Lexapro Description
LEXAPRO™
(escitalopram oxalate)
TABLETS/ORAL SOLUTION Rx
Only
DESCRIPTION
LEXAPRO™
(escitalopram oxalate) is an orally administered
selective serotonin reuptake inhibitor (SSRI).
Escitalopram is the pure S-enantiomer (single isomer) of
the racemic bicyclic phthalane derivative citalopram.
Escitalopram oxalate is designated S-(+)-1-[3-(dimethyl-amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile
oxalate with the following structural formula:
•C2H2O4
The
molecular formula is C20H21FN2O
• C2H2O4
and the molecular weight is 414.40.
Escitalopram oxalate occurs as a
fine, white to slightly-yellow powder and is freely
soluble in methanol and dimethyl sulfoxide (DMSO),
soluble in isotonic saline solution, sparingly soluble
in water and ethanol, slightly soluble in ethyl acetate,
and insoluble in heptane.
LEXAPRO (escitalopram oxalate) is
available as tablets or as an oral solution.
LEXAPRO tablets are film-coated,
round tablets containing escitalopram oxalate in
strengths equivalent to 5 mg, 10 mg, and 20 mg
escitalopram base. The 10 and 20 mg tablets are scored.
The tablets also contain the following inactive
ingredients: talc, croscarmellose sodium,
microcrystalline cellulose/colloidal silicon dioxide,
and magnesium stearate. The film coating contains
hypromellose, titanium dioxide, and polyethylene glycol.
LEXAPRO oral solution contains
escitalopram oxalate equivalent to 1 mg/mL escitalopram
base. It also contains the following inactive
ingredients: sorbitol, purified water, citric acid,
sodium citrate, malic acid, glycerin, propylene glycol,
methylparaben, propylparaben, and natural peppermint
flavor.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The
mechanism of antidepressant action of escitalopram, the
S-enantiomer of racemic citalopram, is presumed to be
linked to potentiation of serotonergic activity in the
central nervous system (CNS) resulting from its
inhibition
of
CNS neuronal reuptake of serotonin (5-HT).
In
vitro
and
in
vivo
studies in animals suggest that escitalopram is
a highly selective serotonin reuptake inhibitor (SSRI)
with minimal effects on norepinephrine and dopamine
neuronal reuptake. Escitalopram is at least 100-fold
more potent than the R-enantiomer with respect to
inhibition
of
5-HT reuptake and inhibition of 5-HT neuronal firing
rate. Tolerance to a model of antidepressant effect in
rats was not induced by
long-term (up to 5 weeks) treatment with escitalopram.
Escitalopram has no or very low affinity for
serotonergic (5-HT1-7) or other receptors
including alpha- and beta-adrenergic, dopamine (D1-5),
histamine (H1-3), muscarinic
(M1-5), and benzodiazepine receptors. Escitalopram
also does not bind to, or has low affinity for, various
ion channels including Na+, K+,
Cl-, and Ca++ channels. Antagonism
of muscarinic, histaminergic, and adrenergic receptors
has been hypothesized to be associated with various
anticholinergic, sedative, and cardiovascular side
effects of other psychotropic drugs.
Pharmacokinetics
The single-
and multiple-dose pharmacokinetics of escitalopram are
linear and dose-proportional in a dose range of 10 to 30
mg/day. Biotransformation of escitalopram is mainly
hepatic, with a mean terminal half-life of about 27-32
hours. With once-daily dosing, steady state plasma
concentrations are achieved within approximately one
week. At steady state, the extent of accumulation of
escitalopram in plasma in young healthy subjects was
2.2-2.5 times the plasma
concentrations observed after a single dose. The tablet
and the oral solution dosage forms of escitalopram
oxalate are bioequivalent.
Absorption and Distribution
Following a single oral dose (20 mg
tablet or solution) of escitalopram, peak blood levels
occur at about 5 hours. Absorption of escitalopram is
not affected by food.
The absolute bioavailability of
citalopram is about 80% relative to an intravenous dose,
and the volume of distribution of citalopram is about 12
L/kg. Data specific on escitalopram are unavailable.
The binding of escitalopram to human
plasma proteins is approximately 56%.
Metabolism and Elimination
Following oral administrations of escitalopram, the
fraction of drug recovered in the urine as escitalopram
and S - demethylcitalopram
(S-DCT) is about 8% and 10%, respectively. The oral
clearance of escitalopram is 600 mL/min, with
approximately 7% of that due to renal clearance.
Escitalopram is metabolized to
S-DCT and S-didemethylcitalopram (S-DDCT). In humans,
unchanged escitalopram is the predominant compound in
plasma. At steady state, the concentration of the
escitalopram metabolite S-DCT in plasma is approximately
one-third that of escitalopram. The level of S-DDCT was
not detectable in most subjects.
In
vitro
studies show that escitalopram is
at least 7 and 27 times more potent than S - DCT and
S-DDCT, respectively, in the inhibition of serotonin
reuptake, suggesting that the metabolites of
escitalopram do not contribute significantly to the
antidepressant actions of escitalopram. S-DCT and S-DDCT
also have no or very low affinity for serotonergic
(5-HT1-7) or other receptors including alpha- and
beta-adrenergic, dopamine (D1-5),
histamine (H1-3), muscarinic
(M1-5), and benzodiazepine receptors. S-DCT
and S-DDCT also do not bind to various ion channels
including Na+, K+, Cl-, and Ca++
channels.
In
vitro studies using human
liver microsomes indicated that CYP3A4 and CYP2C19 are
the primary isozymes involved in the N-demethylation of
escitalopram.
Population Subgroups
Age -
Escitalopram pharmacokinetics in subjects t 65 years of
age were compared to younger subjects in a single-dose
and a multiple-dose study. Escitalopram AUC and
half-life were increased by approximately 50% in elderly
subjects, and Cmax was unchanged. 10 mg is
the recommended dose for elderly patients (see
DOSAGE AND ADMINISTRATION).
Gender - In a multiple-dose study of escitalopram (10
mg/day for 3 weeks) in 18 male (9 elderly and 9 young)
and
18 female (9 elderly and 9 young) subjects, there were
no differences in AUC, Cmax, and half-life
between the male and female subjects. No adjustment of
dosage on the basis of gender is needed.
Reduced
hepatic function - Citalopram oral clearance was reduced
by 37% and half-life was doubled in patients with
reduced hepatic function compared to normal subjects. 10
mg is the recommended dose of escitalopram for most
hepatically impaired patients (see
DOSAGE AND ADMINISTRATION).
Reduced renal function - In patients with mild to
moderate renal function impairment, oral clearance of
citalopram was reduced by
17% compared to normal subjects. No adjustment of dosage
for such patients is recommended. No information is
available about the pharmacokinetics of escitalopram in
patients with severely reduced renal function (creatinine
clearance < 20 mL/min).
Drug-Drug Interactions
In
vitro
enzyme inhibition data did not reveal an inhibitory
effect of escitalopram on CYP3A4, -1A2, -2C9, -2C19,
and -2E1. Based on
in
vitro data, escitalopram
would be expected to have little inhibitory effect on
in
vivo metabolism mediated
by these cytochromes. While
in
vivo
data to address this question are
limited, results from drug interaction studies suggest
that escitalopram, at a dose of 20 mg, has no 3A4
inhibitory effect and a modest
2D6 inhibitory effect. See
Drug Interactions
under
PRECAUTIONS
for more detailed information on available
drug interaction data.
Clinical Efficacy Trials
Major Depressive Disorder
The efficacy of LEXAPRO as a treatment for major
depressive disorder was established in three, 8-week,
placebo-controlled studies
conducted in outpatients between 18 and 65 years of age
who met DSM-IV criteria for major depressive disorder.
The primary outcome in all three studies was change from
baseline to endpoint in the Montgomery Asberg Depression
Rating Scale (MADRS).
A fixed-dose study compared 10 mg/day
LEXAPRO and 20 mg/day LEXAPRO to placebo and 40 mg/day
citalopram. The 10 mg/day and 20 mg/day LEXAPRO
treatment groups showed significantly greater mean
improvement compared to placebo on the MADRS. The 10 mg
and 20 mg LEXAPRO groups were similar on this outcome
measure.
