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
shortterm 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
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 treatmentemergent if it
occurred for the first time or worsened while receiving therapy following
Adverse Findings Observed In Short-Term,
Adverse 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
||Percentage of Patients Discontinuing Due to Adverse Event
|Body Svstem/Adverse Event
|Central and Peripheral Nervous System Disorders
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
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 *
|Body System/Adverse Event
||(Percentage of Patients Reporting Event)
|Autonomic Nervous System Disorders
|Central & Peripheral Nervous System Disorders
|Musculoskeletal System Disorders
|Respiratory System Disorders
|Upper Respiratory Tract Infection
|*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
2Primarily ejaculatory delay.
3Denominator used was for males only (N=4 25 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
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.
|Abnormal Ejaculation (mostly ejaculatory delay)
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.
Patients treated with Celexa in controlled trials
experienced a weight loss of about 0.5 kg compared to no change for placebo
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.
In a thorough QT study, Celexa was found to be associated
with a dose-dependent increase in the QTc interval (see WARNINGS - QT-Prolongation
And Torsade de Pointes).
Electrocardiograms from Celexa (N=802) and placebo
(N=241) groups were compared with respect to outliers defined as subjects with
QTc changes over 60 msec from baseline or absolute values over 500 msec
post-dose, and subjects with heart rate increases to over 100 bpm or decreases
to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic
outliers, respectively). In the Celexa group 1.9% of the patients had a change
from baseline in QTcF >60 msec compared to 1.2% of the patients in the
placebo group. None of the patients in the placebo group had a post-dose QTcF
>500 msec compared to 0.5% of the patients in the Celexa group. The
incidence of tachycardic outliers was 0.5% in the Celexa group and 0.4% in the
placebo group. The incidence of bradycardic outliers was 0.9% in the Celexa
group and 0.4% in the placebo group.
Other Events Observed During The Premarketing Evaluation Of
Celexa (citalopram HBr)
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 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 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
Celexa, 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
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,
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,
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, angle closure 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 follow such
patients closely, observing them for signs of misuse or abuse (e.g.,
development of tolerance, incrementations of dose, drug-seeking behavior).