WARNINGS
Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.
The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.
There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 .
No suicides occurred in any of the pediatric trials.
There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient”s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION – Discontinuation of Treatment with Citalopram Tablets, USP for a description of the risks of discontinuation of citalopram tablets).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.
Such monitoring should include daily observation by families and caregivers.
Prescriptions for citalopram tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
QT-Prolongation and Torsade de Pointes Citalopram causes dose-dependent QTc prolongation, an ECG abnormality that has been associated with Torsade de Pointes (TdP), ventricular tachycardia, and sudden death, all of which have been observed in postmarketing reports for citalopram.
Individually corrected QTc (QTcNi) interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 119 healthy subjects.
The maximum mean (upper bound of the 95% one-sided confidence interval) difference from placebo were 8.5 (10.8) and 18.5 (21) msec for 20 mg and 60 mg citalopram, respectively.
Based on the established exposure-response relationship, the predicted QTcNi change from placebo (upper bound of the 95% one-sided confidence interval) under the C max for the dose of 40 mg is 12.6 (14.3) msec.
Because of the risk of QTc prolongation at higher citalopram doses, it is recommended that citalopram should not be given at doses above 40 mg/day.
It is recommended that citalopram should not be used in patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure.
Citalopram should also not be used in patients who are taking other drugs that prolong the QTc interval.
Such drugs include Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).
The citalopram dose should be limited in certain populations.
The maximum dose should be limited to 20 mg/day in patients who are CYP2C19 poor metabolizers or those patients who may be taking concomitant cimetidine or another CYP2C19 inhibitor, since higher citalopram exposures would be expected.
The maximum dose should also be limited to 20 mg/day in patients with hepatic impairment and in patients who are greater than 60 years of age because of expected higher exposures.
Electrolyte and/or ECG monitoring is recommended in certain circumstances.
Patients being considered for citalopram treatment who are at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring.
Hypokalemia (and/or hypomagnesemia) may increase the risk of QTc prolongation and arrhythmia, and should be corrected prior to initiation of treatment and periodically monitored.
ECG monitoring is recommended in patients for whom citalopram use is not recommended (see above), but, nevertheless, considered essential.
These include those patients with the cardiac conditions noted above, and those taking other drugs that may prolong the QTc interval.
Citalopram should be discontinued in patients who are found to have persistent QTc measurements >500 ms.
If patients taking citalopram experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring.
Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder.
It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.
Whether any of the symptoms described above represent such a conversion is unknown.
However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that citalopram is not approved for use in treating bipolar depression.
Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including citalopram, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St.
John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes eg.
agitation, hallucinations, delirium, and coma), autonomic instability (eg., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of citalopram with MAOIs intended to treat psychiatric disorders is contraindicated.
Citalopram should also not be started in a patient who is being treated with MAOIs such as linezolid of intravenous methylene blue.
All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.
No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.
There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking citalopram.
Citalopram should be discontinued before initiating treatment with the MAOIs (see CONTRAINDIACTIONS and DOSAGE AND ADMINISTRATION ).
If concomitant use of citalopram with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St.
John’s Wort is clinically warranted, patients should be made aware of a potentially increased risk for the serotonin syndrome particularly during treatment initiation and dose increases.
Treatment with citalopram and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Table 1
DRUG INTERACTIONS
Drug Interactions Serotonergic Drugs See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .
Triptans 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 WARNINGS – Serotonin Syndrome ).
CNS Drugs Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs.
Alcohol 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.
Monoamine Oxidase Inhibitors (MAOIs ) – See CONTRAINDICATIONS and WARNINGS .
Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) 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 citaloram is initiated or discontinued.
Cimetidine In subjects who had received 21 days of 40 mg/day citlaopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 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 WARNINGS and DOSAGE AND ADMINISTRATION ).
Digoxin 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.
Lithium 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.
Pimozide 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 Cmax of pimozide.
The mechanism of this pharmacodynamic interaction is not known.
Theophylline 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.
Sumatriptan 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.
Warfarin 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.
Carbamazepine 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.
Triazolam 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.
Ketoconazole Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.
CYP2C19 Inhibitors Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant CYP2C19 inhibitors because of the risk of QT prolongation (see WARNINGS , DOSAGE AND ADMINISTRATION , AND CLINICAL PHARMACOLOGY ).
Metoprolol Administration of 40 mg/day citlaopram 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.
Imipramine and Other Tricyclic Antidepressants (TCAs) In vitro 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.
Electroconvulsive Therapy (ECT) There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and citalopram.