In a second fixed-dose study of 10
mg/day LEXAPRO and placebo, the 10 mg/day LEXAPRO
treatment group showed significantly greater mean
improvement compared to placebo on the MADRS.
In a flexible-dose
study, comparing LEXAPRO, titrated between 10 and 20
mg/day, to placebo and citalopram,
titrated between 20 and 40 mg/day,
the LEXAPRO treatment group showed significantly greater
mean improvement compared to placebo on the MADRS.
Analyses of the relationship between treatment outcome
and age, gender, and race did not suggest any
differential
responsiveness on the basis of these patient
characteristics.
In a longer-term trial, 274 patients
meeting (DSM-IV) criteria for major depressive disorder,
who had responded during an initial 8-week, open-label
treatment phase with LEXAPRO 10 or 20 mg/day, were
randomized to continuation of LEXAPRO at their same
dose, or to placebo, for up to 36 weeks of observation
for relapse. Response during the open-label phase was
defined by having a decrease of the MADRS total score to
d 12. Relapse during the double-blind phase was defined
as an increase of the MADRS total score to t 22, or
discontinuation due to insufficient clinical response.
Patients receiving continued LEXAPRO experienced a
significantly longer time to relapse over the subsequent
36 weeks compared to those receiving placebo.
Generalized Anxiety Disorder
The efficacy
of LEXAPRO in the treatment of Generalized Anxiety
Disorder (GAD) was demonstrated in three,
8-week, multicenter, flexible-dose, placebo-controlled
studies that compared LEXAPRO 10-20 mg/day to placebo
in
outpatients between 18 and 80 years of age who met
DSM-IV criteria for GAD. In all three studies, LEXAPRO
showed significantly greater mean improvement compared
to placebo on the Hamilton Anxiety Scale (HAM-A).
There were too few patients in differing ethnic and age
groups to adequately assess whether or not LEXAPRO has
differential effects in these groups. There was no
difference in response to LEXAPRO between men and women.
INDICATIONS AND USAGE
Major Depressive Disorder
LEXAPRO (escitalopram) is indicated
for the treatment of major depressive disorder.
The efficacy
of LEXAPRO in the treatment of major depressive disorder
was established in three, 8-week, placebo-controlled
trials of outpatients whose diagnoses corresponded most
closely to the DSM-IV category of major depressive
disorder (see CLINICAL
PHARMACOLOGY).
A
major depressive episode (DSM-IV) implies a prominent
and relatively persistent (nearly every day for at least
2 weeks) depressed or dysphoric mood that usually
interferes with daily functioning, and includes at least
five of the following nine symptoms: depressed mood,
loss of interest in usual activities, significant change
in weight
and/or appetite, insomnia or hypersomnia, psychomotor
agitation or retardation, increased fatigue, feelings of
guilt or worthlessness,
slowed thinking or impaired concentration, a suicide
attempt or suicidal ideation.
The efficacy of LEXAPRO in
hospitalized patients with major depressive disorders
has not been adequately studied.
The efficacy
of LEXAPRO in maintaining a response, in patients with
major depressive disorder who responded during an
8-week, acute-treatment phase while taking LEXAPRO and
were then observed for relapse during a period of up to
36 weeks, was demonstrated in a placebo-controlled trial
(see Clinical Efficacy
Trials under
CLINICAL PHARMACOLOGY).
Nevertheless, the physician who
elects to use LEXAPRO for extended periods should
periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Generalized Anxiety Disorder
LEXAPRO is indicated for the
treatment of Generalized Anxiety Disorder (GAD).
The efficacy of LEXAPRO was established in three,
8-week, placebo-controlled trials in patients with GAD
(see
CLINICAL PHARMACOLOGY).
Generalized Anxiety Disorder (DSM-IV)
is characterized by excessive anxiety and worry
(apprehensive expectation) that is persistent for at
least 6 months and which the person finds difficult to
control. It must be associated with at least 3 of the
following symptoms: restlessness or feeling keyed up or
on edge, being easily fatigued, difficulty concentrating
or mind going blank, irritability, muscle tension, and
sleep disturbance.
The efficacy of LEXAPRO in the
long-term treatment of GAD, that is, for more than 8
weeks, has not been systematically evaluated in
controlled trials. The physician who elects to use
LEXAPRO for extended periods should periodically
re-evaluate the long-term usefulness of the drug for the
individual patient.
CONTRAINDICATIONS
Concomitant use
in patients taking monoamine oxidase inhibitors (MAOIs)
is contraindicated (see
WARNINGS).
LEXAPRO is contraindicated in
patients with a hypersensitivity to escitalopram or
citalopram or any of the
inactive ingredients in LEXAPRO.
WARNINGS
Potential for Interaction with
Monoamine Oxidase Inhibitors
In patients
receiving serotonin reuptake inhibitor drugs in
combination with a monoamine oxidase
inhibitor (MAOI), there have been reports of serious,
sometimes fatal, reactions including hyperthermia,
rigidity, myoclonus, autonomic instability with possible
rapid fluctuations of vital signs, and mental status
changes that include extreme agitation progressing to
delirium and coma. These reactions have also been
reported in patients who have recently discontinued SSRI
treatment and have been started on an MAOI. Some cases
presented with features resembling neuroleptic malignant
syndrome. Furthermore, limited
animal data on the effects of
combined use of SSRIs and MAOIs suggest that these drugs
may act
synergistically to elevate blood pressure and evoke
behavioral excitation. Therefore, it is recommended that
LEXAPRO should not be used
in combination with an MAOI, or within 14 days of
discontinuing
treatment with an MAOI. Similarly, at least 14 days
should be allowed after stopping LEXAPRO before
starting an MAOI.
Serotonin syndrome has been reported in two patients who
were concomitantly receiving linezolid, an
antibiotic which is a reversible
non-selective MAOI.
Clinical
Worsening and Suicide Risk
Patients with major depressive
disorder, both adult and pediatric, may experience
worsening of their
depression and/or the emergence of
suicidal ideation and behavior (suicidality), whether or
not they are taking
antidepressant medications, and this risk may persist
until significant remission occurs. Although
there has been a long-standing
concern that antidepressants may have a role in inducing
worsening of depression and
the emergence of suicidality in certain patients, a
causal role for antidepressants in inducing
such behaviors has not been
established. Nevertheless, patients being treated with
antidepressants
should be observed closely for
clinical worsening and suicidality, especially at the
beginning of a course of
drug therapy, or at the time of dose changes, either
increases or decreases. Consideration
should be given to changing the
therapeutic regimen, including possibly discontinuing
the medication, in patients
whose depression is persistently worse or whose emergent
suicidality is severe, abrupt in onset, or
was not part of the patient’s
presenting symptoms.
Because of the possibility of
co-morbidity between major depressive disorder and other
psychiatric and
nonpsychiatric disorders, the same
precautions observed when treating patients with major
depressive disorder should
be observed when treating patients with other
psychiatric and nonpsychiatric disorders.
The following symptoms, anxiety,
agitation, panic attacks, insomnia, irritability,
hostility (aggressiveness),
impulsivity, akathisia (psychomotor restlessness),
hypomania, and mania, have been reported in adult and
pediatric patients being treated
with antidepressants for major depressive disorder as
well as for other
indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such
symptoms and either the worsening
of depression and/or the emergence of suicidal impulses
has not been established,
consideration should be given to changing the
therapeutic regimen, including possibly
discontinuing the medication, in
patients for whom such symptoms are severe, abrupt in
onset, or were not part of
the patient’s presenting symptoms.
Families and caregivers of
patients being treated with antidepressants for major
depressive disorder
or other indications, both
psychiatric and nonpsychiatric, should be alerted about
the need to monitor
patients for the emergence of agitation, irritability,
and the other symptoms described
above, as well as the emergence of
suicidality, and to report such symptoms immediately to
health-care providers.
Prescriptions for LEXAPRO should
be written for the smallest quantity of tablets
consistent with good patient management, in order to
reduce the risk of overdose.
