IMPRINT: F P 40 MG
SHAPE: oval COLOR: white SCORE: 2
Boxed Warning
Boxed Warning Section
Rx OnlySuicidality and Antidepressant Drugs
Antidepressants increased the risk compared to
placebo of suicidal thinking and behavior (suicidality) in children,
adolescents, and young adults in short-term studies of major depressive disorder
(MDD) and other psychiatric disorders. Anyone considering the use of Celexa or
any other antidepressant in a child, adolescent, or young adult must balance
this risk with the clinical need. Short-term studies did not show an increase in
the risk of suicidality with antidepressants compared to placebo in adults
beyond age 24; there was a reduction in risk with antidepressants compared to
placebo in adults aged 65 and older. Depression and certain other psychiatric
disorders are themselves associated with increases in the risk of suicide.
Patients of all ages who are started on antidepressant therapy should be
monitored appropriately and observed closely for clinical worsening,
suicidality, or unusual changes in behavior. Families and caregivers should be
advised of the need for close observation and communication with the prescriber.
Celexa is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk,
PRECAUTIONS: Information for Patients, and PRECAUTIONS:
Pediatric Use.)
Rx Only Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to
placebo of suicidal thinking and behavior (suicidality) in children,
adolescents, and young adults in short-term studies of major depressive disorder
(MDD) and other psychiatric disorders. Anyone considering the use of Celexa or
any other antidepressant in a child, adolescent, or young adult must balance
this risk with the clinical need. Short-term studies did not show an increase in
the risk of suicidality with antidepressants compared to placebo in adults
beyond age 24; there was a reduction in risk with antidepressants compared to
placebo in adults aged 65 and older. Depression and certain other psychiatric
disorders are themselves associated with increases in the risk of suicide.
Patients of all ages who are started on antidepressant therapy should be
monitored appropriately and observed closely for clinical worsening,
suicidality, or unusual changes in behavior. Families and caregivers should be
advised of the need for close observation and communication with the prescriber.
Celexa is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk,
PRECAUTIONS: Information for Patients, and PRECAUTIONS:
Pediatric Use.)
Description
Celexa® (citalopram HBr) is an orally administered selective
serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that
of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant
agents. Citalopram HBr is a racemic bicyclic phthalane derivative designated
(±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile,
HBr with the following structural formula:
The molecular formula is C20H22BrFN2O and its molecular weight is
405.35.
Citalopram HBr occurs as a fine, white to off-white powder. Citalopram HBr is
sparingly soluble in water and soluble in ethanol.
Celexa (citalopram hydrobromide) is available as tablets or as an oral
solution.
Celexa 10 mg tablets are film-coated, oval tablets containing citalopram HBr
in strengths equivalent to 10 mg citalopram base. Celexa 20 mg and 40 mg tablets
are film-coated, oval, scored tablets containing citalopram HBr in strengths
equivalent to 20 mg or 40 mg citalopram base. The tablets also contain the
following inactive ingredients: copolyvidone, corn starch, crosscarmellose
sodium, glycerin, lactose monohydrate, magnesium stearate, hypromellose,
microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Iron
oxides are used as coloring agents in the beige (10 mg) and pink (20 mg)
tablets.
Celexa oral solution contains citalopram HBr equivalent to 2 mg/mL citalopram
base. It also contains the following inactive ingredients: sorbitol, purified
water, propylene glycol, methylparaben, natural peppermint flavor, and
propylparaben.
Clinical Pharmacology
Pharmacodynamics The mechanism of action of citalopram HBr as an antidepressant 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 citalopram is a highly selective
serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE)
and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake
is not induced by long-term (14-day) treatment of rats with citalopram.
Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by
citalopram is primarily due to the (S)-enantiomer.
Citalopram has no or very low affinity for 5-HT1A,
5-HT2A, dopamine D1 and D2, α1-, α2-, and
β-adrenergic, histamine H1, gamma aminobutyric acid
(GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of
muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be
associated with various anticholinergic, sedative, and cardiovascular effects of
other psychotropic drugs. Pharmacokinetics The single- and multiple-dose pharmacokinetics of citalopram are
linear and dose-proportional in a dose range of 10-60 mg/day. Biotransformation
of citalopram is mainly hepatic, with a mean terminal half-life of about 35
hours. With once daily dosing, steady state plasma concentrations are achieved
within approximately one week. At steady state, the extent of accumulation of
citalopram in plasma, based on the half-life, is expected to be 2.5 times the
plasma concentrations observed after a single dose. The tablet and oral solution
dosage forms of citalopram HBr are bioequivalent. Absorption and Distribution Following a single oral dose (40 mg tablet) of citalopram, peak
blood levels occur at about 4 hours. The absolute bioavailability of citalopram
was about 80% relative to an intravenous dose, and absorption is not affected by
food. The volume of distribution of citalopram is about 12 L/kg and the binding
of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to
human plasma proteins is about 80%. Metabolism and Elimination Following intravenous administrations of citalopram, the fraction
of drug recovered in the urine as citalopram and DCT was about 10% and 5%,
respectively. The systemic clearance of citalopram was 330 mL/min, with
approximately 20% of that due to renal clearance.
Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram
(DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In
humans, unchanged citalopram is the predominant compound in plasma. At steady
state, the concentrations of citalopram's metabolites, DCT and DDCT, in plasma
are approximately one-half and one-tenth, respectively, that of the parent drug.
In vitro studies show that citalopram is at least 8
times more potent than its metabolites in the inhibition of serotonin reuptake,
suggesting that the metabolites evaluated do not likely contribute significantly
to the antidepressant actions of citalopram.
In vitro studies using human liver microsomes
indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the
N-demethylation of citalopram. Population Subgroups Age - Citalopram pharmacokinetics in subjects ≥ 60 years of age
were compared to younger subjects in two normal volunteer studies. In a
single-dose study, citalopram AUC and half-life were increased in the elderly
subjects by 30% and 50%, respectively, whereas in a multiple-dose study they
were increased by 23% and 30%, respectively. 20 mg is the recommended dose for
most elderly patients (see DOSAGE AND
ADMINISTRATION).
