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 citalopram tablets 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. Citalopram is not approved
for use in pediatric patients. (See WARNINGS: Clinical
Worsening and Suicide Risk, PRECAUTIONS: Information
for Patients, and PRECAUTIONS: Pediatric
Use.)
DESCRIPTION
Citalopram hydrobromide 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
hydrobromide is a racemic bicyclic phthalane derivative designated
(±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile,
hydrobromide with the following structural formula:
The molecular formula is C20H22BrFN2O and its molecular weight is
405.35.
Citalopram hydrobromide occurs as a fine, white to off-white
powder. Citalopram hydrobromide is sparingly soluble in water and soluble in
ethanol.
Citalopram hydrobromide is available as
tablets.
Citalopram 10 mg tablets are biconvex, round shaped film coated
tablets in strengths equivalent to 10 mg citalopram base. Citalopram 20 mg and
40 mg tablets are scored biconvex capsule shaped film coated tablets containing
citalopram hydrobromide in strengths equivalent to 20 mg or 40 mg citalopram
base. The tablets also contain the following inactive ingredients: copovidone,
corn starch, croscarmellose sodium, lactose monohydrate, magnesium stearate,
hypromellose, microcrystalline cellulose, polyethylene glycol, and titanium
dioxide. Iron oxides are used as coloring agents in the peach (10 mg) and light
pink (20 mg) tablets.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of
citalopram hydrobromide 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-HT
1A, 5-HT
2A, dopamine D
1 and D
2, α
1-,
α
2-, and β-adrenergic, histamine H
1, 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.
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 greaer than or equal to 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 less than 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 citalopram tablets, suggesting that coadministration, with citalopram
tablets, 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
citalopram tablets 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 citalopram tablets doses of
10, 20, 40, and 60 mg/day, showed that citalopram tablets 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 item (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
citalopram tablets showed significantly greater improvement than placebo
patients on the HAMD total score, HAMD item 1, and the CGI Severity score. In
three additional placebo-controlled depression trials, the difference in
response to treatment between patients receiving citalopram tablets 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 citalopram tablets 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 citalopram
tablets or to placebo. In both studies, patients receiving continued citalopram
tablets 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 citalopram tablets.
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
Citalopram tablets are indicated for the treatment of depression.
The
efficacy of citalopram tablets 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 citalopram tablets in hospitalized depressed patients
has not been adequately studied.
The efficacy of citalopram tablets 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 citalopram tablets for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual
patient.
CONTRAINDICTIONS
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is
contraindicated (see WARNINGS).
Concomitant use in patients
taking pimozide is contraindicated (see PRECAUTIONS).
Citalopram tablets are
contraindicated in patients with a hypersensitivity to citalopram or any of the
inactive ingredients in citalopram tablets.
WARNINGS
Clinical 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 |
| Increases Compared to
Placebo
|
Less than 18
| 14 additional cases
|
18-24
| 5 additional cases
|
| Decreases Compared to Placebo
|
25-64
| 1 fewer case
|
Greater than or equal to 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
Citalopram Tablets, for a description of the risks of discontinuation
of citalopram tablets).
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 citalopram
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 citalopram 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 citalopram tablets 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 citalopram tablets 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 citalopram 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 citalopram with MAOIs intended to
treat depression is contraindicated. If concomitant treatment of citalopram 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 citalopram with
serotonin precursors (such as tryptophan) is not recommended. Treatment with
citalopram 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
General
Discontinuation of Treatment with Citalopram
Tablets
During marketing of citalopram 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 citalopram. 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
citalopram, 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 citalopram and NSAIDs, aspirin, or other
drugs that affect coagulation.
Hyponatremia
Hyponatremia may occur as a
result of treatment with SSRIs and SNRIs, including citalopram. In many cases,
this hyponatremia appears to be the result of the syndrome of inappropriate
antidiuretic hormone secretion (SIADH), and was reversible when citalopram 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 citalopram 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, syncope, seizure, coma,
respiratory arrest, and death.
Activation of Mania/Hypomania
In
placebo-controlled trials of citalopram tablets, some of which included patients
with bipolar disorder, activation of mania/hypomania was reported in 0.2% of
1063 patients treated with citalopram tablets 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, citalopram tablets should
be used cautiously in patients with a history of mania.