If the decision has been made to
discontinue treatment, medication should be tapered, as
rapidly as is
feasible, but with recognition
that abrupt discontinuation can be associated with
certain symptoms (see
PRECAUTIONS and
DOSAGE AND ADMINISTRATION,
Discontinuation of Treatment with
LEXAPRO,
for a description of the risks of
discontinuation of LEXAPRO).
It should be noted that LEXAPRO is
not approved for use in treating any indications in the
pediatric population.
A major depressive episode may be
the initial presentation of bipolar disorder. It is
generally believed
(though not established in
controlled trials) that treating such an episode with an
antidepressant alone may
increase the likelihood of precipitation of a
mixed/manic episode in patients at risk for bipolar
disorder. Whether any of
the symptoms described above represent such a conversion
is unknown. However, prior to
initiating treatment with an
antidepressant, patients should be adequately screened
to determine if they are at
risk for bipolar disorder; such screening should include
a detailed psychiatric history, including a family
history of suicide, bipolar
disorder, and depression. It should be noted that
LEXAPRO is not approved for
use in treating bipolar depression.
PRECAUTIONS
General
Discontinuation of Treatment
with LEXAPRO
During
marketing of Lexapro and other SSRIs and SNRIs
(serotonin and norepinephrine reuptake inhibitors),
there have been spontaneous reports of adverse events
occurring upon discontinuation of these drugs,
particularly
when abrupt, including the following: dysphoric mood,
irritability, agitation,
dizziness,
sensory disturbances (e.g.,
paresthesias such as electric shock sensations),
anxiety, confusion, headache, lethargy, emotional
lability, insomnia, and hypomania. While these events
are generally self-limiting, there have been reports of
serious discontinuation symptoms.
Patients should
be monitored for these symptoms when discontinuing
treatment with LEXAPRO. A gradual reduction in the dose
rather than abrupt cessation is recommended whenever
possible. If intolerable symptoms occur following a
decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose
may be considered. Subsequently, the physician may
continue decreasing the dose but at a more gradual rate
(see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
Published case reports have documented the occurrence of
bleeding episodes in patients treated with psychotropic
drugs that interfere with serotonin reuptake. Subsequent
epidemiological studies, both of the case-control and
cohort design, have demonstrated an association between
use of psychotropic drugs that interfere with serotonin
reuptake and the occurrence of upper gastrointestinal
bleeding. In two studies, concurrent use of a
nonsteroidal anti-inflammatory drug (NSAID) or aspirin
potentiated the risk of bleeding (see
Drug Interactions).
Although
these studies focused on upper gastrointestinal
bleeding, there is reason to believe that bleeding at
other sites may be
similarly potentiated. Patients should be cautioned
regarding the risk of bleeding associated with the
concomitant use of LEXAPRO with NSAIDs, aspirin, or
other drugs that affect coagulation.
Hyponatremia
One case of hyponatremia has been
reported in association with LEXAPRO treatment. Several
cases of hyponatremia or SIADH (syndrome of
inappropriate antidiuretic hormone secretion) have been
reported in association with racemic citalopram. All
patients with these events have recovered with
discontinuation of escitalopram or citalopram and/or
medical intervention. Hyponatremia and SIADH have also
been reported in association with other marketed drugs
effective in the treatment of major depressive disorder.
Activation of Mania/Hypomania
In
placebo-controlled trials of LEXAPRO in major depressive
disorder, activation of mania/hypomania was reported in
one (0.1%) of 715 patients treated with LEXAPRO and in
none of the 592 patients treated with placebo. One
additional case of hypomania has been reported in
association with LEXAPRO treatment. Activation of
mania/hypomania has also been reported in a small
proportion of patients with major affective
disorders treated with racemic citalopram and other
marketed drugs effective in the treatment of major
depressive disorder. As
with all drugs effective in the treatment of major
depressive disorder, LEXAPRO should be used cautiously
in patients with a history of mania.
Seizures
Although anticonvulsant effects of racemic citalopram
have been observed in animal studies, LEXAPRO has not
been systematically evaluated in patients with a seizure
disorder. These patients were excluded from clinical
studies during the product's premarketing testing. In
clinical trials of LEXAPRO, cases of convulsion have
been
reported in association with LEXAPRO treatment. Like
other drugs effective in the treatment of major
depressive disorder,
LEXAPRO should be introduced with care in patients with
a history of seizure disorder.
Interference with Cognitive
and Motor Performance
In a study in
normal volunteers, LEXAPRO 10 mg/day did not produce
impairment of intellectual function or psychomotor
performance. Because any psychoactive drug may impair
judgment, thinking, or motor skills,
however, patients should be cautioned about operating
hazardous machinery, including automobiles, until they
are reasonably certain that
LEXAPRO therapy does not affect their ability to engage
in such activities.
Use in Patients with
Concomitant Illness
LEXAPRO has not been systematically
evaluated in patients with a recent history of
myocardial infarction or unstable heart disease.
Patients with these diagnoses were generally excluded
from clinical studies during the product's premarketing
testing.
In subjects with hepatic impairment, clearance of
racemic citalopram was decreased and plasma
concentrations were increased. The recommended dose of
LEXAPRO in hepatically impaired patients is 10 mg/day
(see
DOSAGE AND ADMINISTRATION).
Because
escitalopram is extensively metabolized, excretion of
unchanged drug in urine is a minor route of
elimination. Until adequate numbers of patients with
severe renal impairment have been evaluated during
chronic treatment with
LEXAPRO, however, it should be used with caution in such
patients (see
DOSAGE AND ADMINISTRATION).
Information for Patients
Physicians are advised to discuss the
following issues with patients for whom they prescribe
LEXAPRO.
In a study in
normal volunteers, LEXAPRO 10 mg/day did not impair
psychomotor performance. The effect of LEXAPRO on
psychomotor coordination, judgment, or thinking has not
been systematically examined in
controlled studies. Because psychoactive drugs may
impair judgment, thinking, or motor skills, patients
should be cautioned about
operating hazardous machinery, including automobiles,
until they are reasonably certain that LEXAPRO therapy
does not affect their ability to engage in such
activities.
Patients should be told that,
although LEXAPRO has not been shown in experiments with
normal subjects to increase the mental and motor skill
impairments caused by alcohol, the concomitant use of
LEXAPRO and alcohol in depressed patients is not
advised.
Patients should be made aware that
escitalopram is the active isomer of Celexa (citalopram
hydrobromide) and that the two medications should not be
taken concomitantly.
Patients should be advised to inform their physician if
they are taking, or plan to take, any prescription or
over-the-counter drugs, as
there is a potential for interactions.
Patients should be cautioned about
the concomitant use of LEXAPRO and NSAIDs, aspirin, or
other drugs that affect coagulation since the combined
use of psychotropic drugs that interfere with serotonin
reuptake and these agents has been associated with an
increased risk of bleeding.
Patients should be advised to notify their physician if
they become pregnant or intend to become pregnant during
therapy.
Patients should be advised to notify
their physician if they are breastfeeding an infant.
While patients may notice improvement
with LEXAPRO therapy in 1 to 4 weeks, they should be
advised to continue therapy as directed.
Patients and their families
should be encouraged to be alert to the emergence of
anxiety, agitation, panic
attacks, insomnia, irritability,
hostility, impulsivity, akathisia, hypomania, mania,
worsening of depression,
and suicidal ideation, especially early during
antidepressant treatment. Such symptoms should be
reported to the patient’s
physician, especially if they are severe, abrupt in
onset, or were not part of the patient’s
presenting symptoms.
Laboratory Tests
There are no specific laboratory
tests recommended.
Concomitant Administration with Racemic
Citalopram
Citalopram - Since escitalopram is the active isomer of
racemic citalopram (Celexa), the two agents should not be
coadministered.
Drug Interactions
CNS Drugs - Given the primary CNS effects
of escitalopram, caution should be used when it is taken in
combination with other centrally acting drugs.
