DESCRIPTION

Citalopram HBr 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 HBr is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-flurophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, HBr with the following structural formula:

The molecular formula is C H BrFN O and its molecular weight is 405.35. 20222

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

Citalopram hydrobromide is available as an oral solution.

Citalopram oral solution USP contains citalopram HBr equivalent to 2 mg/mL citalopram base. It also contains the following inactive ingredients: Sorbitol, Purified Water, Propylene Glycol, Methylparaben, Peppermint Flavor, and Propylparaben.

CLINICAL PHARMACOLOGY

INDICATIONS AND USAGE

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

The efficacy of citalopram Oral Solution USP in the treatment of depression was established in 4-6 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 Oral Solution USP in hospitalized depressed patients has not been adequately studied.

The efficacy of citalopram Oral Solution USP 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 for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

CONTRAINDICATIONS

The use of MAOIs intended to treat psychiatric disorders with citalopram or within 14 days of stopping treatment with citalopram is contraindicated because of an increased risk of serotonin syndrome. The use of citalopram within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE and ADMINISTRATION). Starting citalopram in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).

Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).

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

WARNINGS

WARNINGS-Clinical Worsening and Suicide Risk

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 18-24) 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.

Table 1

Age Range	Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
	Increases Compared to Placebo
<18	14 additional cases
18-24	5 additional cases
	Decreases Compared to Placebo
25-64	1 fewer case
≥65	6 fewer cases

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. 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 – Discontinuation of treatment with citalopram Oral Solution USP, for a description of the risks of discontinuation of citalopram). Prescriptions for Citalopram should be written for the smallest quantity consistent with good patient management, in order to reduce the risk of overdose. 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 (21.0) 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 Cmax 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. 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 Oral Solution USP is not approved for use in treating bipolar depression. 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 other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, trytophan, 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 (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., 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 or 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 MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of citalopram with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, trytophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for 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.



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.





PRECAUTIONS and DOSAGE AND ADMINISTRATION

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.

QT-Prolongation and Torsade de Pointes














Screening Patients for Bipolar Disorder:

Serotonin Syndrome

PRECAUTIONS

General

During marketing of Citalopram and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Discontinuation of Treatment with Citalopram

Patients should be monitored for these symptoms when discontinuing treatment with Citalopram. 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 (see DOSAGE AND ADMINISTRATION).

SSRIs and SNRIs, including Citalopram, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Abnormal Bleeding

Patients should be cautioned about the risk of bleeding associated with the concomitant use of Citalopram and NSAIDs, aspirin, or other drugs that affect coagulation.

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including citalopram. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and was reversible when citalopram was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of citalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Hyponatremia

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and /or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

In placebo-controlled trials of citalopram, some of which included patients with bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1063 patients treated with citalopram and in none of the 446 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed antidepressants. As with all antidepressants, citalopram should be used cautiously in patients with a history of mania. Activation of Mania/Hypomania

Although anticonvulsant effects of citalopram have been observed in animal studies, citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of citalopram, seizures occurred in 0.3% of patients treated with citalopram (a rate of one patient per 98 years of exposure) and 0.5% of patients treated with placebo (a rate of one patient per 50 years of exposure). Like other antidepressants, citalopram should be introduced with care in patients with a history of seizure disorder. Seizures

In studies in normal volunteers, citalopram in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, 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. Interference with Cognitive and Motor Performance

Clinical experience with citalopram in patients with certain concomitant systemic illnesses is limited. Due to the risk of QT prolongation, citalopram use should be avoided in patients with certain cardiac conditions, and ECG monitoring is advised if citalopram must be used in such patients. Electrolytes should be monitored in treating patients with diseases or conditions that cause hypokalemia or hypomagnesemia. (see ). Use in Patients with Concomitant Illness
WARNINGS

In subjects with hepatic impairment, citalopram clearance was decreased and plasma concentrations were increased. The use of citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see ). DOSAGE AND ADMINISTRATION

Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with citalopram, however, it should be used with caution in such patients (see ). DOSAGE AND ADMINISTRATION

ADVERSE REACTIONS

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 Findings Observed in Short-Term, Placebo-Controlled Trials

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 TABLE 2. It should be noted that one patient can report more than one reason for discontinuation and be counted more than once in this table. Adverse Events Associated with Discontinuation of Treatment

TABLE 2 Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled, Depression Trials

Body System/Adverse Event		Percentage of Patients Discontinuing Due to Adverse Event
	(N=1063) Citalopram		(N=446) Placebo
General
Asthenia	1%		<1%
Gastrointestinal Disorders
Nausea	4%		0%
Dry Mouth	1%		<1%
Vomiting	1%		0%
Central and Peripheral Nervous System Disorders
Dizziness	2%		<1%
Psychiatric Disorders
Insomnia	3%		1%
Somnolence	2%		1%
Agitation	1%		<1%

Adverse Events Occurring at an incidence of 2% or More Among Citalopram - Treated Patients

TABLE 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 1063 depressed patients who received 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 TABLE 3)

TABLE 3 Treatment-Emergent Adverse Events: Incidence in Placebo-Controlled Clinical Trials*

		(Percentage of Patients Reporting Event)
Body System/Adverse Event	Citalopram HBr(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. Denominator used was for females only (N=638 citalopram; N=252 placebo). Primarily ejaculatory delay. Denominator used was for males only (N=425 citalopram; N=194   placebo). *
1
2
3

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. Dose Dependency of Adverse Events

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. Male and Female Sexual Dysfunction with SSRIs

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

In female depressed patients receiving 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 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 listed in TABLE 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those occurring in only one patient. It is important to emphasize that, although the events reported occurred during treatment with 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. - 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. – 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. - Rare: hypothyroidism, goiter, gynecomastia. – 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. – Infrequent: hot flushes, rigors, alcohol intolerance, syncope, influenza-like symptoms. Rare: hay fever. – Infrequent: purpura, anemia, epistaxis, leukocytosis, leucopenia, lymphadenopathy. Rare: pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorder, gingival bleeding. – 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. –Infrequent: arthritis, muscle weakness, skeletal pain. Rare: bursitis, osteoporosis. –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. - Frequent: amenorrhea. Infrequent: galactorrhea, breast pain, breast enlargement, vaginal hemorrhage. * % based on female subjects only: 2955 – Frequent: coughing. Infrequent: bronchitis, dyspnea, pneumonia. Rare: asthma, laryngitis, bronchospasm, pneumonitis, sputum increased. –Frequent: rash, pruritus. Infrequent: photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia, dermatitis, skin dry, psoriasis. Rare: hypertrichosis, decreased sweating, melanosis, keratitis, cellulitis, pruritus ani. – Frequent: accommodation abnormal, taste perversion. Infrequent: tinnitus, conjunctivitis, eye pain. Rare: mydriasis, photophobia, diplopia, abnormal lacrimation, cataract, taste loss. – Frequent: polyuria. Infrequent: micturition frequency, urinary incontinence, urinary retention, 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, glaucoma, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsades de pointes, and withdrawal syndrome.







Vital Sign Changes


Weight Changes


Laboratory Changes


ECG Changes
WARNINGS - QT-Prolongation and Torsade de Pointes



Other Events Observed During the Premarketing Evaluation of Citalopram Hydrobromide




Cardiovascular

Central and Peripheral Nervous System Disorders

Endocrine Disorders

Gastrointestinal Disorders

General

Hemic and Lymphatic Disorders

Metabolic and Nutritional Disorders

Musculoskeletal System Disorders

Psychiatric Disorders

Reproductive Disorders/Female*



Respiratory System Disorders

Skin and Appendages Disorders

Special Senses

Urinary System Disorders

Other Events Observed During the Postmarketing Evaluation of Citalopram Hydrobromide

DRUG ABUSE AND DEPENDENCE

Citalopram Hydrobromide is not a controlled substance. Controlled Substance Class

Physical and Psychological Dependence

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).