Gender - In three pharmacokinetic studies (total N=32), citalopram AUC in
women was one and a half to two times that in men. This difference was not
observed in five other pharmacokinetic studies (total N=114). In clinical
studies, no differences in steady state serum citalopram levels were seen
between men (N=237) and women (N=388). There were no gender differences in the
pharmacokinetics of DCT and DDCT. No adjustment of dosage on the basis of gender
is recommended.
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. 20 mg is the recommended dose 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 citalopram 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 citalopram on CYP3A4, -2C9, or -2E1, but did
suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would
be expected to have little inhibitory effect on in
vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited.
Since CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of
citalopram, it is expected that potent inhibitors of 3A4 (e.g., ketoconazole,
itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g.,
omeprazole) might decrease the clearance of citalopram. However,
coadministration of citalopram and the potent 3A4 inhibitor ketoconazole did not
significantly affect the pharmacokinetics of citalopram. Because citalopram is
metabolized by multiple enzyme systems, inhibition of a single enzyme may not
appreciably decrease citalopram clearance. Citalopram steady state levels were
not significantly different in poor metabolizers and extensive 2D6 metabolizers
after multiple-dose administration of Celexa, suggesting that coadministration,
with Celexa, of a drug that inhibits CYP2D6, is unlikely to have clinically
significant effects on citalopram metabolism. See Drug Interactions under PRECAUTIONS for more detailed information on available
drug interaction data. Clinical Efficacy Trials The efficacy of Celexa as a treatment for depression was
established in two placebo-controlled studies (of 4 to 6 weeks in duration) in
adult outpatients (ages 18-66) meeting DSM-III or DSM-III-R criteria for major
depression. Study 1, a 6-week trial in which patients received fixed Celexa
doses of 10, 20, 40, and 60 mg/day, showed that Celexa at doses of 40 and 60
mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD)
total score, the HAMD depressed mood li (Item 1), the Montgomery Asberg
Depression Rating Scale, and the Clinical Global Impression (CGI) Severity
scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the
60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a
4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria
for melancholia, the initial dose was 20 mg/day, followed by titration to the
maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with
Celexa showed significantly greater improvement than placebo patients on the
HAMD total score, HAMD li 1, and the CGI Severity score. In three additional
placebo-controlled depression trials, the difference in response to treatment
between patients receiving Celexa and patients receiving placebo was not
statistically significant, possibly due to high spontaneous response rate,
smaller sample size, or, in the case of one study, too low a dose.
In two long-term studies, depressed patients who had responded to Celexa
during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40
mg/day in one study and flexible doses of 20-60 mg/day in the second study) were
randomized to continuation of Celexa or to placebo. In both studies, patients
receiving continued Celexa treatment experienced significantly lower relapse
rates over the subsequent 6 months compared to those receiving placebo. In the
fixed-dose study, the decreased rate of depression relapse was similar in
patients receiving 20 or 40 mg/day of Celexa.
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. Comparison of Clinical Trial Results Highly variable results have been seen in the clinical
development of all antidepressant drugs. Furthermore, in those circumstances
when the drugs have not been studied in the same controlled clinical trial(s),
comparisons among the results of studies evaluating the effectiveness of
different antidepressant drug products are inherently unreliable. Because
conditions of testing (e.g., patient samples, investigators, doses of the
treatments administered and compared, outcome measures, etc.) vary among trials,
it is virtually impossible to distinguish a difference in drug effect from a
difference due to one of the confounding factors just enumerated.
Indications And Usage
Celexa (citalopram HBr) is indicated for the treatment of
depression.
The efficacy of Celexa in the treatment of depression was established in 4-6
week, controlled trials of outpatients whose diagnosis corresponded most closely
to the DSM-III and DSM-III-R 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 antidepressant action of Celexa in hospitalized depressed patients has
not been adequately studied.
The efficacy of Celexa in maintaining an antidepressant response for up to 24
weeks following 6 to 8 weeks of acute treatment was demonstrated in two
placebo-controlled trials (see CLINICAL
PHARMACOLOGY). Nevertheless, the physician who elects to use Celexa
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).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
Celexa is contraindicated in patients with a hypersensitivity to citalopram
or any of the inactive ingredients in Celexa.
Warnings
WARNINGS-Clinical Worsening and Suicide RiskClinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and
pediatric, may experience worsening of their depression and/or the emergence of
suicidal ideation and behavior (suicidality) or unusual changes in behavior,
whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk of
depression and certain other psychiatric disorders, and these disorders
themselves are the strongest predictors of suicide. There has been a
long-standing concern, however, that antidepressants may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients
during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant
drugs (SSRIs and others) showed that these drugs increase the risk of suicidal
thinking and behavior (suicidality) in children, adolescents, and young adults
(ages 18-24) with major depressive disorder (MDD) and other psychiatric
disorders. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24;
there was a reduction with antidepressants compared to placebo in adults aged 65
and older.
The pooled analyses of placebo-controlled trials in children and adolescents
with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders
included a total of 24 short-term trials of 9 antidepressant drugs in over 4400
patients. The pooled analyses of placebo-controlled trials in adults with MDD or
other psychiatric disorders included a total of 295 short-term trials (median
duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There
was considerable variation in risk of suicidality among drugs, but a tendency
toward an increase in the younger patients for almost all drugs studied. There
were differences in absolute risk of suicidality across the different
indications, with the highest incidence in MDD. The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of
cases of suicidality per 1000 patients treated) are provided in Table 1.
TABLE 1
Age
Range
Drug-Placebo Difference in Number of Cases of Suicidality per 1000
Patients Treated
IncreasesCompared to
Placebo
<18
14 additional cases
18-24
5 additional cases
DecreasesCompared to
Placebo
25-64
1 fewer case
>65
6 fewer
cases
No suicides occurred in any of the pediatric trials. There were suicides in
the adult trials, but the number was not sufficient to reach any conclusion
about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e.,
beyond several months. However, there is substantial evidence from
placebo-controlled maintenance trials in adults with depression that the use of
antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any
indication should be monitored appropriately and observed closely for clinical
worsening, suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases.