Alcohol - Although
LEXAPRO did not potentiate the cognitive and motor effects
of alcohol in a clinical trial, as with other psychotropic
medications, the use of alcohol by patients taking LEXAPRO
is not recommended. Monoamine Oxidase Inhibitors (MAOIs) -
See CONTRAINDICATIONS
and
WARNINGS.
Drugs That Interfere With Hemostasis
(NSAIDs, Aspirin, Warfarin, etc.)
Serotonin release
by platelets plays an important role in hemostasis.
Epidemiological studies of the case-control and cohort
design that have demonstrated an association between use of
psychotropic drugs that interfere with
serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent
use of an
NSAID
or aspirin potentiated the risk of bleeding. Thus, patients
should be cautioned about the use of such drugs
concurrently with LEXAPRO.
Cimetidine - In subjects who had received 21 days of 40
mg/day racemic citalopram, combined administration of
400 mg/day cimetidine for 8 days resulted in an increase in
citalopram AUC and Cmax of 43% and 39%,
respectively. The clinical significance of these findings is
unknown.
Digoxin - In
subjects who had received 21 days of 40 mg/day racemic
citalopram, combined administration of
citalopram and digoxin (single dose of 1 mg) did not
significantly affect the pharmacokinetics of either
citalopram
or digoxin.
Lithium - Coadministration of racemic citalopram (40 mg/day
for 10 days) and lithium (30 mmol/day for 5 days)
had no significant effect on the pharmacokinetics of
citalopram or lithium. Nevertheless, plasma lithium levels
should
be monitored with appropriate adjustment to the lithium dose
in accordance with standard clinical practice.
Because lithium may enhance the serotonergic effects of
escitalopram, caution should be exercised when LEXAPRO and
lithium are coadministered.
Sumatriptan - There have been rare
postmarketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of an
SSRI and sumatriptan. If concomitant treatment with
sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine,
paroxetine, sertraline, citalopram, escitalopram) is
clinically warranted, appropriate observation of the patient
is advised.
Theophylline - Combined administration of
racemic citalopram (40 mg/day for 21 days) and the CYP1A2
substrate theophylline (single dose of 300 mg) did not
affect the pharmacokinetics of theophylline. The effect of
theophylline on the pharmacokinetics of citalopram was not
evaluated.
Warfarin - Administration of 40 mg/day
racemic citalopram for 21 days did not affect the
pharmacokinetics of warfarin, a CYP3A4 substrate.
Prothrombin time was increased by 5%, the clinical
significance of which is unknown.
Carbamazepine - Combined administration
of racemic citalopram (40 mg/day for 14 days) and
carbamazepine (titrated to 400 mg/day for 35 days) did not
significantly affect the pharmacokinetics of carbamazepine,
a CYP3A4 substrate. Although trough citalopram plasma levels
were unaffected, given the enzyme-inducing properties of
carbamazepine, the possibility that carbamazepine might
increase the clearance of escitalopram should be considered
if the two drugs are coadministered.
Triazolam - Combined administration of racemic citalopram
(titrated to 40 mg/day for 28 days) and the CYP3A4
substrate triazolam (single dose of 0.25 mg) did not
significantly affect the pharmacokinetics of either
citalopram
or triazolam.
Ketoconazole - Combined administration of
racemic citalopram (40 mg) and ketoconazole (200 mg), a
potent CYP3A4 inhibitor, decreased the Cmax and
AUC of ketoconazole by 21% and 10%, respectively, and did
not significantly affect the pharmacokinetics of citalopram.
Ritonavir - Combined administration of a single dose of
ritonavir (600 mg), both a CYP3A4 substrate and a potent
inhibitor of CYP3A4, and escitalopram (20 mg) did not affect
the pharmacokinetics of either ritonavir or escitalopram.
CYP3A4 and -2C19 Inhibitors -
In vitro
studies indicated that CYP3A4
and -2C19 are the primary enzymes involved in the metabolism
of escitalopram. However, coadministration of escitalopram
(20 mg) and ritonavir (600 mg), a potent inhibitor of
CYP3A4, did not significantly affect the pharmacokinetics of
escitalopram.
Because escitalopram is metabolized by
multiple enzyme systems, inhibition of a single enzyme may
not appreciably decrease escitalopram clearance.
Drugs Metabolized
by Cytochrome P4502D6 - In
vitro studies did not reveal an
inhibitory effect of escitalopram on CYP2D6. In addition,
steady state levels of racemic citalopram were not
significantly different in poor metabolizers and extensive
CYP2D6 metabolizers after multiple-dose administration of
citalopram, suggesting
that
coadministration, with escitalopram, of a drug that inhibits
CYP2D6, is unlikely to have clinically significant
effects on escitalopram metabolism. However, there are
limited in vivo
data suggesting a modest CYP2D6
inhibitory effect for escitalopram, i.e., coadministration
of escitalopram (20 mg/day for 21 days) with the tricyclic
antidepressant desipramine (single dose of 50 mg), a
substrate for CYP2D6, resulted in a 40% increase in
Cmax and a 100% increase in AUC of desipramine. The
clinical significance of this finding is unknown.
Nevertheless, caution is indicated in the coadministration
of escitalopram and drugs metabolized by CYP2D6.
Metoprolol -
Administration of 20 mg/day LEXAPRO for 21 days in healthy
volunteers resulted in a 50% increase in Cmax and
82% increase in AUC of the beta-adrenergic blocker
metoprolol (given in a single dose of 100
mg).
Increased metoprolol plasma levels have been associated with
decreased cardioselectivity. Coadministration
of LEXAPRO and metoprolol had no clinically significant
effects on blood pressure or heart rate.
Electroconvulsive Therapy (ECT) - There
are no clinical studies of the combined use of ECT and
escitalopram.
Carcinogenesis, Mutagenesis, Impairment
of Fertility
Carcinogenesis
Racemic citalopram
was administered in the diet to NMRI/BOM strain mice and
COBS WI strain rats for 18 and
24
months, respectively. There was no evidence for
carcinogenicity of racemic citalopram in mice receiving up
to
240
mg/kg/day. There was an increased incidence of small
intestine carcinoma in rats receiving 8 or 24 mg/kg/day
racemic citalopram. A no-effect dose for this finding was
not established. The relevance of these findings to humans
is unknown.
Mutagenesis
Racemic citalopram
was mutagenic in the in vitro
bacterial reverse mutation
assay (Ames test) in 2 of 5 bacterial strains (Salmonella
TA98 and TA1 537) in the absence of metabolic activation. It
was clastogenic in the in vitro
Chinese hamster lung cell assay for chromosomal aberrations
in the presence and absence of metabolic activation.
Racemic citalopram was not mutagenic in the
in
vitro
mammalian forward gene mutation assay (HPRT) in mouse
lymphoma cells or in a coupled
in vitro/in vivo unscheduled
DNA synthesis (UDS) assay in rat liver. It was not
clastogenic in the in vitro
chromosomal aberration assay in
human lymphocytes or in two in
vivo mouse micronucleus assays.
Impairment of Fertility
When racemic
citalopram was administered orally to 16 male and 24 female
rats prior to and throughout mating
and
gestation at doses of 32, 48, and 72 mg/kg/day, mating was
decreased at all doses, and fertility was decreased
at doses t 32 mg/kg/day. Gestation duration was increased at
48 mg/kg/day.
Pregnancy
Pregnancy Category C
In a rat
embryo/fetal development study, oral administration of
escitalopram (56, 112, or 150 mg/kg/day) to
pregnant animals during the period of organogenesis resulted
in decreased fetal body weight and associated delays
in ossification at the two higher doses (approximately t 56
times the maximum recommended human dose [MRHD] of 20 mg/day
on a body surface area [mg/m2] basis). Maternal
toxicity (clinical signs and decreased
body
weight gain and food consumption), mild at 56 mg/kg/day, was
present at all dose levels. The developmental
no-effect dose of 56 mg/kg/day is approximately 28 times the
MRHD on a mg/m2 basis. No teratogenicity was
observed at any of the doses tested (as high as 75 times the
MRHD on a mg/m2 basis).
When female rats were treated with
escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy
and through weaning, slightly increased offspring mortality
and growth retardation were noted at 48 mg/kg/day which is
approximately 24 times the MRHD on a mg/m2 basis.
