Citalopram Hydrobromide

Citalopram oral solution is indicated for the treatment of depression.

The efficacy of citalopram oral solution, in the treatment of depression was established in 4 to 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

).

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 oral solution in hospitalized depressed patients has not been adequately studied.

The efficacy of citalopram oral solution, 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

). Nevertheless, the physician who elects to use citalopram oral solution for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Citalopram oral solution should be administered once daily, in the morning or evening, with or without food.

Citalopram oral solution should be administered at an initial dose of 20 mg once daily, with an increase to a maximum dose of 40 mg/day at an interval of no less than one week. Doses above 40 mg/day are not recommended due to the risk of QT prolongation. Additionally, 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.

20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age, patients with hepatic impairment, and for CYP2C19 poor metabolizers or those patients taking cimetidine or another CYP2C19 inhibitor. (see
)

No dosage adjustment is necessary for patients with mild or moderate renal impairment. Citalopram should be used with caution in patients with severe renal impairment.

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
). When treating pregnant women with citalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Systematic evaluation of citalopram 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 oral solution (20 to 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 oral solution 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
under
). 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.

Symptoms associated with discontinuation of citalopram and other SSRIs and SNRIs have been reported (see
). 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.

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with citalopram oral solution. Conversely, at least 14 days should be allowed after stopping citalopram before starting an MAOI intended to treat psychiatric disorders (see
).




Do not start citalopram oral solution in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see
).


In some cases, a patient already receiving citalopram therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, citalopram should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with citalopram may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see
).


The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with citalopram is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see
).

The premarketing development program for citalopram 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 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 Events Associated with Discontinuation of Treatment


Among 1063 depressed patients who received citalopram 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-treated patients at a rate at least twice that of placebo) are shown in
It should be noted that one patient can report more than one reason for discontinuation and be counted more than once in this table.

		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%

:
enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 1063 depressed patients who received citalopram 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 and for which the incidence in patients treated with citalopram 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 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
).

	(Percentage of Patients Reporting Event)
Body System/Adverse Event	Citalopram (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%
Dysmenorrhea 1	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 Disorder 2,3	6%	1%
Impotence 3	3%	<1%

*Events reported by at least 2% of patients treated with citalopram are reported, except for the following events which had an incidence on placebo ≥ citalopram: headache, asthenia, dizziness, constipation, palpitation, vision abnormal, sleep disorder, nervousness, pharyngitis, micturition disorder, back pain.


¹Denominator used was for females only (N=638 citalopram; N=252 placebo).


²Primarily ejaculatory delay.


³Denominator used was for males only (N=425 citalopram; N=194 placebo).

The potential relationship between the dose of citalopram administered and the incidence of adverse events was examined in a fixed-dose study in depressed patients receiving placebo or citalopram 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.




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 in a pool of placebo-controlled clinical trials in patients with depression.

Treatment	Citalopram (425 males)	Placebo (194 males)
Abnormal Ejaculation (mostly ejaculatory delay)	6.1% (males only)	1% (males only)
Decreased Libido	3.8% (males only)	<1% (males only)
Impotence	2.8% (males only)	<1% (males only)

In female depressed patients receiving citalopram, 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.

Citalopram 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 treatment. In addition, a comparison of supine and standing vital sign measures for citalopram and placebo treatments indicated that citalopram treatment is not associated with orthostatic changes.




Patients treated with citalopram in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.




Citalopram 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 treatment.




In a thorough QT study, citalopram was found to be associated with a dose-dependent increase in the QTc interval (see
).


Electrocardiograms from citalopram (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 citalopram 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 citalopram group. The incidence of tachycardic outliers was 0.5% in the citalopram group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the citalopram group and 0.4% in the placebo group.




Following is a list of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the
section, reported by patients treated with citalopram 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
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, 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.