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,
there is concern that such symptoms may represent precursors to emerging
suicidality.
Consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication, in patients whose depression is
persistently worse, or who are experiencing emergent suicidality or symptoms
that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient's
presenting symptoms.
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 Celexa, for a description
of the risks of discontinuation of Celexa.
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, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of
suicidality, and to report such symptoms immediately to health care providers.
Such monitoring should include daily observation by families and
caregivers. Prescriptions for Celexa should be written for the smallest
quantity of tablets consistent with good patient management, in order to reduce
the risk of overdose. Screening Patients for Bipolar Disorder:
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 with depressive symptoms 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 Celexa is not approved
for use in treating bipolar depression. 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 Celexa 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 Celexa before starting an MAOI.
Serotonin Syndrome or Neuroleptic Malignant Syndrome
(NMS)-like Reactions The development of a potentially life-threatening serotonin
syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been
reported with SNRIs and SSRIs alone, including Celexa treatment, but
particularly with concomitant use of serotonergic drugs (including triptans)
with drugs which impair metabolism of serotonin (including MAOIs), or with
antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may
include mental status changes (e.g., agitation, hallucinations, coma), autonomic
instability (e.g., tachycardia, labile blood pressure, hyperthermia),
neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin
syndrome, in its most severe form can resemble neuroleptic malignant syndrome,
which includes hyperthermia, muscle rigidity, autonomic instability with
possible rapid fluctuation of vital signs, and mental status changes. Patients
should be monitored for the emergence of serotonin syndrome or NMS-like signs
and symptoms.
The concomitant use of Celexa with MAOIs intended to treat depression is
contraindicated. If concomitant treatment of Celexa with a 5-hydroxytryptamine
receptor agonist (triptan) is clinically warranted, careful observation of the
patient is advised, particularly during treatment initiation and dose
increases.
The concomitant use of Celexa with serotonin precursors (such as tryptophan)
is not recommended. Treatment with Celexa and any concomitant serotonergic or
antidopaminergic agents, including antipsychotics, should be discontinued
immediately if the above events occur and supportive symptomatic treatment
should be initiated.
Precautions
GeneralDiscontinuation of Treatment with Celexa During marketing of Celexa 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 Celexa. 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 SSRIs and SNRIs, including Lexapro, may increase the risk of
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory
drugs, warfarin, and other anticoagulants may add to the risk. Case reports and
epidemiological studies (case-control and cohort design) have demonstrated an
association between use of drugs that interfere with serotonin reuptake and the
occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and
SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the
concomitant use of Lexapro and NSAIDs, aspirin, or other drugs that affect
coagulation. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and
SNRIs, including Celexa. In many cases, this hyponatremia appears to be the
result of the syndrome of inappropriate antidiureic hormone secretion (SIADH),
and was reversible when Celexa was discontinued. Cases with serum sodium lower
than 110 mmol/L have been reported. Elderly patients may be at greater risk of
developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or
who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of Celexa should be considered
in patients with symptomatic hyponatremia and appropriate medical intervention
should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty
concentrating, memory impairment, confusion, weakness, and unsteadiness, which
may lead to falls. signs and symptoms associated with more severe and/or acute
cases have included hallucination, syncompe, seizure, coma, respiratory arrest,
and death. Activation of Mania/Hypomania In placebo-controlled trials of Celexa, some of which included
patients with bipolar disorder, activation of mania/hypomania was reported in
0.2% of 1063 patients treated with Celexa and in none of the 446 patients
treated with placebo. Activation of mania/hypomania has also been reported in a
small proportion of patients with major affective disorders treated with other
marketed antidepressants. As with all antidepressants, Celexa should be used
cautiously in patients with a history of mania. Seizures Although anticonvulsant effects of citalopram have been observed
in animal studies, Celexa 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 Celexa, seizures
occurred in 0.3% of patients treated with Celexa (a rate of one patient per 98
years of exposure) and 0.5% of patients treated with placebo (a rate of one
patient per 50 years of exposure). Like other antidepressants, Celexa should be
introduced with care in patients with a history of seizure disorder. Interference with Cognitive and Motor
Performance In studies in normal volunteers, Celexa in doses of 40 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 Celexa therapy
does not affect their ability to engage in such activities. Use in Patients with Concomitant Illness Clinical experience with Celexa in patients with certain
concomitant systemic illnesses is limited. Caution is advisable in using Celexa
in patients with diseases or conditions that produce altered metabolism or
hemodynamic responses.
Celexa 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. However, the electrocardiograms of 1116 patients who
received Celexa in clinical trials were evaluated and the data indicate that
Celexa is not associated with the development of clinically significant ECG
abnormalities.
In subjects with hepatic impairment, citalopram clearance was decreased and
plasma concentrations were increased. The use of Celexa in hepatically impaired
patients should be approached with caution and a lower maximum dosage is
recommended (see DOSAGE AND
ADMINISTRATION).
Because citalopram 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
Celexa, 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 Celexa.
Patients should be cautioned about the risk of serotonin syndrome with the
concomitant use of Celexa and triptans, tramadol or
other serotonergic agents.
Although in controlled studies Celexa has not been shown to impair
psychomotor performance, any psychoactive drug may impair judgment, thinking, or
motor skills, so patients should be cautioned about operating hazardous
machinery, including automobiles, until they are reasonably certain that Celexa
therapy does not affect their ability to engage in such activities.
Patients should be told that, although Celexa has not been shown in
experiments with normal subjects to increase the mental and motor skill
impairments caused by alcohol, the concomitant use of Celexa and alcohol in
depressed patients is not advised.
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 Celexa and NSAIDs,
aspirin, warfarin, or other drugs that affect coagulation since 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 Celexa therapy in 1 to 4 weeks,
they should be advised to continue therapy as directed.