OVERDOSAGE
Human Experience In clinical trials of citalopram, there were reports of citalopram overdose, including overdoses of up to 2000 mg, with no associated fatalities.
During the postmarketing evaluation of citalopram, citalopram overdoses, including overdoses of up to 6000 mg, have been reported.
As with other SSRIs, a fatal outcome in a patient who has taken an overdose of citalopram has been rarely reported.
Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia.
In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes).
Acute renal failure has been very rarely reported accompanying overdose.
Management of Overdose Establish and maintain an airway to ensure adequate ventilation and oxygenation.
Gastric evacuation by lavage and use of activated charcoal should be considered.
Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care.
Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.
There are no specific antidotes for citalopram.
In managing overdosage, consider the possibility of multiple-drug involvement.
The physician should consider contacting a poison control center for additional information on the treatment of any overdose.
DESCRIPTION
Citalopram HBr is an orally administered selective serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant agents.
Citalopram HBr is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, HBr with the following structural formula: The molecular formula is C 20 H 22 BrFN 2 O and its molecular weight is 405.35.
Citalopram hydrobromide, USP occurs as a fine, white to off-white powder.
Citalopram HBr is sparingly soluble in water and soluble in ethanol.
Citalopram hydrobromide, USP is available as tablets.
Citalopram hydrobromide, USP 10 mg tablets are film-coated, round tablets containing citalopram hydrobromide in strengths equivalent to 10 mg citalopram base.
Citalopram hydrobromide, USP 20 mg and 40 mg tablets are film-coated, round, scored tablets containing citalopram hydrobromide in strengths equivalent to 20 mg or 40 mg of citalopram base.
The tablets also contain the following inactive ingredients: copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, opadry beige (HPMC 2910/hypromellose 6cp, titanium dioxide, macrogol/ Peg400, iron oxide yellow and iron oxide red), opadry pink (HPMC 2910/hypromellose 6cP, titanium dioxide, macrogol/Peg400 and iron oxide red) and opadry white(titanium dioxide, HPMC 2910/hypromellose 3cp, HPMC 2910/hypromellose 6cp, Macrogol/Peg400 and Polysorbate 80) are used as coating agents in the beige (10 mg), pink (20 mg) and white (40 mg) tablets.
Structure
HOW SUPPLIED
Citalopram Tablets, USP 10 mg.
They are supplied in Bottle of 30 NDC # 24658-140-30, Bottle of 100 NDC # 24658-140-01 and Bottles of 1000 NDC # 24658-140-10 Beige, film coated round, bi-convex tablets de-bossed with IG on one side and “ 206 ” on the other.
20 mg.
They are supplied in Bottle of 30 NDC # 24658-141-30, Bottle of 100 NDC # 24658-141-01 and Bottles of 1000 NDC # 24658-141-10 Pink, film coated, round, bi-convex tablets de-bossed with I on the left side of bisect and G on right side of bisect on one side and “ 207 ” on the other.
40 mg.
They are supplied in Bottle of 30 NDC # 24658-142-30, Bottle of 100 NDC # 24658-142-01 and Bottles of 1000 NDC # 24658-142-10 White, film coated, round, bi-convex tablets de-bossed with I on the left side of bisect and G on right side of bisect on one side and “ 208 ” on the other.
Store at 20°C to 25° C (68° F to 77° F) [see USP Controlled Room Temperature] ANIMAL TOXICOLOGY Retinal Changes in Rats Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with citalopram.
There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day (13 times the maximum recommended daily human dose of 60 mg on a mg/m 2 basis).
Similar findings were not present in rats receiving 24 mg/kg/day for two years, in mice treated for 18 months at doses up to 240 mg/kg/day, or in dogs treated for one year at doses up to 20 mg/kg/day (4, 20, and 10 times, respectively, the maximum recommended daily human dose on a mg/m 2 basis).
Additional studies to investigate the mechanism for this pathology have not been performed, and the potential significance of this effect in humans has not been established.
Cardiovascular Changes in Dogs In a one-year toxicology study, 5 of 10 beagle dogs receiving oral doses of 8 mg/kg/day (4 times the maximum recommended daily human dose of 60 mg on a mg/m 2 basis) died suddenly between weeks 17 and 31 following initiation of treatment.
Although appropriate data from that study are not available to directly compare plasma levels of citalopram (CT) and its metabolites, demethylcitalopram (DCT) and didemethylcitalopram (DDCT), to levels that have been achieved in humans, pharmacokinetic data indicate that the relative dog-to-human exposure was greater for the metabolites than for citalopram.
