ADVERSE REACTIONS
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
|
Placebo
|
|
(N=1063)
|
(N=446)
|
Body System/Adverse
Event
|
|
|
General
|
|
|
Asthenia |
1% |
<1% |
Gastrointestinal
Disorders
|
|
|
Nausea |
4% |
0% |
Dry Mouth |
1% |
<1% |
Vomiting |
1% |
0% |
Central and Peripheral
|
|
|
Nervous System Disorders
|
|
|
Dizziness |
2% |
<1% |
Psychiatric Disorders
|
|
|
Insomnia |
3% |
1% |
Somnolence |
2% |
1% |
Agitation |
1% |
<1% |
Adverse Events Occurring at an Incidence of 2% or
More Among Celexa -Treated Patients
Table 3
enumerates the
incidence, rounded to the nearest percent, of treatment-emergent adverse events
that occurred among 1063 depressed patients who received Celexa at doses ranging
from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration.
Events included are those occurring in 2% or more of patients treated with
Celexa and for which the incidence in patients treated with Celexa was greater
than the incidence in placebo-treated patients.
The prescriber should be aware that these figures cannot be used to predict
the incidence of adverse events in the course of usual medical practice where
patient characteristics and other factors differ from those which prevailed in
the clinical trials. Similarly, the cited frequencies cannot be compared with
figures obtained from other clinical investigations involving different
treatments, uses, and investigators. The cited figures, however, do provide the
prescribing physician with some basis for estimating the relative contribution
of drug and non-drug factors to the adverse event incidence rate in the
population studied.
The only commonly observed adverse event that occurred in Celexa patients
with an incidence of 5% or greater and at least twice the incidence in placebo
patients was ejaculation disorder (primarily ejaculatory delay) in male patients
(see
TABLE 3).
TABLE 3 Treatment-Emergent Adverse Events: Incidence in
Placebo-Controlled Clinical Trials*
(Percentage of Patients
Reporting Event)
|
|
|
|
Body System/Adverse
Event
|
Celexa
|
Placebo
|
|
(N=1063)
|
(N=446)
|
Autonomic Nervous
System
|
|
|
Disorders
|
|
|
Dry Mouth |
20% |
14% |
Sweating Increased |
11% |
9% |
Central & Peripheral
Nervous
|
|
|
System Disorders
|
|
|
Tremor |
8% |
6% |
Gastrointestinal
Disorders
|
|
|
Nausea |
21% |
14% |
Diarrhea |
8% |
5% |
Dyspepsia |
5% |
4% |
Vomiting |
4% |
3% |
Abdominal Pain |
3% |
2% |
General
|
|
|
Fatigue |
5% |
3% |
Fever |
2% |
<1% |
Musculoskeletal System
|
|
|
Disorders
|
|
|
Arthralgia |
2% |
1% |
Myalgia |
2% |
1% |
Psychiatric Disorders
|
|
|
Somnolence |
18% |
10% |
Insomnia |
15% |
14% |
Anxiety |
4% |
3% |
Anorexia |
4% |
2% |
Agitation |
3% |
1% |
Dysmenorrhea1
|
3% |
2% |
Libido Decreased |
2% |
<1% |
Yawning |
2% |
<1% |
Respiratory System
Disorders
|
|
|
Upper Respiratory Tract Infection |
5% |
4% |
Rhinitis |
5% |
3% |
Sinusitis |
3% |
<1% |
Urogenital
|
|
|
Ejaculation Disorder2,3
|
6% |
1% |
Impotence3
|
3% |
<1% |
*Events reported by at least 2% of patients treated with
Celexa are reported, except for the following events which had an incidence on
placebo > Celexa: headache, asthenia, dizziness, constipation, palpitation,
vision abnormal, sleep disorder, nervousness, pharyngitis, micturition disorder,
back pain.
1Denominator used was for females
only (N=638 Celexa; N=252 placebo).
2Primarily ejaculatory delay.
3Denominator used was for males
only (N=425 Celexa; N=194 placebo).
Dose Dependency of Adverse Events
The potential relationship between the dose of Celexa
administered and the incidence of adverse events was examined in a fixed-dose
study in depressed patients receiving placebo or Celexa 10, 20, 40, and 60 mg.
Jonckheere's trend test revealed a positive dose response (p<0.05) for the
following adverse events: fatigue, impotence, insomnia, sweating increased,
somnolence, and yawning.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance, and sexual
satisfaction often occur as manifestations of a psychiatric disorder, they may
also be a consequence of pharmacologic treatment. In particular, some evidence
suggests that SSRIs can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences
involving sexual desire, performance, and satisfaction are difficult to obtain,
however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and
performance cited in product labeling, are likely to underestimate their actual
incidence.
The table below displays the incidence of sexual side effects reported by at
least 2% of patients taking Celexa in a pool of placebo-controlled clinical
trials in patients with depression.
Treatment
|
Celexa
(425 males) |
Placebo
(194 males) |
Abnormal
Ejaculation (mostly ejaculatory delay) |
6.1% (males only) |
1% (males only) |
Libido Decreased |
3.8% (males only) |
<1% (males only) |
Impotence |
2.8% (males only) |
<1% (males
only) |
In female depressed patients receiving Celexa, the reported incidence of
decreased libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252
females), respectively.
There are no adequately designed studies examining sexual dysfunction with
citalopram treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction
associated with the use of SSRIs, physicians should routinely inquire about such
possible side effects.
Vital Sign Changes
Celexa and placebo groups were compared with respect to (1) mean
change from baseline in vital signs (pulse, systolic blood pressure, and
diastolic blood pressure) and (2) the incidence of patients meeting criteria for
potentially clinically significant changes from baseline in these variables.
These analyses did not reveal any clinically important changes in vital signs
associated with Celexa treatment. In addition, a comparison of supine and
standing vital sign measures for Celexa and placebo treatments indicated that
Celexa treatment is not associated with orthostatic changes.
Weight Changes
Patients treated with Celexa in controlled trials experienced a
weight loss of about 0.5 kg compared to no change for placebo patients.
Laboratory Changes
Celexa and placebo groups were compared with respect to (1) mean
change from baseline in various serum chemistry, hematology, and urinalysis
variables, and (2) the incidence of patients meeting criteria for potentially
clinically significant changes from baseline in these variables. These analyses
revealed no clinically important changes in laboratory test parameters
associated with Celexa treatment.
ECG Changes
Electrocardiograms from Celexa (N=802) and placebo (N=241) groups
were compared with respect to (1) mean change from baseline in various ECG
parameters, and (2) the incidence of patients meeting criteria for potentially
clinically significant changes from baseline in these variables. The only
statistically significant drug-placebo difference observed was a decrease in
heart rate for Celexa of 1.7 bpm compared to no change in heart rate for
placebo. There were no observed differences in QT or other ECG intervals.
Other Events Observed During the Premarketing
Evaluation of Celexa (citalopram HBr)
Following is a 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 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.
|