The premarketing development program for Celexa included citalopram exposures
in patients and/or normal subjects from 3 different groups of studies: 429 normal
subjects in clinical pharmacology/pharmacokinetic studies; 4422 exposures from
patients in controlled and uncontrolled clinical trials, corresponding to approximately
1370 patient-exposure years. There were, in addition, over 19,000 exposures
from mostly open-label, European postmarketing studies. The conditions and duration
of treatment with Celexa varied greatly and included (in overlapping categories)
open-label and double-blind studies, inpatient and outpatient studies, fixed-dose
and dose-titration studies, and short-term and long-term exposure. Adverse reactions
were assessed by collecting adverse events, results of physical examinations,
vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic
examinations.
Adverse events during exposure were obtained primarily by general inquiry and
recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the proportion
of individuals experiencing adverse events without first grouping similar types
of events into a smaller number of standardized event categories. In the tables
and tabulations that follow, standard World Health Organization (WHO) terminology
has been used to classify reported adverse events.
The stated frequencies of adverse events represent the proportion of individuals
who experienced, at least once, a treatment-emergent adverse event of the type
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 Celexa at doses ranging from 10 to 80 mg/day in placebo-controlled
trials of up to 6 weeks in duration, 16% discontinued treatment due to an adverse
event, as compared to 8% of 446 patients receiving placebo. The adverse events
associated with discontinuation and considered drug-related (i.e., associated
with discontinuation in at least 1% of Celexa-treated patients at a rate at
least twice that of placebo) are shown in TABLE 2. It should be noted that one
patient can report more than one reason for discontinuation and be counted more
than once in this table.
TABLE 2 : Adverse Events Associated with Discontinuation
of Treatment in Short-Term, Placebo-Controlled, Depression Trials
|
Percentage of Patients Discontinuing Due to Adverse Event |
Citalopram
(N=1063) |
Placebo
(N=446) |
Body System/Adverse Event |
General |
Asthenia |
1% |
< 1% |
Gastrointestinal Disorders |
Nausea |
4% |
0% |
Dry Mouth |
1% |
< 1% |
Vomiting |
1% |
0% |
Central and Peripheral |
Nervous System Disorders |
Dizziness |
2% |
< 1% |
Psychiatric Disorders |
Insomnia |
3% |
1% |
Somnolence |
2% |
1% |
Agitation |
1% |
< 1% |
Adverse Events Occurring at an Incidence of 2% or More Among Celexa-Treated
Patients
Table 3 enumerates the incidence, rounded to the nearest percent, of
treatment-emergent adverse events that occurred among 1063 depressed patients
who received Celexa at doses ranging from 10 to 80 mg/day in placebo-controlled
trials of up to 6 weeks in duration. Events included are those occurring in
2% or more of patients treated with Celexa and for which the incidence in patients
treated with Celexa was greater than the incidence in placebo-treated patients.
The prescriber should be aware that these figures cannot be used to predict
the incidence of adverse events in the course of usual medical practice where
patient characteristics and other factors differ from those which prevailed
in the clinical trials. Similarly, the cited frequencies cannot be compared
with figures obtained from other clinical investigations involving different
treatments, uses, and investigators. The cited figures, however, do provide
the prescribing physician with some basis for estimating the relative contribution
of drug and non-drug factors to the adverse event incidence rate in the population
studied.
The only commonly observed adverse event that occurred in Celexa patients with
an incidence of 5% or greater and at least twice the incidence in placebo patients
was ejaculation disorder (primarily ejaculatory delay) in male patients (see
TABLE 3).