Sudden deaths were not observed in rats at doses up to 120 mg/kg/day, which produced plasma levels of CT, DCT, and DDCT similar to those observed in dogs at doses of 8 mg/kg/day.
A subsequent intravenous dosing study demonstrated that in beagle dogs, DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs.
This effect occurred in dogs at doses producing peak DDCT plasma levels of 810 to 3,250 nM (39 to 155 times the mean steady state DDCT plasma level measured at the maximum recommended human daily dose of 60 mg).
In dogs, peak DDCT plasma concentrations are approximately equal to peak CT plasma concentrations, whereas in humans, steady state DDCT plasma concentrations are less than 10% of steady state CT plasma concentrations.
Assays of DDCT plasma concentrations in 2,020 citalopram-treated individuals demonstrated that DDCT levels rarely exceeded 70 nM; the highest measured level of DDCT in human overdose was 138 nM.
While DDCT is ordinarily present in humans at lower levels than in dogs, it is unknown whether there are individuals who may achieve higher DDCT levels.
The possibility that DCT, a principal metabolite in humans, may prolong the QT interval in dogs has not been directly examined because DCT is rapidly converted to DDCT in that species.
Rev: 08/13
INDICATIONS AND USAGE
Citalopram tablets, USP are indicated for the treatment of depression.
The efficacy of citalopram 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 CLINICAL PHARMACOLOGY ).
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 tablets, USP in hospitalized depressed patients has not been adequately studied.
The efficacy of citalopram 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 CLINICAL PHARMACOLOGY ).
Nevertheless, the physician who elects to use Citalopram for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
PEDIATRIC USE
Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING and WARNINGS—Clinical Worsening and Suicide Risk ).
Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with citalopram, and the data were not sufficient to support a claim for use in pediatric patients.
Anyone considering the use of citalopram in a child or adolescent must balance the potential risks with the clinical need.
Decreased appetite and weight loss have been observed in association with the use of SSRIs.
Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with citalopram.
PREGNANCY
Pregnancy 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 two rat embryo/fetal development studies, oral administration of citalopram (32 mg, 56 mg, 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 MRHD of 60 mg/day on a body surface area (mg/m 2 ) basis.
This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain).
The developmental, no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on a mg/m 2 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/m 2 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 mg, 12.8 mg, 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/m 2 basis.
The no-effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m 2 basis.
Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the MRHD on a mg/m 2 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.
Pregnancy Pregnancy- Nonteratogenic Effects Neonates exposed to citalopram and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.
Such complications can arise immediately upon delivery.
Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.
These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.
It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome ).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN).
PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality.
Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including citalopram) in pregnancy and PPHN.
Other studies do not show a significant statistical association.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history if major depression, who were either on antidepressants or had received antidepressant less than 12 weeks prior to their last menstrual period, and were in remission.
Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with citalopram, the physician should carefully consider both the potential risks and benefits of treating depression with an antidepressant.
This decision can only be made on a case by case basis (see DOSAGE AND ADMINISTRATION ).
Labor and Delivery The effect of citalopram on labor and delivery in humans is unknown.
NUSRING MOTHERS
Nursing Mothers As has been found to occur with many other drugs, citalopram is excreted in human breast milk.
There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding 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 therapy should take into account the risks of citalopram exposure for the infant and the benefits of citalopram treatment for the mother.
BOXED WARNING
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of citalopram tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide.
Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.
Families and caregivers should be advised of the need for close observation and communication with the prescriber.
Citalopram tablets are not approved for use in pediatric patients (see WARNINGS: Clinical Worsening and Suicide Risk , PRECAUTIONS : Information for Patients and PRECAUTIONS: Pediatric Use ).
DOSAGE AND ADMINISTRATION
Citalopram tablets, USP should be administered once daily, in the morning or evening, with or without food.
Initial Treatment Citalopram tablets, USP 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.
Special Populations 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 WARNINGS ) 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.
Treatment of Pregnant Women During the Third Trimester 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 PRECAUTIONS ).
When treating pregnant women with citalopram tablets, USP during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Maintenance 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 (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 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 Clinical Trials under CLINICAL PHARMACOLOGY ).
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.
Discontinuation of Treatment with Citalopram tablets, USP Symptoms associated with discontinuation of citalopram and other SSRIs and SNRIs have been reported (see PRECAUTIONS ).
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.
Switching Patients To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with citalopram..
Conversely, at least 14 days should be allowed after stopping citalopram before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS ).
Use of Citalopram with Other MAOIs, Such as Linezolid or Methylene Blue Do not start citalopram 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 CONTRAINDICATIONS ) 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 WARNINGS ).
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 WARNINGS ).