Slight maternal toxicity (clinical signs and decreased body
weight gain and food consumption) was seen at this dose.
Slightly increased offspring mortality was seen at 24
mg/kg/day. The no-effect dose was 12 mg/kg/day which is
approximately 6 times the MRHD on a mg/m2 basis.
In animal reproduction studies, racemic
citalopram has been shown to have adverse effects on
embryo/fetal and postnatal development, including
teratogenic effects, when administered at doses greater than
human therapeutic doses.
In
two rat embryo/fetal development studies, oral
administration of racemic citalopram (32, 56, or 112
mg/kg/day)
to
pregnant animals during the period of organogenesis resulted
in decreased embryo/fetal growth and survival and
an
increased incidence of fetal abnormalities (including
cardiovascular and skeletal defects) at the high dose. This
dose was also associated with maternal toxicity (clinical
signs, decreased body weight gain). The developmental
no-effect dose was 56 mg/kg/day. In a rabbit study, no
adverse effects on embryo/fetal development were observed at
doses of racemic citalopram of up to 16 mg/kg/day. Thus,
teratogenic effects of racemic citalopram were observed at a
maternally toxic dose in the rat and were not observed in
the rabbit.
When female rats
were treated with racemic citalopram (4.8, 12.8, or 32
mg/kg/day) from late gestation through
weaning, increased offspring mortality during the first 4
days after birth and persistent offspring growth retardation
were
observed at the highest dose. The no-effect dose was 12.8
mg/kg/day. Similar effects on offspring mortality
and growth were seen when dams were treated throughout
gestation and early lactation at doses t 24 mg/kg/day. A
no-effect dose was not determined in that study.
There are no adequate and well-controlled
studies in pregnant women; therefore, escitalopram should be
used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Pregnancy-Nonteratogenic Effects
Neonates exposed
to LEXAPRO and other SSRIs or SNRIs, late in the third
trimester, have developed
complications requiring prolonged hospitalization,
respiratory support, and tube feeding. Such complications
can arise immediately upon
delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea,
seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia,
tremor, jitteriness, irritability, and constant crying.
These features are consistent with either a direct toxic
effect of
SSRIs
and SNRIs or, possibly, a drug discontinuation syndrome. It
should be noted that, in some cases, the clinical
picture is consistent with serotonin syndrome (see
WARNINGS).
When treating a
pregnant woman with LEXAPRO during the third trimester, the
physician should carefully consider the potential risks and
benefits of treatment (see
DOSAGE AND ADMINISTRATION).
Labor and Delivery
The effect of LEXAPRO on labor and
delivery in humans is unknown.
Nursing Mothers
Racemic citalopram,
like many other drugs, is excreted in human breast milk.
There have been two reports of infants experiencing
excessive somnolence, decreased feeding, and weight loss in
association with breastfeeding from a citalopram-treated
mother; in one case, the infant was reported to recover
completely upon
discontinuation of citalopram by its mother and, in the
second case, no follow-up information was available. The
decision whether to continue or discontinue either nursing
or LEXAPRO therapy should take into account the risks of
citalopram exposure for the infant and the benefits of
LEXAPRO treatment for the mother.
Pediatric Use
Safety and
effectiveness in pediatric patients have not been
established (see
WARNINGS-Clinical Worsening and Suicide Risk.
Geriatric Use
Approximately 6%
of the 1144 patients receiving escitalopram in controlled
trials of LEXAPRO in major
depressive disorder and GAD were 60 years of age or older;
elderly patients in these trials received daily doses of
LEXAPRO between 10 and 20 mg. The number of elderly patients
in these trials was insufficient to adequately
assess
for possible differential efficacy and safety measures on
the basis of age. Nevertheless, greater sensitivity of
some elderly individuals to effects of LEXAPRO cannot be
ruled out.
In
two pharmacokinetic studies, escitalopram half-life was
increased by approximately 50% in elderly subjects as
compared to young subjects and Cmax was unchanged
(see CLINICAL PHARMACOLOGY).
10 mg/day is the recommended
dose for elderly patients (see
DOSAGE AND ADMINISTRATION).
Of
4422 patients in clinical studies of racemic citalopram,
1357 were 60 and over, 1034 were 65 and over, and 457
were 75 and over. No overall differences in safety or
effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly
and younger patients, but again, greater sensitivity of some
elderly individuals cannot be ruled out.
ADVERSE REACTIONS
Adverse event information for LEXAPRO
was collected from 715 patients with major depressive
disorder who were exposed to escitalopram and from 592
patients who were exposed to placebo in double-blind,
placebo-controlled
trials. An additional 284 patients with major depressive
disorder were newly exposed to escitalopram in
open-label trials. The adverse event information for LEXAPRO
in patients with GAD was collected from 429 patients exposed
to escitalopram and from 427 patients exposed to placebo in
double-blind, placebo-controlled trials.
Adverse events during exposure were obtained primarily by
general inquiry and recorded by clinical investigators
using
terminology of their own choosing. Consequently, it is not
possible to provide a meaningful estimate of the
proportion of individuals experiencing adverse events
without first grouping similar types of events into a
smaller
number of standardized event categories. In the tables and
tabulations that follow, standard World Health Organization
(WHO) terminology has been used to classify reported adverse
events.
The stated
frequencies of adverse events represent the proportion of
individuals who experienced, at least once, a
treatment-emergent adverse event of the type listed. An
event was considered treatment-emergent if it occurred for
the first time or worsened while receiving therapy following
baseline evaluation.
Adverse Events Associated with
Discontinuation of Treatment
Major Depressive Disorder
Among the 715
depressed patients who received LEXAPRO in
placebo-controlled trials, 6% discontinued
treatment due to an adverse event, as compared to 2% of 592
patients receiving placebo. In two fixed-dose studies,
the rate of discontinuation for adverse events in patients
receiving 10 mg/day LEXAPRO was not significantly different
from the rate of discontinuation for adverse events in
patients receiving placebo. The rate of discontinuation for
adverse events in patients assigned to a fixed dose of 20
mg/day LEXAPRO was 10%, which was significantly different
from the rate of discontinuation for adverse events in
patients receiving 10 mg/day
LEXAPRO (4%) and placebo (3%). Adverse events that were
associated with the discontinuation of at least 1% of
patients treated with LEXAPRO, and for which the rate was at
least twice that of placebo, were nausea (2%) and
ejaculation disorder (2% of male patients).
Generalized Anxiety Disorder
Among the 429 GAD patients who received
LEXAPRO 10-20 mg/day in placebo-controlled trials, 8%
discontinued treatment due to an adverse event, as compared
to 4% of 427 patients receiving placebo. Adverse events that
were associated with the discontinuation of at least 1% of
patients treated with LEXAPRO, and for which the rate was at
least twice the placebo rate, were nausea (2%), insomnia
(1%), and fatigue (1%).
Incidence of Adverse Events in
Placebo-Controlled Clinical Trials
Major Depressive Disorder
Table 1 enumerates the incidence,
rounded to the nearest percent, of treatment-emergent
adverse events that occurred among 715 depressed patients
who received LEXAPRO at doses ranging from 10 to 20 mg/day
in placebo-controlled trials. Events included are those
occurring in 2% or more of patients treated with LEXAPRO and
for which the incidence in patients treated with LEXAPRO was
greater than the incidence in placebo-treated patients.
The
prescriber should be aware that these figures can not be
used to predict the incidence of adverse events in the
course of usual medical practice where patient
characteristics and other factors differ from those which
prevailed
in the
clinical trials. Similarly, the cited frequencies cannot be
compared with figures obtained from other clinical
investigations involving different treatments, uses, and
investigators. The cited figures, however, do provide the
prescribing physician with some basis for estimating the
relative contribution of drug and non-drug factors to the
adverse event incidence rate in the population studied.
The most commonly
observed adverse events in LEXAPRO patients (incidence of
approximately 5% or greater and approximately twice the
incidence in placebo patients) were insomnia, ejaculation
disorder (primarily ejaculatory delay), nausea, sweating
increased, fatigue, and somnolence (see
TABLE 1).
