CONTRAINDICATIONS
Concomitant use in patients taking monoamine oxidase inhibitors (MAOI's) is contraindicated (see
WARNINGS).
Citalopram hydrobromide tablets or oral solution are contraindicated in patients with a
hypersensitivity to citalopram or any of the inactive ingredients in either formulation.
WARNINGS
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 a MAOI. Some cases
presented with features resembling neuroleptic malignant syndrome. Furthermore,
limited animal data on the effects of combined use of SSRI's and MAOI's suggest that
these drugs may act synergistically to elevate blood pressure and evoke behavioral
excitation. Therefore, it is recommended that citalopram hydrobromide should not be
used in combination with a MAOI, or within 14 days of discontinuing treatment with a
MAOI. Similarly, at least 14 days should be allowed after stopping citalopram
hydrobromide before starting a MAOI.
PRECAUTIONS
General
Hyponatremia
Several cases of hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone
secretion) have been reported in association with citalopram hydrobromide treatment. All patients
with these events have recovered with discontinuation of citalopram hydrobromide and/or medical
intervention.
Activation of Mania/Hypomania
In placebo-controlled trials of citalopram hydrobromide, some of which included patients with
bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1063 patients treated with
citalopram hydrobromide 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
hydrobromide should be used cautiously in patients with a history of mania.
Seizures
Although anticonvulsant effects of citalopram have been observed in animal studies, citalopram
hydrobromide has not been systematically evaluated in patients with a seizure disorder. These
patients were excluded from clinical studies during the product's premarketing testing. In clinical
trials of citalopram hydrobromide, seizures occurred in 0.3% of patients treated with citalopram
hydrobromide (a rate of 1 patient per 98 years of exposure) and 0.5% of patients treated with
placebo (a rate of 1 patient per 50 years of exposure). Like other antidepressants, citalopram
hydrobromide should be introduced with care in patients with a history of seizure disorder.
Suicide
The possibility of a suicide attempt is inherent in depression and may persist until significant
remission occurs. Close supervision of high risk patients should accompany initial drug therapy.
Prescriptions for citalopram hydrobromide should be written for the smallest quantity of tablets
consistent with good patient management, in order to reduce the risk of overdose.
Interference with Cognitive and Motor Performance
In studies in normal volunteers, citalopram hydrobromide in doses of 40 mg/day did not produce
impairment of intellectual function or psychomotor performance. Because any psychoactive drug
may impair judgement, thinking, or motor skills, however, patients should be cautioned about
operating hazardous machinery, including automobiles, until they are reasonably certain that
citalopram hydrobromide therapy does not affect their ability to engage in such activities.
Use in Patients with Concomitant Illness
Clinical experience with citalopram hydrobromide in patients with certain concomitant systemic
illnesses is limited. Caution is advisable in using citalopram hydrobromide in patients with diseases or
conditions that produce altered metabolism or hemodynamic responses.
Citalopram hydrobromide has not been systematically evaluated in patients with a recent history of
myocardial infarction or unstable heart disease. Patients with these diagnoses were generally
excluded from clinical studies during the products premarketing testing. However, the
electrocardiograms of 1116 patients who received citalopram hydrobromide in clinical trials were
evaluated and the data indicate that citalopram hydrobromide is not associated with the development
of clinically significant ECG abnormalities.
In subjects with hepatic impairment, citalopram clearance was decreased and plasma
concentrations were increased. The use of citalopram hydrobromide 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 hydrobromide, however, it should be used with
caution in such patients (see DOSAGE AND ADMINISTRATION).
Information for the Patient
Physicians are advised to discuss the following issues with patients for whom they prescribe
citalopram hydrobromide;
Although in controlled studies citalopram hydrobromide has not been shown to impair psychomotor
performance, any psychoactive drug may impair judgment, thinking or motor skills, and so patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that citalopram hydrobromide therapy does not affect their ability to engage in
such activities.
Patients should be told that, although citalopram hydrobromide has not been shown in experiments
with normal subjects to increase the mental and motor skill impairments caused by alcohol, the
concomitant use of citalopram hydrobromide 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 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 breast feeding an infant.
While patients may notice improvement with citalopram hydrobromide therapy in 1-4 weeks, they
should be advised to continue therapy as directed.
Laboratory Tests
There are no specific laboratory tests recommended.
Carcinogenesis, Mutagenesis, and 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/m2) basis. There was an
increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day, doses which
are approximately 1.3 and 4 times the MRHD, respectively, on a mg/m2 basis. A no-effect dose for
this finding was not established. The relevance of these findings to humans is unknown.
Mutagenesis: Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames
test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic
activation. It was castogenic 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 2 in vivo
mouse micronucleus assays.
Impairment of Fertility: When citalopram was administered orally to male and female rats prior to
and throughout mating and gestation at doses of 16/24 (males/females), 32, 48, and 72 mg/kg/day,
mating was decreased at all doses, and fertility was decreased at doses ³32 mg/kg/day,
approximately 5 times the maximum recommended human dose (MRHD) of 60 mg/day on a body
surface area (mg/m2) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8
times the MRHD.
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 2 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 maximum
recommended human dose (MRHD) of 60 mg/day on a body surface area (mg/m2) basis. This
dose was also associated with maternal toxicity (clinical signs, decreased BW gain). The
developmental no effect dose of 56 mg/kg/day is approximately 9 times the MRHD on a mg/m2
basis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of
up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/m2 basis. Thus, teratogenic
effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit.
When female rats were treated with citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation
through weaning, increased offspring mortality during the first 4 days after birth and persistent
offspring growth retardation were observed at the highest dose, which is approximately 5 times the
MRHD on a mg/m2 basis. The no effect dose of 12.8 mg/kg/day is approximately 2 times the
MRHD on a mg/m2 basis. Similar effects on offspring mortality and growth were seen when dams
were treated throughout gestation and early lactation at doses ³24 mg/kg/day, approximately 4
times the MRHD on a mg/m2 basis. A no effect dose was not determined in that study.
There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should
be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of citalopram hydrobromide 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 2 reports of infants experiencing excessive somnolence, decreased feeding, and
weight loss in association with breast feeding 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 hydrobromide therapy should take into account the risks of
citalopram exposure for the infant and the benefits of citalopram hydrobromide treatment for the
mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Of 4422 patients in clinical studies of citalopram hydrobromide, 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 hydrobromide in clinical trials received daily doses between 20 and 40 mg (see
DOSAGE AND ADMINISTRATION).
In 2 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).