Seizures
Although anticonvulsant effects of
citalopram have been observed in animal studies, citalopram tablets have 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 citalopram tablets, seizures occurred in 0.3% of
patients treated with citalopram tablets (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, citalopram tablets should be
introduced with care in patients with a history of seizure disorder.
Interference with Cognitive and Motor
Performance
In studies in normal volunteers, citalopram tablets 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
citalopram tablets therapy does not affect their ability to engage in such
activities.
Use in Patients with Concomitant
Illness
Clinical experience with citalopram tablets are in patients with
certain concomitant systemic illnesses is limited. Caution is advisable in using
citalopram tablets in patients with diseases or conditions that produce altered
metabolism or hemodynamic responses.
Citalopram tablets have 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
citalopram tablets in clinical trials were evaluated and the data indicate that
citalopram tablets are 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 citalopram tablets 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 citalopram tablets,
however, they 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
citalopram tablets.
Patients should be cautioned about the risk of
serotonin syndrome with the concomitant use of citalopram and triptans, tramadol
or other serotonergic agents.
Although in controlled studies citalopram
tablets have 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 citalopram tablets therapy does not affect their
ability to engage in such activities.
Patients should be told that,
although citalopram tablets have not been shown in experiments with normal
subjects to increase the mental and motor skill impairments caused by alcohol,
the concomitant use of citalopram tablets 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 citalopram 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
citalopram tablets 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 citalopram 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 citalopram. 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 citalopram.
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
citalopram, and the potential for serotonin syndrome, caution is advised when
citalopram 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 citalopram 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 citalopram 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 citalopram tablets
are 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 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 citalopram is initiated or
discontinued.
Cimetidine - In subjects who had received 21 days of 40
mg/day citalopram tablets, combined administration of 400 mg/day cimetidine for
8 days resulted in an increase in citalopram AUC and C
max
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
citalopram tablets, combined administration of citalopram tablets and digoxin
(single dose of 1 mg) did not significantly affect the pharmacokinetics of
either citalopram or digoxin.
Lithium
-
Coadministration of citalopram tablets (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 citalopram tablets 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
C
max of pimozide. The mechanism of this pharmacodynamic
interaction is not known.
Theophylline
-
Combined administration of citalopram tablets (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
citalopram tablets 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 citalopram tablets (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 citalopram tablets (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 citalopram tablets (40 mg)
and ketoconazole (200 mg) decreased the C
max 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 citalopram tablets for 22 days resulted in a
two-fold increasein the plasma levels of the beta-adrenergic blocker
metoprolol. Increased metoprolol plasma levels have been associated with
decreased cardioselectivity. Coadministration of citalopram tablets 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 citalopram tablets (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 citalopram
tablets.
Electroconvulsive Therapy (ECT) - There are no clinical studies
of the combined use of electroconvulsive therapy (ECT) and citalopram tablets.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
Carcinogenesis
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/m
2) 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/m
2 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/m
2) basis. Gestation duration was increased at 48 mg/kg/day,
approximately 8 times the MRHD.
Pregnancy
Pregnancy 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/m
2) 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/m
2 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/m
2 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/m
2 basis. The
no-effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a
mg/m
2 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/m
2 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.
Nonteratogenic Effects
Neonates exposed to
citalopram 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 citalopram 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 citalopram
tablets 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 citalopram tablets therapy should take into
account the risks of citalopram exposure for the infant and the benefits of
citalopram tablets 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 citalopram tablets, and the data were not
sufficient to support a claim for use in pediatric patients. Anyone considering
the use of citalopram tablets in a child or adolescent must balance the
potential risks with the clinical need.
Geriatric Use
Of 4422 patients in clinical
studies of citalopram tablets, 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 citalopram tablets in
clinical trials received daily doses between 20 and 40 mg (see
DOSAGE AND
ADMINISTRATION).
SSRIs and SNRIs, including
citalopram, 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).
