CITALOPRAM HYDROBROMIDE Oral Solution, 10 mg/5 mL

Rx only

Citalopram hydrobromide is an orally administered selective serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that of other SSRI's or of tricyclic, tetracyclic, or other available antidepressant agents. Citalopram hydrobromide 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 C₂₀H₂₂BrFN₂O and its molecular weight is 405.35.

Citalopram hydrobromide occurs as a fine white to off-white powder. Citalopram hydrobromide is sparingly soluble in water and soluble in ethanol.

Citalopram hydrobromide is available as an oral solution.

Citalopram Hydrobromide Oral Solution contains citalopram hydrobromide equivalent to 2 mg/mL citalopram base. It also contains the following inactive ingredients: methylparaben, peppermint stick, propylene glycol, propylparaben, purified water, and sorbitol solution.

The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long term (14 day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer.

Citalopram has no or very low affinity for 5-HT_1A, 5-HT_2A, dopamine D₁ and D₂, α₁-, α ₂-, and β-adrenergic, histamine H₁, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular effects of other psychotropic drugs.

The single- and multiple-dose pharmacokinetics of citalopram are linear and dose proportional in a dose range of 10 to 60 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose.

The efficacy of citalopram as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18 to 66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed citalopram doses of 10, 20, 40, and 60 mg/day, showed that citalopram at doses of 40 and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood li (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram showed significantly greater improvement than placebo patients on the HAMD total score, HAMD li 1, and the CGI Severity score. In three additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose.

In two long-term studies, depressed patients who had responded to citalopram during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20 to 60 mg/day in the second study) were randomized to continuation of citalopram or to placebo. In both studies, patients receiving continued citalopram treatment experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg/day of citalopram.

Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.

Citalopram Hydrobromide Oral Solution is indicated for the treatment of depression.

The efficacy of Citalopram Hydrobromide 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 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 Hydrobromide Oral Solution in hospitalized depressed patients has not been adequately studied.

The efficacy of Citalopram Hydrobromide 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 CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use Citalopram Hydrobromide Oral Solution for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Concomitant use in patients taking monoamine oxidase inhibitors (MAOI’s) is contraindicated (see WARNINGS).

Citalopram Hydrobromide Oral Solution is contraindicated in patients with a hypersensitivity to citalopram or any of the inactive ingredients in Citalopram Hydrobromide Oral Solution.

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. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.

Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults.

All pediatric patients being treated with antidepressants for any indication should be 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. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, 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, for a description of the risks of discontinuation of Citalopram Hydrobromide).

Families and caregivers of pediatric 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 Hydrobromide should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.

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 Hydrobromide is not approved for use in treating bipolar depression.

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 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 before starting a MAOI.

Physicians are advised to discuss the following issues with patients for whom they prescribe citalopram:

Although in controlled studies citalopram 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 therapy does not affect their ability to engage in such activities.

Patients should be told that, although citalopram 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 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 cautioned about the concomitant use of citalopram and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents had been associated with an increased risk of bleeding.

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 therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Citalopram Hydrobromide and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Citalopram Hydrobromide. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its spans.

Patients should be given the opportunity to discuss the spans of the Medication Guide and to obtain answers to any questions they may have. The complete div of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Citalopram Hydrobromide.

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

There are no specific laboratory tests recommended.

The effect of citalopram on labor and delivery in humans is unknown.

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 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 therapy should take into account the risks of citalopram exposure for the infant and the benefits of citalopram treatment for the mother.

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS-WARNINGS-Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with Citalopram Hydrobromide, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Citalopram Hydrobromide in a child or adolescent must balance the potential risks with the clinical need.

Of 4422 patients in clinical studies of citalopram, 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 in clinical trials received daily doses between 20 and 40 mg (see DOSAGE AND ADMINISTRATION).

In two 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).