TABLE 3 : Treatment-Emergent Adverse Events: Incidence in
Placebo-Controlled Clinical Trials*
Body System/Adverse Event |
(Percentage of Patients Reporting Event) |
Celexa
(N=1063) |
Placebo
(N=446) |
Autonomic Nervous System Disorders |
Dry Mouth |
20% |
14% |
Sweating Increased |
11% |
9% |
Central & Peripheral Nervous System Disorders |
Tremor |
8% |
6% |
Gastrointestinal Disorders |
Nausea |
21% |
14% |
Diarrhea |
8% |
5% |
Dyspepsia |
5% |
4% |
Vomiting |
4% |
3% |
Abdominal Pain |
3% |
2% |
General |
Fatigue |
5% |
3% |
Fever |
2% |
< 1% |
Musculoskeletal System Disorders |
Arthralgia |
2% |
1% |
Myalgia |
2% |
1% |
Psychiatric Disorders |
Somnolence |
18% |
10% |
Insomnia |
15% |
14% |
Anxiety |
4% |
3% |
Anorexia |
4% |
2% |
Agitation |
3% |
1% |
Dysmenorrhea1 |
3% |
2% |
Libido Decreased |
2% |
< 1% |
Yawning |
2% |
< 1% |
Respiratory System Disorders |
Upper Respiratory Tract Infection |
5% |
4% |
Rhinitis |
5% |
3% |
Sinusitis |
3% |
< 1% |
Urogenital |
Ejaculation Disorder2,3 |
6% |
1% |
Impotence3 |
3% |
< 1% |
*Events reported by at least 2% of patients
treated with Celexa are reported, except for the following events which
had an incidence on placebo ≥ Celexa: headache, asthenia, dizziness,
constipation, palpitation, vision abnormal, sleep disorder, nervousness,
pharyngitis, micturition disorder, back pain.
1Denominator used was for females only (N=638 Celexa; N=252
placebo).
2Primarily ejaculatory delay.
3Denominator used was for males only (N=425 Celexa; N=194 placebo). |
Dose Dependency of Adverse Events
The potential relationship between the dose of Celexa administered and the
incidence of adverse events was examined in a fixed-dose study in depressed
patients receiving placebo or Celexa 10, 20, 40, and 60 mg. Jonckheere's trend
test revealed a positive dose response (p < 0.05) for the following adverse
events: fatigue, impotence, insomnia, sweating increased, somnolence, and yawning.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance, and sexual satisfaction
often occur as manifestations of a psychiatric disorder, they may also be a
consequence of pharmacologic treatment. In particular, some evidence suggests
that SSRIs can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving
sexual desire, performance, and satisfaction are difficult to obtain, however,
in part because patients and physicians may be reluctant to discuss them. Accordingly,
estimates of the incidence of untoward sexual experience and performance cited
in product labeling, are likely to underestimate their actual incidence.
The table below displays the incidence of sexual side effects reported by at
least 2% of patients taking Celexa in a pool of placebo-controlled clinical
trials in patients with depression.
Treatment |
Celexa (425 males) |
Placebo (194 males) |
Abnormal Ejaculation (mostly ejaculatory delay) |
6.1% (males only) |
1% (males only) |
Libido Decreased |
3.8% (males only) |
< 1% (males only) |
Impotence |
2.8% (males only) |
< 1% (males only) |
In female depressed patients receiving Celexa, the reported incidence of decreased
libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252 females), respectively.
There are no adequately designed studies examining sexual dysfunction with
citalopram treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated
with the use of SSRIs, physicians should routinely inquire about such possible
side effects.
Vital Sign Changes
Celexa and placebo groups were compared with respect to (1) mean change from
baseline in vital signs (pulse, systolic blood pressure, and diastolic blood
pressure) and (2) the incidence of patients meeting criteria for potentially
clinically significant changes from baseline in these variables. These analyses
did not reveal any clinically important changes in vital signs associated with
Celexa treatment. In addition, a comparison of supine and standing vital sign
measures for Celexa and placebo treatments indicated that Celexa treatment is
not associated with orthostatic changes.
Weight Changes
Patients treated with Celexa in controlled trials experienced a weight loss
of about 0.5 kg compared to no change for placebo patients.
Laboratory Changes
Celexa and placebo groups were compared with respect to (1) mean change from
baseline in various serum chemistry, hematology, and urinalysis variables, and
(2) the incidence of patients meeting criteria for potentially clinically significant
changes from baseline in these variables. These analyses revealed no clinically
important changes in laboratory test parameters associated with Celexa treatment.
ECG Changes
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
pec toris, extrasystoles, cardiac failure, flushing, myocardial infarction,
cerebrovascular accident, myocardial ischemia. Rare: transient ischemic
attack, phlebitis, atrial fibrillation, cardiac arrest, bundle branch block.
Central and Peripheral Nervous System Disorders -Frequent: paresthesia,
migraine. Infrequent: hyperkinesia, vertigo, hypertonia, extrapyramidal
disorder, leg cramps, involuntary muscle contractions, hypokinesia, neuralgia,
dystonia, abnormal gait, hypesthesia, ataxia. Rare: abnormal coordination,
hyperesthesia, ptosis, stupor.