TABLE 1
Treatment-Emergent Adverse
Events:
Incidence in
Placebo-Controlled Clinical Trials for
Major Depressive Disorder*
(Percentage of Patients
Reporting Event)
Body
System /
LEXAPRO
Placebo
Adverse Event
(N=715)
(N=592)
Autonomic Nervous
System Disorders
Dry Mouth
|
6%
|
5%
|
Sweating Increased
|
5%
|
2%
|
Central & Peripheral
Nervous System Disorders
Dizziness
|
5%
|
3%
|
Gastrointestinal Disorders
Nausea
|
15%
|
7%
|
Diarrhea
|
8%
|
5%
|
Constipation
|
3%
|
1%
|
Indigestion
|
3%
|
1%
|
Abdominal Pain
|
2%
|
1%
|
General
Influenza-like Symptoms
|
5%
|
4%
|
Fatigue
|
5%
|
2%
|
Psychiatric Disorders
Insomnia
|
9%
|
4%
|
Somnolence
|
6%
|
2%
|
Appetite Decreased
|
3%
|
1%
|
Libido Decreased
|
3%
|
1%
|
Respiratory System
Disorders
Rhinitis
|
5%
|
4%
|
Sinusitis
|
3%
|
2%
|
Urogenital
Ejaculation Disorder1,2
|
9%
|
<1%
|
Impotence2
|
3%
|
<1%
|
Anorgasmia3
|
2%
|
<1%
|
*Events reported by at least 2% of
patients treated with LEXAPRO are reported, except for the
following events which had an incidence on placebo t
LEXAPRO: headache, upper respiratory tract infection, back
pain, pharyngitis, inflicted injury, anxiety.
1Primarily
ejaculatory delay.
2Denominator
used was for males only (N=225 LEXAPRO; N=1 88 placebo).
3Denominator
used was for females only (N=490 LEXAPRO; N=404 placebo).
Generalized Anxiety Disorder
Table 2 enumerates
the incidence, rounded to the nearest percent of
treatment-emergent adverse events that
occurred among 429 GAD patients who received LEXAPRO 10 to
20 mg/day in placebo-controlled trials. Events
included are those occurring in 2% or more of patients
treated with LEXAPRO and for which the incidence in patients
treated with LEXAPRO was greater than the incidence in
placebo-treated patients.
The most commonly
observed adverse events in LEXAPRO patients (incidence of
approximately 5% or greater and approximately twice the
incidence in placebo patients) were nausea, ejaculation
disorder (primarily ejaculatory delay), insomnia, fatigue,
decreased libido, and anorgasmia (see
TABLE 2).
TABLE 2
Treatment-Emergent
Adverse Events: Incidence in Placebo-Controlled
Clinical Trials
for Generalized Anxiety Disorder*
(Percentage of
Patients Reporting Event)
|
Body System /
|
LEXAPRO
|
Placebo
|
Adverse Event
|
(N=429)
|
(N=427)
|
Autonomic Nervous System
Disorders
Dry Mouth
|
9%
|
5%
|
Sweating Increased
|
4%
|
1%
|
Central & Peripheral
Nervous System Disorders
|
|
|
Headache
|
24%
|
17%
|
|
Paresthesia
|
2%
|
1%
|
|
Gastrointestinal Disorders
Nausea
|
18%
|
8%
|
|
Diarrhea
|
8%
|
6%
|
|
Constipation
|
5%
|
4%
|
|
Indigestion
|
3%
|
2%
|
|
Vomiting
|
3%
|
1%
|
|
Abdominal Pain
|
2%
|
1%
|
|
Flatulence
|
2%
|
1%
|
|
Toothache
|
2%
|
0%
|
|
General
Fatigue
|
8%
|
2%
|
|
Influenza-like Symptoms
|
5%
|
4%
|
|
Musculoskeletal
Neck/Shoulder Pain
|
3%
|
1%
|
|
Psychiatric Disorders
Somnolence
|
13%
|
7%
|
|
Insomnia
|
12%
|
6%
|
|
Libido Decreased
|
7%
|
2%
|
|
Dreaming Abnormal
|
3%
|
2%
|
|
Appetite Decreased
|
3%
|
1%
|
|
Lethargy
|
3%
|
1%
|
|
Yawning
|
2%
|
1%
|
|
Urogenital
Ejaculation Disorder1,2
|
14%
|
2%
|
|
Anorgasmia3
|
6%
|
<1%
|
|
Menstrual Disorder
|
2%
|
1%
|
|
|
|
|
|
|
|
*Events reported by at least 2% of
patients treated with LEXAPRO are reported, except for the
following events which had an incidence on placebo t
LEXAPRO: inflicted injury, dizziness, back pain, upper
respiratory tract infection, rhinitis, pharyngitis.
1Primarily
ejaculatory delay.
2Denominator
used was for males only (N=182 LEXAPRO; N=195 placebo).
3Denominator
used was for females only (N=247 LEXAPRO; N=232 placebo).
Dose Dependency of Adverse Events
The potential dose
dependency of common adverse events (defined as an incidence
rate of t5% in either the 10 mg or 20 mg LEXAPRO groups) was
examined on the basis of the combined incidence of adverse
events in two fixed-dose trials. The overall incidence rates
of adverse events in 10 mg LEXAPRO-treated patients (66%)
was similar to that of the placebo-treated patients (6 1%),
while the incidence rate in 20 mg/day LEXAPRO-treated
patients was greater (86%). Table 3 shows common adverse
events that occurred in the 20 mg/day LEXAPRO
group
with an incidence that was approximately twice that of the
10 mg/day LEXAPRO group and approximately
twice that of the placebo group.
TABLE 3
Incidence of Common Adverse Events* in Patients with Major
Depressive Disorder Receiving Placebo, 10 mg/day LEXAPRO, or
20 mg/day LEXAPRO
Adverse Event
|
Placebo
|
10 mg/day
|
20 mg/day
|
|
|
(N=311)
|
LEXAPRO
|
LEXAPRO
|
|
|
|
(N=310)
|
(N=125)
|
|
Insomnia
|
4%
|
7%
|
14%
|
|
Diarrhea
|
5%
|
6%
|
14%
|
|
Dry Mouth
|
3%
|
4%
|
9%
|
|
Somnolence
|
1%
|
4%
|
9%
|
Dizziness
|
2%
|
4%
|
7%
|
Sweating Increased
|
<1%
|
3%
|
8%
|
Constipation
|
1%
|
3%
|
6%
|
Fatigue
|
2%
|
2%
|
6%
|
Indigestion
|
1%
|
2%
|
6%
|
*Adverse events with an
incidence rate of at
|
least 5% in either
of the LEXAPRO
|
groups and with an
incidence
|
rate in the 20 mg/day LEXAPRO
group that
and the placebo group.
|
was approximately
twice that of the
|
10 mg/day LEXAPRO
group
|
|
|
|
|
|
|
|
|
Male and Female Sexual Dysfunction with
SSRIs
Although changes in sexual desire, sexual
performance, and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a
consequence of pharmacologic treatment. In particular, some
evidence suggests that SSRIs can cause such untoward sexual
experiences.
Reliable estimates
of the incidence and severity of untoward experiences
involving sexual desire, performance,
and
satisfaction are difficult to obtain, however, in part
because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward
sexual experience and performance cited in product labeling
are likely to underestimate their actual incidence.
Table 4 shows the incidence rates of
sexual side effects in patients with major depressive
disorder and GAD in placebo-controlled trials.
TABLE 4
Incidence of Sexual Side
Effects in Placebo-Controlled Clinical Trials
Adverse Event
LEXAPRO
Placebo
|
|
In Males Only
|
|
|
(N=407)
|
|
(N=383)
|
Ejaculation Disorder
(primarily
ejaculatory delay)
|
12%
|
|
1%
|
Libido Decreased
|
6%
|
|
2%
|
Impotence
|
2%
|
|
<1%
|
|
(N=737)
|
In Females Only
|
(N=636)
|
Libido Decreased
|
3%
|
|
1%
|
Anorgasmia
|
3%
|
|
<1%
|
There
are no adequately designed studies examining sexual
dysfunction with escitalopram treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the
precise risk of sexual dysfunction associated with the use
of SSRIs, physicians should routinely inquire about such
possible side effects.