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 smaller 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 uled. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Following is a ul of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS 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 uled in Table 2 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 uled 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

% 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, uticaria, 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 rentention, dysuria. Rare: 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, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, neuroleptic malignant syndrome, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, serotonin syndrome, spontaneous abortion, thrombocytopenia, ventricular arrhythmia, Torsades de pointes, and withdrawal syndrome.

Citalopram hydrobromide is not a controlled substance.

Animal studies suggest that the abuse liability of citalopram is low. Citalopram has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. The premarketing clinical experience with citalopram did not reveal any drug seeking behavior. However, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate citalopram patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug seeking behavior).

In clinical trials of citalopram, there were reports of Citalopram Hydrobromide overdose, including overdoses of up to 2000 mg, with no associated fatalities. During the postmarketing evaluation of citalopram, Citalopram Hydrobromide overdoses, including overdoses of up to 6000 mg, have been reported. As with other SSRI’s, a fatal outcome in a patient who has taken an overdose of Citalopram Hydrobromide 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 one possible case of Torsades de pointes).

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.

Citalopram hydrobromide should be administered at an initial dose of 20 mg once daily, generally with an increase to a dose of 40 mg/day. Dose increases should usually occur in increments of 20 mg at intervals of no less than one week. Although certain patients may require a dose of 60 mg/day, 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; doses above 40 mg are therefore not ordinarily recommended.

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

20 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment, with titration to 40 mg/day only for nonresponding patients.

No dosage adjustment is necessary for patients with mild or moderate renal impairment. Citalopram should be used with caution in patients with severe real 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 PRECAUTIONS). When treating pregnant women with citalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering citalopram in the third trimester.

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 Efficacy 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.

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.

At least 14 days should elapse between discontinuation of an MAOI and initiation of citalopram therapy. Similarly, at least 14 days should be allowed after stopping citalopram before starting a MAOI (see CONTRAINDICATIONS and WARNINGS).

Citalopram Hydrobromide Oral Solution is supplied as a peppermint flavored oral solution.

0054-0062-58 10 mg/5 mL, 240 mL per bottle

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]

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/m² 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/m² 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.

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/m² 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 3250 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 the dog has not been directly examined because DCT is rapidly converted to DDCT in that species.

10003824/01

© RLI, 2005

About Using Antidepressants in Children and Teenagers

Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant:

• There is a risk of suicidal thoughts or actions
• How to try to prevent suicidal thoughts or actions in your child
• You should watch for certain signs if your child is taking an antidepressant
• There are benefits and risks when using antidepressants

• There is a Risk of Suicidal Thoughts or Actions

• Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepres-sants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself called suicidality or being suicidal.

• A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal.

• For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with:

• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide

• If any of these are present, make sure you tell your healthcare provider before your child takes antidepressant.

• How to Try to Prevent Suicidal Thoughts and Actions

• To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in child’s life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, other important people). The changes to look out for are uled in Section 3, on what to watch for.

• Whenever an antidepressant is started or its dose is changed, pay close attention to your child.

• After starting an antidepressant, your child should generally see his or her healthcare provider:

• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider’s advice about how often to come back
• More often if problems or questions arise (see Section 3)

• You should call your child’s healthcare provider between visits if needed.

• You Should Watch for Certain Signs If Your Child is Taking an Antidepressant

• Contact your child’s healthcare provider right awayif your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child’s teacher:

• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood

• Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms.

• There are Benefits and Risks When Using Antidepressants

• Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants.

• Other side effects can occur with antidepressants (see section below).

• Of all the antidepressants, only fluoxetine (Prozac®) has been FDA approved to treat pediatric depression.

• For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac®), sertraline (Zoloft®), fluvoxamine, and clomipramine (Anafranil®). Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members.

No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information.

*Prozac® is a registered trademark of Eli Lilly and Company

*Zoloft® is a registered trademark of Pfizer Pharmaceuticals

*Anafranil® is a registered trademark of Mallinckrodt Inc.

This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

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© RLI, 2005