 patients with renal impairment suggest that
mild, moderate, or severe renal impairment does not affect the pharmacokinetics
of selegiline after transdermal application. EMSAM has not been studied in
patients with end-stage renal disease (eGFR < 15 mL/min/1.73 m² or requiring
dialysis).