Endocrine Disorders -Rare: hypothyroidism, goiter, gynecomastia.
Gastrointestinal Disorders -Frequent: saliva increased, flatulence.
Infrequent: gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids,
dysphagia, teeth grinding, gingivitis, esophagitis. Rare: colitis, gastric
ulcer, cholecystitis, cholelithiasis, duodenal ulcer, gastroesophageal reflux,
glossitis, jaundice, diverticulitis, rectal hemorrhage, hiccups.
General -Infrequent: hot flushes, rigors, alcohol intolerance,
syncope, influenza-like symptoms. Rare: hayfever.
Hemic and Lymphatic Disorders -Infrequent: purpura, anemia, epistaxis,
leukocytosis, leucopenia, lymphadenopathy. Rare: pulmonary embolism,
granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation
disorder, gingival bleeding.
Metabolic and Nutritional Disorders -Frequent: decreased weight,
increased weight. Infrequent: increased hepatic enzymes, thirst, dry
eyes, increased alkaline phosphatase, abnormal glucose tolerance. Rare:
bilirubinemia, hypokalemia, obesity, hypoglycemia, hepatitis, dehydration.
Musculoskeletal System Disorders -Infrequent: arthritis, muscle
weakness, skeletal pain. Rare: bursitis, osteoporosis.
Psychiatric Disorders -Frequent: impaired concentration, amnesia,
apathy, depression, increased appetite, aggravated depression, suicide attempt,
confusion. Infrequent: increased libido, aggressive reaction, paroniria,
drug dependence, depersonalization, hallucination, euphoria, psychotic depression,
delusion, paranoid reaction, emotional lability, panic reaction, psychosis.
Rare: catatonic reaction, melancholia.
Reproductive Disorders/Female* -Frequent: amenorrhea. Infrequent:
galactorrhea, breast pain, breast enlargement, vaginal hemorrhage. *% based
on female subjects only: 2955
Respiratory System Disorders -Frequent: coughing. Infrequent:
bronchitis, dyspnea, pneumonia. Rare: asthma, laryngitis, bronchospasm,
pneumonitis, sputum increased.
Skin and Appendages Disorders -Frequent: rash, pruritus. Infrequent:
photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia,
dermatitis, skin dry, psoriasis. Rare: hypertrichosis, decreased sweating,
melanosis, keratitis, cellulitis, pruritus ani.
Special Senses -Frequent: accommodation abnormal, taste perversion.
Infrequent: tinnitus, conjunctivitis, eye pain. Rare: mydriasis,
photophobia, diplopia, abnormal lacrimation, cataract, taste loss.
Urinary System Disorders -Frequent: polyuria. Infrequent:
micturition frequency, urinary incontinence, urinary retention, dysuria. Rare:
facial edema, hematuria, oliguria, pyelonephritis, renal calculus, renal pain.
Other Events Observed During the Postmarketing Evaluation of Celexa (citalopram
HBr)
It is estimated that over 30 million patients have been treated with Celexa
since market introduction. Although no causal relationship to Celexa treatment
has been found, the following adverse events have been reported to be temporally
associated with Celexa treatment, and have not been described elsewhere in labeling:
acute renal failure, akathisia, allergic reaction, anaphylaxis, angioedema,
choreoathetosis, chest pain, delirium, dyskinesia, ecchymosis, epidermal necrolysis,
erythema multiforme, gastrointestinal hemorrhage, glaucoma, grand mal convulsions,
hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism,
prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous
abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsade de pointes,
and withdrawal syndrome.
Drug Abuse And Dependence
Controlled Substance Class
Celexa (citalopram HBr) is not a controlled substance.
Physical and Psychological Dependence
Animal studies suggest that the abuse liability of Celexa is low. Celexa has
not been systematically studied in humans for its potential for abuse, tolerance,
or physical dependence. The premarketing clinical experience with Celexa did
not reveal any drug-seeking behavior. However, these observations were not systematic
and it is not possible to predict, on the basis of this limited experience,
the extent to which a CNS-active drug will be misused, diverted, and/or abused
once marketed. Consequently, physicians should carefully evaluate Celexa patients
for history of drug abuse and follow such patients closely, observing them for
signs of misuse or abuse (e.g., development of tolerance, incrementations of
dose, drug-seeking behavior).