Prescribers or other health professionals should inform patients, their
families, and their caregivers about the benefits and risks associated with
treatment with Celexa and should counsel them in its appropriate use. A patient
Medication Guide about “Antidepressant Medicines, Depression and other Serious
Mental Illness, and Suicidal Thoughts or Actions†is available for Celexa. The
prescriber or health professional should instruct patients, their families, and
their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss
the contents of the Medication Guide and to obtain answers to any questions they
may have. 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 Celexa. Clinical Worsening and Suicide Risk:
Patients, their families, and their caregivers should be encouraged to be alert
to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression,
and suicidal ideation, especially early during antidepressant treatment and when
the dose is adjusted up or down. Families and caregivers of patients should be
advised to look for the emergence of such symptoms on a day-to-day basis, since
changes may be abrupt. Such symptoms should be reported to the patient's
prescriber or health professional, especially if they are severe, abrupt in
onset, or were not part of the patient's presenting symptoms. Symptoms such as
these may be associated with an increased risk for suicidal thinking and
behavior and indicate a need for very close monitoring and possibly changes in
the medication. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions Serotonergic Drugs: Based on the
mechanism of action of SNRIs and SSRIs including Celexa, and the potential for
serotonin syndrome, caution is advised when Celexa is coadministered with other
drugs that may affect the serotonergic neurotransmitter systems, such as
triptans, linezolid (an antibiotic which is a reversible non-selective MAOI),
lithium, tramadol, or St. John's Wort (see WARNINGS-Serotonin Syndrome). The concomitant use of
Celexa with other SSRIs, SNRIs or tryptophan is not
recommended (see PRECAUTIONS - Drug
Interactions). Triptans: There have been rare
postmarketing reports of serotonin syndrome with use of an SSRI and a triptan.
If concomitant treatment of Celexa with a triptan is clinically warranted,
careful observation of the patient is advised, particularly during treatment
initiation and dose increases (see WARNINGS -
Serotonin Syndrome ). CNS Drugs - Given the primary CNS effects of citalopram, caution
should be used when it is taken in combination with other centrally acting
drugs. Alcohol - Although citalopram did not potentiate the cognitive
and motor effects of alcohol in a clinical trial, as with other psychotropic
medications, the use of alcohol by depressed patients taking Celexa 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.
These studies have also shown that concurrent use of an NSAID or aspirin may
potentiate the risk of bleeding.
Altered anticoagulant effects, including increased bleeding, have been
reported when SSRIs and SNRIs are coadministered with warfarin. Patients
receiving warfarin therapy should be carefully monitored when Lexapro is
initiated or discontinued. Cimetidine - In subjects who had received 21 days of 40 mg/day
Celexa, 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
Celexa, combined administration of Celexa and digoxin (single dose of 1 mg) did
not significantly affect the pharmacokinetics of either citalopram or
digoxin. Lithium - Coadministration of Celexa (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 citalopram, caution should be exercised when Celexa and
lithium are coadministered. Pimozide - In a controlled study, a single dose of pimozide 2 mg
co-administered with citalopram 40 mg given once daily for 11 days was
associated with a mean increase in QTc values of approximately 10 msec compared
to pimozide given alone. Citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic
interaction is not known. Theophylline - Combined administration of Celexa (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. Sumatriptan - There have been rare postmarketing reports
describing patients with weakness, hyperreflexia, and incoordination following
the use of a SSRI and sumatriptan. If concomitant treatment with sumatriptan and
an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is
clinically warranted, appropriate observation of the patient is advised. Warfarin - Administration of 40 mg/day Celexa 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 Celexa (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 citalopram should be considered if the two drugs
are coadministered. Triazolam - Combined administration of Celexa (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 Celexa (40 mg) and
ketoconazole (200 mg) decreased the Cmax and AUC of
ketoconazole by 21% and 10%, respectively, and did not significantly affect the
pharmacokinetics of citalopram. CYP3A4 and 2C19 Inhibitors - In vitro
studies indicated that CYP3A4 and 2C19 are the primary enzymes involved in the
metabolism of citalopram. However, coadministration of citalopram (40 mg) and
ketoconazole (200 mg), a potent inhibitor of CYP3A4, did not significantly
affect the pharmacokinetics of citalopram. Because citalopram is metabolized by
multiple enzyme systems, inhibition of a single enzyme may not appreciably
decrease citalopram clearance.
Metoprolol - Administration of 40 mg/day Celexa for 22 days resulted in a
two-fold increase in the plasma levels of the beta-adrenergic blocker
metoprolol. Increased metoprolol plasma levels have been associated with
decreased cardioselectivity. Coadministration of Celexa and metoprolol had no
clinically significant effects on blood pressure or heart rate. Imipramine and Other Tricyclic Antidepressants (TCAs) - In vitro studies suggest that citalopram is a relatively
weak inhibitor of CYP2D6. Coadministration of Celexa (40 mg/day for 10 days)
with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not
significantly affect the plasma concentrations of imipramine or citalopram.
However, the concentration of the imipramine metabolite desipramine was
increased by approximately 50%. The clinical significance of the desipramine
change is unknown. Nevertheless, caution is indicated in the coadministration of
TCAs with Celexa. Electroconvulsive Therapy (ECT) - There are no clinical studies
of the combined use of electroconvulsive therapy (ECT) and Celexa. Carcinogenesis, Mutagenesis, Impairment of
FertilityCarcinogenesis 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 citalopram in mice receiving up to 240
mg/kg/day, which is equivalent to 20 times the maximum recommended human daily
dose (MRHD) of 60 mg on a surface area (mg/m2) basis.
There was an increased incidence of small intestine carcinoma in rats receiving
8 or 24 mg/kg/day, doses which are approximately 1.3 and 4 times the MRHD,
respectively, on a mg/m2 basis. A no-effect dose for this
finding was not established. The relevance of these findings to humans is
unknown. Mutagenesis Citalopram was mutagenic in the in
vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial
strains (Salmonella TA98 and TA1537) 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. 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 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 ≥ 32 mg/kg/day, approximately 5 times the MRHD of 60 mg/day on a body
surface area (mg/m2) basis. Gestation duration was
increased at 48 mg/kg/day, approximately 8 times the MRHD. PregnancyPregnancy Category C In animal reproduction studies, 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
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, which is approximately 18 times the MRHD of
60 mg/day on a body surface area (mg/m2) basis. This dose
was also associated with maternal toxicity (clinical signs, decreased body
weight gain). The developmental, no-effect dose of 56 mg/kg/day is approximately
9 times the MRHD on a mg/m2 basis. In a rabbit study, no
adverse effects on embryo/fetal development were observed at doses of up to 16
mg/kg/day, or approximately 5 times the MRHD on a mg/m2
basis. Thus, teratogenic effects were observed at a maternally toxic dose in the
rat and were not observed in the rabbit.