Vital Sign Changes
LEXAPRO and placebo groups were compared
with respect to (1) mean change from baseline in vital signs
(pulse, systolic blood pressure, and diastolic blood
pressure) and (2) the incidence of patients meeting criteria
for potentially clinically significant changes from baseline
in these variables. These analyses did not reveal any
clinically important changes in vital signs associated with
LEXAPRO treatment. In addition, a comparison of supine and
standing vital sign measures in subjects receiving LEXAPRO
indicated that LEXAPRO treatment is not associated with
orthostatic changes.
Weight Changes
Patients treated with LEXAPRO in
controlled trials did not differ from placebo-treated
patients with regard to clinically important change in body
weight.
Laboratory Changes
LEXAPRO and placebo groups were compared
with respect to (1) mean change from baseline in various
serum
chemistry, hematology, and urinalysis
variables, and (2) the incidence of patients meeting
criteria for potentially clinically significant changes from
baseline in these variables. These analyses revealed no
clinically important changes in laboratory test parameters
associated with LEXAPRO treatment.
ECG Changes
Electrocardiograms from LEXAPRO (N=625),
racemic citalopram (N=351), and placebo (N=527) groups were
compared with respect to (1) mean change from baseline in
various ECG parameters and (2) the incidence of patients
meeting criteria for potentially clinically significant
changes from baseline in these variables. These analyses
revealed (1) a decrease in heart rate of 2.2 bpm for LEXAPRO
and 2.7 bpm for racemic citalopram, compared to an increase
of 0.3 bpm for placebo and (2) an increase in QTc interval
of 3.9 msec for LEXAPRO and 3.7 msec for racemic citalopram,
compared to 0.5 msec for placebo. Neither LEXAPRO nor
racemic citalopram were associated with the development of
clinically significant ECG abnormalities.
Other Events Observed During the
Premarketing Evaluation of LEXAPRO
Following is a
list of WHO terms that reflect treatment-emergent adverse
events, as defined in the introduction to
the
ADVERSE REACTIONS
section, reported by the 1428 patients treated with LEXAPRO
for periods of up to one year
in double-blind or open-label clinical trials during its
premarketing evaluation. All reported events are included
except those already listed in Tables 1 & 2, those occurring
in only one patient, event terms that are so general as to
be uninformative, and those that are unlikely to be drug
related. It is important to emphasize that, although the
events reported occurred during treatment with LEXAPRO, they
were not necessarily caused by it.
Events are further
categorized by body system and listed in order of decreasing
frequency according to the following definitions: frequent
adverse events are those occurring on one or more occasions
in at least 1/100 patients; infrequent adverse events are
those occurring in less than 1/100 patients but at least 1/1
000 patients. Cardiovascular -
Frequent: palpitation,
hypertension. Infrequent:
bradycardia, tachycardia, ECG
abnormal, flushing, varicose vein.
Central and
Peripheral Nervous System Disorders -
Frequent:
light-headed feeling, migraine.
Infrequent:
tremor, vertigo, restless legs,
shaking, twitching, dysequilibrium, tics, carpal tunnel
syndrome, muscle contractions involuntary, sluggishness,
coordination abnormal, faintness, hyperreflexia, muscular
tone increased. Gastrointestinal Disorders -
Frequent:
heartburn, abdominal cramp,
gastroenteritis. Infrequent:
gastroesophageal reflux,
bloating, abdominal discomfort, dyspepsia, increased stool
frequency, belching, gastritis, hemorrhoids, gagging,
polyposis gastric, swallowing difficult.
General -
Frequent:
allergy, pain in limb, fever, hot
flushes, chest pain.
Infrequent: edema of
extremities, chills, tightness of chest, leg pain, asthenia,
syncope, malaise, anaphylaxis, fall.
Hemic and Lymphatic
Disorders - Infrequent:
bruise, anemia, nosebleed, hematoma,
lymphadenopathy cervical. Metabolic and Nutritional
Disorders - Frequent:
increased weight.
Infrequent:
decreased weight, hyperglycemia,
thirst, bilirubin increased, hepatic enzymes increased,
gout, hypercholesterolemia.
Musculoskeletal
System Disorders - Frequent:
arthralgia, myalgia.
Infrequent:
jaw stiffness, muscle cramp, muscle
stiffness, arthritis, muscle weakness, back discomfort,
arthropathy, jaw pain, joint stiffness. Psychiatric
Disorders - Frequent:
appetite increased, lethargy,
irritability, concentration impaired.
Infrequent:
jitteriness, panic reaction,
agitation, apathy, forgetfulness, depression aggravated,
nervousness, restlessness
aggravated, suicide attempt, amnesia, anxiety attack,
bruxism, carbohydrate craving, confusion, depersonalization,
disorientation, emotional lability, feeling unreal,
tremulousness nervous, crying abnormal, depression,
excitability, auditory
hallucination, suicidal tendency.
Reproductive
Disorders/Female* - Frequent:
menstrual cramps, menstrual
disorder. Infrequent:
menorrhagia, breast neoplasm, pelvic
inflammation, premenstrual syndrome, spotting between
menses.
*% based on female subjects only: N= 905
Respiratory System
Disorders - Frequent:
bronchitis, sinus congestion,
coughing, nasal congestion, sinus headache.
Infrequent:
asthma, breath shortness, laryngitis,
pneumonia, tracheitis.
Skin and Appendages
Disorders - Frequent:
rash.
Infrequent: pruritus, acne,
alopecia, eczema, dermatitis, dry skin, folliculitis, lipoma,
furunculosis, dry lips, skin nodule.
Special Senses -
Frequent:
vision blurred, tinnitus.
Infrequent:
taste alteration, earache,
conjunctivitis, vision abnormal, dry eyes, eye irritation,
visual disturbance, eye infection, pupils dilated, metallic
taste. Urinary System Disorders -
Frequent:
urinary frequency, urinary tract
infection. Infrequent:
urinary urgency, kidney stone, dysuria,
blood in urine.
Events Reported Subsequent to the
Marketing of Racemic Citalopram and Escitalopram
Although no causal
relationship to racemic citalopram or escitalopram treatment
has been found, the following adverse events have been
reported to have occurred in patients and to be temporally
associated with racemic citalopram treatment and with
escitalopram treatment during postmarketing experience and
were not observed
during
the premarketing evaluation of citalopram or escitalopram:
acute renal failure, angioedema, toxic epidermal
necrolysis, gastrointestinal hemorrhage, grand mal seizures
(or convulsions), neuroleptic malignant syndrome,
pancreatitis, QT prolongation, rhabdomyolysis, serotonin
syndrome, thrombocytopenia, torsades de pointes.
Events Reported Subsequent to the
Marketing of Racemic Citalopram (not observed during the
postmarketing experience with escitalopram)
Although no causal
relationship to racemic citalopram treatment has been found,
the following adverse events
have
been reported to have occurred in patients and to be
temporally associated with racemic citalopram treatment
and
were not observed during the premarketing evaluation of
citalopram: akathisia, allergic reaction, anaphylaxis,
choreoathetosis, delirium, dyskinesia, ecchymosis, erythema
multiforme, hemolytic anemia, hepatic necrosis, myoclonus,
nystagmus, priapism, prolactinemia, prothrombin decreased,
spontaneous abortion, thrombosis, and ventricular
arrhythmia.
Events Reported Subsequent to the
Marketing of Escitalopram (not observed during the
postmarketing experience with citalopram)
Although no causal relationship to escitalopram treatment
has been found, the following adverse events have been
reported to have occurred in patients and to be temporally
associated with escitalopram treatment and were not observed
during the premarketing evaluation of escitalopram:
aggression, atrial fibrillation, seizures, diplopia,
dystonia, extrapyramidal disorders, abnormal gait, visual
hallucinations, hepatitis, hypotension, myocardial
infarction, orthostatic hypotension, pulmonary embolism,
SIADH, ventricular tachycardia.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
LEXAPRO is not a controlled substance.