20 mg/day is the
recommended dose for most elderly patients (see
DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
The premarketing development program for citalopram tablets 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 citalopram tablets 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 listed. 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 Trials
Adverse Events Associated with Discontinuation of
Treatment
Among 1063 depressed patients who received citalopram tablets
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 citalopram tablets-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
Body System/Adverse
Event | Percentage of Patients
Discontinuing Due to Adverse Event |
Citalopram (N=1063) | Placebo (N=446) |
General
|
|
|
Asthenia
| 1%
| less than 1%
|
Gastrointestinal
Disorders
|
|
|
Nausea
| 4%
| 0%
|
Dry Mouth
| 1%
| less than 1%
|
Vomiting
| 1%
| 0%
|
Central and
Peripheral
Nervous System
Disorders
|
|
|
Dizziness
| 2%
| less than 1%
|
Psychiatric Disorders
|
|
|
Insomnia
| 3%
| 1%
|
Somnolence
| 2%
| 1%
|
Agitation
| 1%
| less than 1%
|
Adverse Events Occurring at an Incidence of 2% or
More Among Citalopram-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
citalopram tablets 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 citalopram tablets and for which the incidence
in patients treated with citalopram tablets were 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 citalopram 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 | Citalopram Tablets (N=1063) | Placebo (N=446) |
Autonomic Nervous System Disorders |
|
|
Dry Mouth
| 20%
| 14%
|
Sweating Increased
| 11%
| 9%
|
Central and 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%
| less than 1%
|
Musculoskeletal System Disorders |
|
|
Arthralgia
| 2%
| 1%
|
Myalgia
| 2%
| 1%
|
Psychiatric Disorder |
|
|
Somnolence
| 18%
| 10%
|
Insomnia
| 15%
| 14%
|
Anxiety
| 4%
| 3%
|
Anorexia
| 4%
| 2%
|
Agitation
| 3%
| 1%
|
Dysmenorrhea (1)
| 3%
| 2%
|
Libido Decreased
| 2%
| less than 1%
|
Yawning
| 2%
| less than 1%
|
Respiratory System Disorders |
|
|
Upper Respiratory Tract Infection
| 5%
| 4%
|
Rhinitis
| 5%
| 3%
|
Sinusitis
| 3%
| less than 1%
|
Urogenital |
|
|
Ejaculation Disorder (2,3)
| 6%
| 1%
|
Impotence (3)
| 3%
| less than 1%
|
(*) Events reported by at least 2% of patients treated with citalopram tablets
are reported, except for the following events which had an incidence on
placebo greater than or equal to citalopram tablets: headache, asthenia,
dizziness, constipation, palpitation, vision abnormal, sleep disorder,
nervousness, pharyngitis, micturition disorder, back pain.
(1) Denominator used was for females only (N=638 citalopram tablets;
N=252 placebo).
(2) Primarily ejaculatory delay.
(3) Denominator used was for males only (N=425 citalopram tablets;
N=194 placebo).
Dose Dependency of Adverse Events
The
potential relationship between the dose of citalopram tablets administered and
the incidence of adverse events was examined in a fixed-dose study in depressed
patients receiving placebo or citalopram tablets 10, 20, 40, and 60 mg.
Jonckheere’s trend test revealed a positive dose response (p less than 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 citalopram tablets in a pool of
placebo-controlled clinical trials in patients with depression.
Treatment | Citalopram Tablets (425 males) | Placebo (194 males) |
Abnormal Ejaculation (mostly ejaculatory delay)
| 6.1% (males only)
| 1% (males only)
|
Libido Decreased
| 3.8% (males only)
| less than 1% (males only)
|
Impotence
| 2.8% (males only)
| less than 1% (males only)
|
In female depressed patients receiving citalopram tablets, 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
Citalopram tablets 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
citalopram hydrobromide treatment. In addition, a comparison of supine and
standing vital sign measures for citalopram tablets and placebo treatments
indicated that citalopram tablets treatment is not associated with orthostatic
changes.
Weight Changes
Patients treated with
citalopram tablets in controlled trials experienced a weight loss of about 0.5
kg compared to no change for placebo patients.
Laboratory Changes
Citalopram tablets 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 citalopram
tablets treatment.
ECG Changes
Electrocardiograms from
citalopram tablets (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 citalopram
tablets 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 Citalopram Tablets
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 patients treated with citalopram tablets 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
listed 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
citalopram tablets, 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
1/1000 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 Citalopram Tablets
It is estimated that over 30 million
patients have been treated with citalopram since market introduction. Although
no causal relationship to citalopram treatment has been found, the following
adverse events have been reported to be temporally associated with citalopram
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
Citalopram
hydrobromide is not a controlled substance.