When female rats were treated with 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, which is approximately 5 times the MRHD on a
mg/m2 basis. The no-effect dose of 12.8 mg/kg/day is
approximately 2 times the MRHD on a mg/m2 basis. Similar
effects on offspring mortality and growth were seen when dams were treated
throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately
4 times the MRHD on a mg/m2 basis. A no-effect dose was
not determined in that study.
There are no adequate and well-controlled studies in pregnant women;
therefore, citalopram should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus. Pregnancy-Nonteratogenic Effects Neonates exposed to Celexa 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).
Infants exposed to SSRIs in late pregnancy may have an increased risk for
persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1—2 per
1000 live births in the general population and is associated with substantial
neonatal morbidity and mortality. In a retrospective, case-control study of 377
women whose infants were born with PPHN and 836 women whose infants were born
healthy, the risk for developing PPHN was approximately six-fold higher for
infants exposed to SSRIs after the 20th week of gestation compared to infants
who had not been exposed to antidepressants during pregnancy. There is currently
no corroborative evidence regarding the risk for PPHN following exposure to
SSRIs in pregnancy; this is the first study that has investigated the potential
risk. The study did not include enough cases with exposure to individual SSRIs
to determine if all SSRIs posed similar levels of PPHN risk.
When treating a pregnant woman with Celexa during the third trimester, the
physician should carefully consider both the potential risks and benefits of
treatment (see DOSAGE AND
ADMINISTRATION). Physicians should note that in a prospective
longitudinal study of 201 women with a history of major depression who were
euthymic at the beginning of pregnancy, women who discontinued antidepressant
medication during pregnancy were more likely to experience a relapse of major
depression than women who continued antidepressant medication. Labor and Delivery The effect of Celexa on labor and delivery in humans is
unknown. Nursing Mothers As has been found to occur with many other drugs, citalopram 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 Celexa therapy
should take into account the risks of citalopram exposure for the infant and the
benefits of Celexa treatment for the mother. Pediatric Use Safety and effectiveness in the pediatric population have not
been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Two
placebo-controlled trials in 407 pediatric patients with MDD have been conducted
with Celexa, and the data were not sufficient to support a claim for use in
pediatric patients. Anyone considering the use of Celexa in a child or
adolescent must balance the potential risks with the clinical need. Geriatric Use Of 4422 patients in clinical studies of Celexa, 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 greater sensitivity
of some older individuals cannot be ruled out. Most elderly patients treated
with Celexa in clinical trials received daily doses between 20 and 40 mg (see
DOSAGE AND ADMINISTRATION).
SSRIs and SNRIs, including Celexa, have been associated with cases of
clinically significant hyponatremia in elderly patients, who may be at greater
risk for this adverse event (see PRECAUTIONS,
Hyponatremia).
In two pharmacokinetic studies, citalopram AUC was increased by 23% and 30%,
respectively, in elderly subjects as compared to younger subjects, and its
half-life was increased by 30% and 50%, respectively (see CLINICAL PHARMACOLOGY).
The premarketing development program for Celexa included
citalopram exposures in patients and/or normal subjects from 3 different groups
of studies: 429 normal subjects in clinical pharmacology/pharmacokinetic
studies; 4422 exposures from patients in controlled and uncontrolled clinical
trials, corresponding to approximately 1370 patient-exposure years. There were,
in addition, over 19,000 exposures from mostly open-label, European
postmarketing studies. The conditions and duration of treatment with Celexa
varied greatly and included (in overlapping categories) open-label and
double-blind studies, inpatient and outpatient studies, fixed-dose and
dose-titration studies, and short-term and long-term exposure. Adverse reactions
were assessed by collecting adverse events, results of physical examinations,
vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic
examinations.
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 uled. An event was considered treatment-emergent if it occurred
for the first time or worsened while receiving therapy following baseline
evaluation. Adverse Findings Observed in Short-Term,
Placebo-Controlled TrialsAdverse Events Associated with Discontinuation of
Treatment Among 1063 depressed patients who received Celexa at doses
ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in
duration, 16% discontinued treatment due to an adverse event, as compared to 8%
of 446 patients receiving placebo. The adverse events associated with
discontinuation and considered drug-related (i.e., associated with
discontinuation in at least 1% of Celexa-treated patients at a rate at least
twice that of placebo) are shown in TABLE
2
. It should be noted that one patient can report more than one
reason for discontinuation and be counted more than once in this table.
TABLE 2 Adverse Events Associated with Discontinuation of Treatment in
Short-Term, Placebo-Controlled, Depression Trials
Percentage of Patients
Discontinuing
Due to Adverse
Event
Citalopram
Placebo
(N=1063)
(N=446)
Body System/Adverse
Event
General
   Asthenia
1%
<1%
Gastrointestinal
Disorders
   Nausea
4%
0%
   Dry Mouth
1%
<1%
   Vomiting
1%
0%
Central and Peripheral
Nervous System Disorders
   Dizziness
2%
<1%
Psychiatric Disorders
   Insomnia
3%
1%
   Somnolence
2%
1%
   Agitation
1%
<1%
Adverse Events Occurring at an Incidence of 2% or
More Among Celexa -Treated Patients Table 3
enumerates the
incidence, rounded to the nearest percent, of treatment-emergent adverse events
that occurred among 1063 depressed patients who received Celexa at doses ranging
from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration.
Events included are those occurring in 2% or more of patients treated with
Celexa and for which the incidence in patients treated with Celexa was greater
than the incidence in placebo-treated patients.