: tachycardia, postural hypotension, hypotension.
hypertension, bradycardia, edema (extremities), angina pectoris, extrasystoles, cardiac failure, flushing, myocardial infarction, cerebrovascular accident, myocardial ischemia.
transient ischemic attack, phlebitis, atrial fibrillation, cardiac arrest, bundle branch block.


-
paresthesia, migraine.
: hyperkinesia, vertigo, hypertonia, extrapyramidal disorder, leg cramps, involuntary muscle contractions, hypokinesia, neuralgia, dystonia, abnormal gait, hypesthesia, ataxia.
abnormal coordination, hyperesthesia, ptosis, stupor.


-
hypothyroidism, goiter, gynecomastia.


-
saliva increased, flatulence.
: gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids, dysphagia, teeth grinding, gingivitis, esophagitis.
: colitis, gastric ulcer, cholecystitis, cholelithiasis, duodenal ulcer, gastroesophageal reflux, glossitis, jaundice, diverticulitis, rectal hemorrhage, hiccups.


-
hot flushes, rigors, alcohol intolerance, syncope, influenza-like symptoms.
: hayfever.


-
purpura, anemia, epistaxis, leukocytosis, leucopenia, lymphadenopathy.
pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorder, gingival bleeding.


-
decreased weight, increased weight.
: increased hepatic enzymes, thirst, dry eyes, increased alkaline phosphatase, abnormal glucose tolerance.
bilirubinemia, hypokalemia, obesity, hypoglycemia, hepatitis, dehydration.


-
arthritis, muscle weakness, skeletal pain.
: bursitis, osteoporosis.


-
impaired concentration, amnesia, apathy, depression, increased appetite, aggravated depression, suicide attempt, confusion.
: increased libido, aggressive reaction, paroniria, drug dependence, depersonalization, hallucination, euphoria, psychotic depression, delusion, paranoid reaction, emotional lability, panic reaction, psychosis.
catatonic reaction, melancholia.


-
amenorrhea.
galactorrhea, breast pain, breast enlargement, vaginal hemorrhage.


*% based on female subjects only: 2955


-
coughing.
bronchitis, dyspnea, pneumonia.
asthma, laryngitis, bronchospasm, pneumonitis, sputum increased.


-
rash, pruritus.
photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia, dermatitis, skin dry, psoriasis.
hypertrichosis, decreased sweating, melanosis, keratitis, cellulitis, pruritus ani.


: accommodation abnormal, taste perversion.
tinnitus, conjunctivitis, eye pain.
mydriasis, photophobia, diplopia, abnormal lacrimation, cataract, taste loss.


-
polyuria.
micturition frequency, urinary incontinence, urinary retention, dysuria.
: facial edema, hematuria, oliguria, pyelonephritis, renal calculus, renal pain.




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, 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, withdrawal syndrome, anosmia and hyposmia.

Based on the mechanism of action of SNRIs and SSRIs, including citalopram hydrobromide, and the potential for serotonin syndrome, caution is advised when citalopram is co- administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium,  opioids,  amphetamines,  or  St.  John's  Wort  (
).


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
).


Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs.


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 is not recommended.


See
.


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.


In subjects who had received 21 days of 40 mg/day citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and C
_maxof 43% and 39%, respectively.


Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant cimetidine because of the risk of QT prolongation (see
and
).


In subjects who had received 21 days of 40 mg/day citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.


Coadministration of citalopram (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 and lithium are coadministered.


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
_maxof pimozide. The mechanism of this pharmacodynamic interaction is not known.


: Combined administration of citalopram (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.


: 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.


: Administration of 40 mg/day citalopram 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.


Combined administration of citalopram (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.


: Combined administration of citalopram (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.


: Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the C
_maxand AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.


Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant CYP2C19 inhibitors because of the risk of QT prolongation (see 
 
 
).


Administration of 40 mg/day citalopram for 22 days resulted in a two-fold increase in the plasma levels of the beta-adrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of citalopram and metoprolol had no clinically significant effects on blood pressure or heart rate.


 
studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of citalopram (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.


There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and citalopram.