Physical and
Psychological Dependence
Animal studies
suggest that the abuse liability of racemic citalopram is
low. LEXAPRO has not been
systematically studied in humans for its potential for
abuse, tolerance, or physical dependence. The premarketing
clinical experience with LEXAPRO did not reveal any
drug-seeking behavior. However, these observations were
not systematic and it is not possible to predict on the
basis of this limited experience the extent to which a
CNS-active drug will be misused, diverted, and/or abused
once marketed. Consequently, physicians should carefully
evaluate LEXAPRO patients for history of drug abuse and
follow such patients closely, observing them for signs
of misuse or abuse (e.g., development of tolerance,
incrementations of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience
There have been
reports of LEXAPRO overdose involving doses of up to 600 mg.
All patients recovered and no symptoms associated with the
overdoses were reported. In clinical trials of racemic
citalopram, there were no
reports of fatal citalopram overdose involving overdoses of
up to 2000 mg. During the postmarketing evaluation of
citalopram, like other SSRIs, a fatal outcome in a patient
who has taken an overdose of citalopram has been rarely
reported.
Postmarketing reports of drug overdoses involving citalopram
have included 12 fatalities, 10 in combination with
other
drugs and/or alcohol and 2 with citalopram alone (3920 mg
and 2800 mg), as well as non-fatal overdoses of
up to 6000 mg. Symptoms most often accompanying citalopram
overdose, alone or in combination with other
drugs
and/or alcohol, included
dizziness,
sweating, nausea, vomiting, tremor, somnolence, sinus
tachycardia, and convulsions.
In more rare cases, observed symptoms included amnesia,
confusion, coma, hyperventilation,
cyanosis, rhabdomyolysis, and ECG changes (including QTc
prolongation, nodal rhythm, ventricular arrhythmia,
and one possible case of torsades de pointes).
Management of Overdose
Establish and
maintain an airway to ensure adequate ventilation and
oxygenation. Gastric evacuation by lavage
and
use of activated charcoal should be considered. Careful
observation and cardiac and vital sign monitoring are
recommended, along with general symptomatic and supportive
care. Due to the large volume of distribution of
escitalopram, forced diuresis, dialysis, hemoperfusion, and
exchange transfusion are unlikely to be of benefit. There
are no specific antidotes for LEXAPRO.
In managing overdosage, consider the
possibility of multiple-drug involvement. The physician
should consider contacting a poison control center for
additional information on the treatment of any overdose.
DOSAGE AND ADMINISTRATION
Major Depressive Disorder
Initial Treatment
The recommended
dose of LEXAPRO is 10 mg once daily. A fixed-dose trial of
LEXAPRO demonstrated the
effectiveness of both 10 mg and 20 mg of LEXAPRO, but failed
to demonstrate a greater benefit of 20 mg over 10
mg (see Clinical Efficacy
Trials under
CLINICAL PHARMACOLOGY).
If the dose is increased to 20 mg,
this should occur after a minimum of one week.
LEXAPRO should be administered once daily, in the morning or
evening, with or without food.
Special Populations
10 mg/day is the recommended dose for
most elderly patients and patients with hepatic impairment.
No dosage adjustment is necessary for
patients with mild or moderate renal impairment. LEXAPRO
should be used with caution in patients with severe renal
impairment.
Treatment of Pregnant Women During the
Third Trimester
Neonates exposed
to LEXAPRO and other SSRIs or SNRIs, late in the third
trimester, have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding (see
PRECAUTIONS).
When treating pregnant women with
LEXAPRO during the third trimester, the physician should
carefully consider the potential risks and benefits of
treatment. The physician may consider tapering LEXAPRO in
the third trimester.
Maintenance Treatment
It is generally
agreed that acute episodes of major depressive disorder
require several months or longer of sustained
pharmacological therapy beyond response to the acute
episode. Systematic evaluation of continuing LEXAPRO 10 or
20 mg/day for periods of up to 36 weeks in patients with
major depressive disorder who responded while taking LEXAPRO
during an 8-week, acute-treatment phase demonstrated a
benefit of such maintenance treatment (see
Clinical Efficacy Trials
under
CLINICAL PHARMACOLOGY).
Nevertheless, patients should be periodically reassessed to
determine the need for maintenance treatment.
Generalized Anxiety Disorder
Initial Treatment
The
recommended starting dose of LEXAPRO is 10 mg once daily. If
the dose is increased to 20 mg, this should
occur after a minimum of one week.
LEXAPRO should be administered once
daily, in the morning or evening, with or without food.
Maintenance Treatment
Generalized anxiety disorder is recognized as a chronic
condition. The efficacy of LEXAPRO in the treatment of
GAD beyond 8 weeks has not been systematically studied. The
physician who elects to use LEXAPRO for extended periods
should periodically re-evaluate the long-term usefulness of
the drug for the individual patient.
Discontinuation of Treatment with
LEXAPRO
Symptoms associated
with discontinuation of LEXAPRO and other SSRIs and SNRIs
have been reported (see
PRECAUTIONS). Patients should
be monitored for these symptoms when discontinuing
treatment. A gradual reduction in the dose rather than
abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose
or upon discontinuation of treatment, then resuming the
previously prescribed dose may be considered. Subsequently,
the physician may continue decreasing the dose but at a more
gradual rate.
Switching Patients To or From a
Monoamine Oxidase Inhibitor
At least 14 days
should elapse between discontinuation of an MAOI and
initiation of LEXAPRO therapy. Similarly, at least 14 days
should be allowed after stopping LEXAPRO before starting an
MAOI (see CONTRAINDICATIONS
and
WARNINGS).
HOW SUPPLIED
5 mg Tablets:
Bottle of 100
NDC # 0456-2005-01
White to off-white, round, non-scored,
film-coated. Imprint "FL" on one side of the tablet and "5"
on the other side.
10 mg Tablets:
Bottle of 100
NDC # 0456-2010-01
10 x 10 Unit Dose
NDC # 0456-2010-63
White
to off-white, round, scored, film-coated. Imprint on scored
side with "F" on the left side and "L" on the right
side.
Imprint on the non-scored side with
"10".
20 mg Tablets:
Bottle of 100
NDC # 0456-2020-0 1
10 x 10 Unit Dose
NDC # 0456-2020-63
White
to off-white, round, scored, film-coated. Imprint on scored
side with "F" on the left side and "L" on the right
side.
Imprint on the non-scored side with
"20".
Oral Solution:
5 mg/5 mL, peppermint flavor (240 mL)
NDC # 0456-2101-08
Store at 25°C (77°F); excursions
permitted to 15 - 30°C (59-86°F).
ANIMAL TOXICOLOGY
Retinal Changes in Rats
Pathologic changes (degeneration/atrophy) were observed in
the retinas of albino rats in the 2-year carcinogenicity
study with racemic citalopram. There was an increase in both
incidence and severity of retinal pathology in both
male
and female rats receiving 80 mg/kg/day. Similar findings
were not present in rats receiving 24 mg/kg/day of
racemic citalopram for two years, in mice receiving up to
240 mg/kg/day of racemic citalopram for 18 months, or
in dogs receiving up to 20 mg/kg/day of racemic citalopram
for one year.
Additional studies to investigate the
mechanism for this pathology have not been performed, and
the potential significance of this effect in humans has not
been established.
Cardiovascular Changes in Dogs
In a one-year
toxicology study, 5 of 10 beagle dogs receiving oral racemic
citalopram doses of 8 mg/kg/day died suddenly between weeks
17 and 31 following initiation of treatment. Sudden deaths
were not observed in rats at
doses
of racemic citalopram up to 120 mg/kg/day, which produced
plasma levels of citalopram and its metabolites
demethylcitalopram and didemethylcitalopram (DDCT) similar
to those observed in dogs at 8 mg/kg/day. A
subsequent intravenous dosing study demonstrated that in
beagle dogs, racemic DDCT caused QT prolongation, a
known risk factor for the observed outcome in dogs
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