The prescriber should be aware that these figures cannot 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 only commonly observed adverse event that occurred in Celexa patients
with an incidence of 5% or greater and at least twice the incidence in placebo
patients was ejaculation disorder (primarily ejaculatory delay) in male patients
(see TABLE 3
).
TABLE 3 Treatment-Emergent Adverse Events: Incidence in
Placebo-Controlled Clinical Trials*
(Percentage of Patients
Reporting Event)
Body System/Adverse
Event
Celexa
Placebo
(N=1063)
(N=446)
Autonomic Nervous
System
Disorders
   Dry Mouth
20%
14%
   Sweating Increased
11%
9%
Central & Peripheral
Nervous
System Disorders
   Tremor
8%
6%
Gastrointestinal
Disorders
   Nausea
21%
14%
   Diarrhea
8%
5%
   Dyspepsia
5%
4%
   Vomiting
4%
3%
   Abdominal Pain
3%
2%
General
   Fatigue
5%
3%
   Fever
2%
<1%
Musculoskeletal System
Disorders
   Arthralgia
2%
1%
   Myalgia
2%
1%
Psychiatric Disorders
   Somnolence
18%
10%
   Insomnia
15%
14%
   Anxiety
4%
3%
   Anorexia
4%
2%
   Agitation
3%
1%
   Dysmenorrhea1
3%
2%
   Libido Decreased
2%
<1%
   Yawning
2%
<1%
Respiratory System
Disorders
   Upper Respiratory Tract Infection
5%
4%
   Rhinitis
5%
3%
   Sinusitis
3%
<1%
Urogenital
   Ejaculation Disorder2,3
6%
1%
   Impotence3
3%
<1%
*Events reported by at least 2% of patients treated with
Celexa are reported, except for the following events which had an incidence on
placebo > Celexa: headache, asthenia, dizziness, constipation, palpitation,
vision abnormal, sleep disorder, nervousness, pharyngitis, micturition disorder,
back pain.
1Denominator used was for females
only (N=638 Celexa; N=252 placebo).
2Primarily ejaculatory delay.
3Denominator used was for males
only (N=425 Celexa; N=194 placebo).
Dose Dependency of Adverse Events The potential relationship between the dose of Celexa
administered and the incidence of adverse events was examined in a fixed-dose
study in depressed patients receiving placebo or Celexa 10, 20, 40, and 60 mg.
Jonckheere's trend test revealed a positive dose response (p<0.05) for the
following adverse events: fatigue, impotence, insomnia, sweating increased,
somnolence, and yawning. 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.
The table below displays the incidence of sexual side effects reported by at
least 2% of patients taking Celexa in a pool of placebo-controlled clinical
trials in patients with depression.
Treatment
Celexa
(425 males)
Placebo
(194 males)
Abnormal
Ejaculation(mostly ejaculatory delay)
6.1%(males only)
1%(males only)
Libido Decreased
3.8%(males only)
<1%(males only)
Impotence
2.8%(males only)
<1%(males
only)
In female depressed patients receiving Celexa, the reported incidence of
decreased libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252
females), respectively.
There are no adequately designed studies examining sexual dysfunction with
citalopram 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 Celexa 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 Celexa treatment. In addition, a comparison of supine and
standing vital sign measures for Celexa and placebo treatments indicated that
Celexa treatment is not associated with orthostatic changes. Weight Changes Patients treated with Celexa in controlled trials experienced a
weight loss of about 0.5 kg compared to no change for placebo patients. Laboratory Changes Celexa 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 Celexa treatment. ECG Changes Electrocardiograms from Celexa (N=802) and placebo (N=241) 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. The only
statistically significant drug-placebo difference observed was a decrease in
heart rate for Celexa of 1.7 bpm compared to no change in heart rate for
placebo. There were no observed differences in QT or other ECG intervals. Other Events Observed During the Premarketing
Evaluation of Celexa (citalopram HBr) Following is a ul of WHO terms that reflect treatment-emergent
adverse events, as defined in the introduction to the ADVERSE REACTIONS
section, reported by patients treated
with Celexa at multiple doses in a range of 10 to 80 mg/day during any phase of
a trial within the premarketing database of 4422 patients. All reported events
are included except those already uled in Table
3
or elsewhere in labeling, those events for which a drug cause was
remote, those event terms which were so general as to be uninformative, and
those occurring in only one patient. It is important to emphasize that, although
the events reported occurred during treatment with Celexa, they were not
necessarily caused by it.
Events are further categorized by body system and uled 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 1/1000 patients; rare events are those occurring in fewer than 1/1000
patients. Cardiovascular - Frequent: tachycardia, postural hypotension, hypotension.
Infrequent: hypertension, bradycardia, edema
(extremities), angina pectoris, extrasystoles, cardiac failure, flushing,
myocardial infarction, cerebrovascular accident, myocardial ischemia. Rare: transient ischemic attack, phlebitis, atrial
fibrillation, cardiac arrest, bundle branch block. Central and Peripheral Nervous System
Disorders - Frequent: paresthesia, migraine.
Infrequent: hyperkinesia, vertigo, hypertonia,
extrapyramidal disorder, leg cramps, involuntary muscle contractions,
hypokinesia, neuralgia, dystonia, abnormal gait, hypesthesia, ataxia. Rare: abnormal coordination, hyperesthesia, ptosis,
stupor. Endocrine Disorders - Rare: hypothyroidism, goiter, gynecomastia. Gastrointestinal Disorders - Frequent: saliva increased, flatulence. Infrequent: gastritis, gastroenteritis, stomatitis,
eructation, hemorrhoids, dysphagia, teeth grinding, gingivitis, esophagitis.
Rare: colitis, gastric ulcer, cholecystitis,
cholelithiasis, duodenal ulcer, gastroesophageal reflux, glossitis, jaundice,
diverticulitis, rectal hemorrhage, hiccups. General - Infrequent: hot flushes, rigors, alcohol intolerance,
syncope, influenza-like symptoms. Rare:
hayfever. Hemic and Lymphatic Disorders - Infrequent: purpura, anemia, epistaxis, leukocytosis,
leucopenia, lymphadenopathy. Rare: pulmonary
embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia,
coagulation disorder, gingival bleeding. Metabolic and Nutritional Disorders -
Frequent: decreased weight, increased weight. Infrequent: increased hepatic enzymes, thirst, dry eyes,
increased alkaline phosphatase, abnormal glucose tolerance. Rare: bilirubinemia, hypokalemia, obesity, hypoglycemia,
hepatitis, dehydration. Musculoskeletal System Disorders - Infrequent: arthritis, muscle weakness, skeletal pain.