Physical and Psychological Dependence
Animal
studies suggest that the abuse liability of citalopram tablets is
low. Citalopram tablets have not been systematically studied in humans for its
potential for abuse, tolerance, or physical dependence. The premarketing
clinical experience with citalopram tablets 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 citalopram 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
In clinical trials of
citalopram, there were reports of citalopram overdose, including overdoses of up
to 2000 mg, with no associated fatalities. During the postmarketing evaluation
of citalopram, citalopram overdoses, including overdoses of up to 6000 mg, have
been reported. As with other SSRIs, 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 citalopram
tablets.
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
Citalopram tablets 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.
Citalopram tablets 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. Citalopram tablets should be used with caution in patients with
severe renal impairment.
Treatment of Pregnant Women During the Third
Trimester
Neonates exposed to citalopram 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
citalopram during the third trimester, the physician should carefully consider
the potential risks and benefits of treatment. The physician may consider
tapering citalopram 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 citalopram tablets 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
citalopram tablets (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 citalopram tablets 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 Citalopram
Tablets
Symptoms associated with discontinuation of citalopram 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 citalopram tablets therapy. Similarly, at least 14 days
should be allowed after stopping citalopram tablets before starting an MAOI (see
CONTRAINDICATIONS and
WARNINGS).
HOW SUPPLIED
Citalopram tablets are supplied as:
10 mg Tablets
– Peach coloured, biconvex, round shaped film coated tablets debossed
with ‘A’ on one side and ‘05’ on the other side.
Bottles of 30
| NDC 54868-5275-0
|
Bottles of 60
| NDC 54868-5275-2
|
Bottles of 90
| NDC 54868-5275-1
|
20 mg Tablets – Light pink
coloured, biconvex, capsule shaped film coated tablets debossed with ‘A’ on one
side and with a score line in between ‘0’ and ‘6’ on other side.
Bottles of 15
| NDC 54868-5178-1
|
Bottles of 30
| NDC 54868-5178-0
|
Bottles of 60
| NDC 54868-5178-2
|
Bottles of 90
| NDC 54868-5178-4
|
Bottles of 100
| NDC 54868-5178-3
|
Bottles of 135
| NDC 54868-5178-5
|
40 mg Tablets – White coloured,
biconvex, capsule shaped film coated tablets debossed with ‘A’ on one side and
with a score line in between ‘0’ and ‘7’ on other side.
Bottles of 15
| NDC 54868-1239-1
|
Bottles of 30
| NDC 54868-1239-0
|
Bottles of 60
| NDC 54868-1239-4
|
Bottles of 90
| NDC 54868-1239-3
|
Bottles of 100
| NDC 54868-1239-2
|
Store at 20° to 25°C (68° to 77°F);
excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room
Temperature].
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/m
2 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/m
2 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/m
2 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.
Manufactured for:
Aurobindo Pharma USA,
Inc.
2400 Route 130 North
Dayton, NJ 08810
Manufactured
by:
Aurobindo Pharma Limited
Hyderabad-500 072,
India
Revised: 02/2009
Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, OK 74146
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?
-
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
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 list 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.
Call your doctor for medical advice
about side effects. You may report side effects to FDA at
1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food
and Drug Administration for all antidepressants.
Manufactured
for:
Aurobindo Pharma USA, Inc.
2400 Route 130
North
Dayton, NJ 08810
Manufactured by:
Aurobindo
Pharma Limited
Hyderabad-500 072, India
Revised: 02/2009
PRINCIPAL DISPLAY PANEL
Citalopram Tablets, USP
10 mg
PHARMACIST: PLEASE DISPENSE WITH
MEDICATION GUIDE PROVIDED SEPARATELY
Rx
only
20 mg
PHARMACIST: PLEASE DISPENSE WITH
MEDICATION GUIDE PROVIDED SEPARATELY
Rx
only
40 mg
PHARMACIST: PLEASE DISPENSE WITH
MEDICATION GUIDE PROVIDED SEPARATELY
Rx
only
Physicians Total Care, Inc.