Rare: bursitis, osteoporosis. Psychiatric Disorders - Frequent: impaired concentration, amnesia, apathy,
depression, increased appetite, aggravated depression, suicide attempt,
confusion. Infrequent: increased libido, aggressive
reaction, paroniria, drug dependence, depersonalization, hallucination,
euphoria, psychotic depression, delusion, paranoid reaction, emotional lability,
panic reaction, psychosis. Rare: catatonic reaction,
melancholia.
Reproductive Disorders/Female* - Frequent: amenorrhea. Infrequent: galactorrhea, breast pain, breast enlargement,
vaginal hemorrhage. *% based on female subjects only: 2955 Respiratory System Disorders - Frequent: coughing. Infrequent:
bronchitis, dyspnea, pneumonia. Rare: asthma,
laryngitis, bronchospasm, pneumonitis, sputum increased. Skin and Appendages Disorders - Frequent: rash, pruritus. Infrequent: photosensitivity reaction, urticaria, acne,
skin discoloration, eczema, alopecia, dermatitis, skin dry, psoriasis. Rare: hypertrichosis, decreased sweating, melanosis,
keratitis, cellulitis, pruritus ani. Special Senses - Frequent: accommodation abnormal, taste perversion. Infrequent: tinnitus, conjunctivitis, eye pain. Rare: mydriasis, photophobia, diplopia, abnormal
lacrimation, cataract, taste loss. Urinary System Disorders - Frequent: polyuria. Infrequent:
micturition frequency, urinary incontinence, urinary retention, dysuria. Rare: facial edema, hematuria, oliguria, pyelonephritis,
renal calculus, renal pain. Other Events Observed During the Postmarketing
Evaluation of Celexa (citalopram HBr) It is estimated that over 30 million patients have been treated
with Celexa since market introduction. Although no causal relationship to Celexa
treatment has been found, the following adverse events have been reported to be
temporally associated with Celexa treatment, and have not been described
elsewhere in labeling: acute renal failure, akathisia, allergic reaction,
anaphylaxis, angioedema, choreoathetosis, chest pain, delirium, dyskinesia,
ecchymosis, epidermal necrolysis, erythema multiforme, gastrointestinal
hemorrhage, glaucoma, grand mal convulsions, hemolytic anemia, hepatic necrosis,
myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin
decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia,
thrombosis, ventricular arrhythmia, torsade de pointes, and withdrawal
syndrome.
Drug Abuse And Dependence
Controlled Substance Class Celexa (citalopram HBr) is not a controlled substance. Physical and Psychological Dependence Animal studies suggest that the abuse liability of Celexa is low.
Celexa has not been systematically studied in humans for its potential for
abuse, tolerance, or physical dependence. The premarketing clinical experience
with Celexa 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 Celexa patients for history of drug abuse and
Overdosage
Human Experience In clinical trials of citalopram, there were reports of
citalopram overdose, including overdoses of up to 2000mg, with no associated
fatalities. During the postmarketing evaluation of citalopram, Celexa overdoses,
including overdoses of up to 6000 mg, have been reported. As with other SSRI's,
a fatal outcome in a patient who has taken an overdose of citalopram has been
rarely reported.
Symptoms most often accompanying citalopram overdose, alone or in combination
with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting,
tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms
included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis,
rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm,
ventricular arrhythmia, and very rare cases of torsade de pointes). Acute renal
failure has been very rarely reported accompanying overdose. 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 citalopram, forced diuresis, dialysis,
hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are
no specific antidotes for Celexa.
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
Initial Treatment Celexa (citalopram HBr) should be administered at an initial dose
of 20 mg once daily, generally with an increase to a dose of 40 mg/day. Dose
increases should usually occur in increments of 20 mg at intervals of no less
than one week. Although certain patients may require a dose of 60 mg/day, the
only study pertinent to dose response for effectiveness did not demonstrate an
advantage for the 60 mg/day dose over the 40 mg/day dose; doses above 40 mg are
therefore not ordinarily recommended.
Celexa should be administered once daily, in the morning or evening, with or
without food. Special Populations 20 mg/day is the recommended dose for most elderly patients and
patients with hepatic impairment, with titration to 40 mg/day only for
nonresponding patients.
No dosage adjustment is necessary for patients with mild or moderate renal
impairment. Celexa should be used with caution in patients with severe renal
impairment. Treatment of Pregnant Women During the Third
Trimester Neonates exposed to Celexa 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 Celexa
during the third trimester, the physician should carefully consider the
potential risks and benefits of treatment. The physician may consider tapering
Celexa in the third trimester. Maintenance Treatment It is generally agreed that acute episodes of depression require
several months or longer of sustained pharmacologic therapy. Systematic
evaluation of Celexa in two studies has shown that its antidepressant efficacy
is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial
treatment (32 weeks total). In one study, patients were assigned randomly to
placebo or to the same dose of Celexa (20-60 mg/day) during maintenance
treatment as they had received during the acute stabilization phase, while in
the other study, patients were assigned randomly to continuation of Celexa 20 or
40 mg/day, or placebo, for maintenance treatment. In the latter study, the rates
of relapse to depression were similar for the two dose groups (see Clinical Trials under CLINICAL PHARMACOLOGY). Based on these limited data, it is
not known whether the dose of citalopram needed to maintain euthymia is
identical to the dose needed to induce remission. If adverse reactions are
bothersome, a decrease in dose to 20 mg/day can be considered. Discontinuation of Treatment with Celexa Symptoms associated with discontinuation of Celexa 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 Celexa therapy. Similarly, at least 14 days should be allowed
after stopping Celexa before starting an MAOI (see CONTRAINDICATIONS and WARNINGS).
How Supplied
Tablets: 10 mg        Beige, oval, film-coated. Imprint on one side with "FP".  Imprint on the other side with "10 mg".
Bottles of 10
NDC 54868-4985-1
Bottles of 30
NDC 54868-4985-0
20 mg         Pink, oval, scored, film-coated.  Imprint on scored side with "F" on the left side and "P" on the right
side.  Imprint on the non-scored side with "20 mg".
Bottles of 10
NDC 54868-4159-1
Bottles of 15
NDC 54868-4159-3
Bottles of 30
NDC 54868-4159-0
Bottles of 90
NDC 54868-4159-2
Bottles of 100
NDC 54868-4159-4
40 mg          White, oval, scored, film-coated. Imprint on scored side with "F" on the left side and "P" on the right
side. Imprint on the non-scored side with "40 mg".
Bottles of 10
NDC 54868-4226-1
Bottles of 30
NDC 54868-4226-0
Bottles of 50
NDC 54868-4226-2
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 citalopram.
There was an increase in both incidence and severity of retinal pathology in
both male and female rats receiving 80 mg/kg/day (13 times the maximum
recommended daily human dose of 60 mg on a mg/m2 basis).
Similar findings were not present in rats receiving 24 mg/kg/day for two years,
in mice treated for 18 months at doses up to 240 mg/kg/day, or in dogs treated
for one year at doses up to 20 mg/kg/day (4, 20, and 10 times, respectively, the
maximum recommended daily human dose on a mg/m2
basis).
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 doses of 8 mg/kg/day (4 times the maximum recommended daily human dose of
60 mg on a mg/m2 basis) died suddenly between weeks 17
and 31 following initiation of treatment. Although appropriate data from that
study are not available to directly compare plasma levels of citalopram (CT) and
its metabolites, demethylcitalopram (DCT) and didemethylcitalopram (DDCT), to
levels that have been achieved in humans, pharmacokinetic data indicate that the
relative dog-to-human exposure was greater for the metabolites than for
citalopram. Sudden deaths were not observed in rats at doses up to 120
mg/kg/day, which produced plasma levels of CT, DCT, and DDCT similar to those
observed in dogs at doses of 8 mg/kg/day. A subsequent intravenous dosing study
demonstrated that in beagle dogs, DDCT caused QT prolongation, a known risk
factor for the observed outcome in dogs. This effect occurred in dogs at doses
producing peak DDCT plasma levels of 810 to 3250 nM (39-155 times the mean
steady state DDCT plasma level measured at the maximum recommended human daily
dose of 60 mg). In dogs, peak DDCT plasma concentrations are approximately equal
to peak CT plasma concentrations, whereas in humans, steady state DDCT plasma
concentrations are less than 10% of steady state CT plasma concentrations.
Assays of DDCT plasma concentrations in 2020 citalopram-treated individuals
demonstrated that DDCT levels rarely exceeded 70 nM; the highest measured level
of DDCT in human overdose was 138 nM. While DDCT is ordinarily present in humans
at lower levels than in dogs, it is unknown whether there are individuals who
may achieve higher DDCT levels. The possibility that DCT, a principal metabolite
in humans, may prolong the QT interval in dogs has not been directly examined
because DCT is rapidly converted to DDCT in that species.
Forest Pharmaceuticals, Inc.Subsidiary of Forest Laboratories,
Inc.St. Louis, MO 63045 USA
Relabeling and Repackaging by:
Physicians Total Care, Inc.Tulsa, OKÂ Â Â Â Â Â 74146
Spl Medguide Section
Medication Guide Antidepressant Medicines, Depression and other
Serious Mental Illnesses, and Suicidal Thoughts or Actions
Read the Medication Guide that comes with you or your family member's
antidepressant medicine. This Medication Guide is only about the risk of
suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider
about:
all risks and benefits of treatment with antidepressant medicines
all treatment choices for depression or other serious mental
illness
What is the most important information I should know about
antidepressant medicines, depression and other serious mental illnesses, and
suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts
or actions in some children, teenagers, and young adults within the first few
months of treatment.
Depression and other serious mental illnesses are the most
important causes of suicidal thoughts and actions. Some people may have a
particularly high risk of having suicidal thoughts or actions. These
include people who have (or have a family history of) bipolar illness (also
called manic-depressive illness) or suicidal thoughts or actions.
How can I watch for and try to prevent suicidal thoughts
and actions in myself or a family member?
Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
Call the healthcare provider right away to report new or sudden changes in
mood, behavior, thoughts, or feelings.
Keep all follow-up visits with the healthcare provider as scheduled. Call
the healthcare provider between visits as needed, especially if you have
concerns about symptoms.
Call a healthcare provider right away if you or your family
member has any of the following symptoms, especially if they are new, worse, or
worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling very agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking(mania)
other unusual changes in behavior or mood
Call your doctor for medical advice about side effects. You
may report side effects to FDA at 1-800-FDA-1088
What else do I need to know about antidepressant
medicines?
Never stop an antidepressant medicine without first talking
to a healthcare provider. Stopping an antidepressant medicine suddenly
can cause other symptoms.
Antidepressants are medicines used to treat depression and
other illnesses. It is important to discuss all the risks of treating
depression and also the risks of not treating it. Patients and their families or
other caregivers should discuss all treatment choices with the healthcare
provider, not just the use of antidepressants.
Antidepressant medicines have other side effects.
Talk to the healthcare provider about the side effects of the medicine
prescribed for you or your family member.
Antidepressant medicines can interact with other
medicines. Know all of the medicines that you or your family member
takes. Keep a ul of all medicines to show the healthcare provider. Do not
start new medicines without first checking with your healthcare provider.
Not all antidepressant medicines prescribed for children
are FDA approved for use in children. Talk to your child's healthcare
provider for more information.
This Medication Guide has been approved by the U.S. Food and Drug
Administration for all antidepressants.
Rev. 01/09
Principal Display Panel
Celexa® (citalopram HBr)
10 mg tablets
20 mg tablets
40 mg tablets
DISCLAIMER:
"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."
"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."
"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."
PillSync may earn a commission via links on our site