OVERDOSAGE

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 SSRI’s, a fatal outcome in a patient who has taken an overdose of citalopram has been rarely reported. Human Experience

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). Actual renal failure has been very rarely reported accompanying 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. Management of Overdose

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.

DOSAGE AND ADMINISTRATION

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

Citalopram oral solution 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. Initial Treatment

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 ) Special Populations
WARNINGS

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

Neonates exposed to Citalopram Oral Solution USP 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 Oral Solution USP during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Citalopram Oral Solution USP in the third trimester. Treatment of Pregnant Women During 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 Oral Solution USP 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 USP (20-60 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 USP 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 ). 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. Maintenance Treatment
CLINICAL PHARMACOLOGY

Symptoms associated with discontinuation of Citalopram Oral Solution USP 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. Discontinuation of Treatment with Citalopram Oral Solution USP
PRECAUTIONS

At least 14 days should elapse between discontinuation of an MAOI and initiation of citalopram Oral Solution USP therapy. Similarly, at least 14 days should be allowed after stopping Citalopram Oral Solution USP before starting a MAOI (see ). Switching Patients To or From a Monoamine Oxidase Inhibitor
CONTRAINDICATIONS AND WARNINGS

HOW SUPPLIED

NDC:17856-0540-2 in a CUP of 10 SOLUTIONS

ANIMAL TOXICOLOGY

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 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 basis). Retinal Changes in Rats
22

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/m 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 (39-155 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. Cardiovascular Changes in Dogs
2

Silarx Pharmaceuticals, Inc. Carmel, NY 10512 USA

Medication Guide

Read the Medication Guide that comes with Citalopram Oral Solution before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. Citalopram Oral Solution

Citalopram Oral Solution and other antidepressant medicines may cause serious side effects, including: : What is the most important information I should know about Citalopram Oral Solution?

1. Suicidal thoughts or actions

• in some children, teenagers, or young adults within the . Citalopram Oral Solution and other antidepressant medicines may increase suicidal thoughts or actionsfirst few months of treatment or when the dose is changed
• Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.
• Watch for these changes and call your healthcare provider right away if you notice:
• • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
  • Pay particular attention to such changes when Citalopram Oral Solution is started or when the dose is changed.
    

Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

: Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you

• attempts to commit suicide
• acting on dangerous impulses
• acting aggressive or violent
• thoughts about suicide or dying
• new or worse depression
• new or worse anxiety or panic attacks
• feeling agitated, restless, angry or irritable
• trouble sleeping
• an increase in activity or talking more than what is normal for you
• other unusual changes in behavior or mood
  

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Citalopram Oral Solution may be associated with these serious side effects:

2. Changes in the electrical activity of your heart (QT prolongation and Torsade de Pointes).

This condition can be life threatening. The symptoms may include:

• chest pain
• fast or slow heartbeat
• shortness of breath
• dizziness or fainting
  

3. Serotonin Syndrome or Neuroleptic Malignant Syndrome like reactions. This condition can be life-threatening and may include:

• agitation, hallucinations, coma or other changes in mental status
• coordination problems or muscle twitching (overactive reflexes)
• racing heartbeat, high or low blood pressure
• sweating or fever
• nausea, vomiting, or diarrhea
• muscle rigidity
  

4. Severe allergic reactions:

• trouble breathing
• swelling of the face, tongue, eyes or mouth
• rash, itchy welts (hives) or blisters, alone or with fever or joint pain
  

: Citalopram Oral Solution and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin, a non-steroidal antiinflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 5. Abnormal bleeding

6. Seizures or convulsions

7. Manic episodes:

• greatly increased energy
• severe trouble sleeping
• racing thoughts
• reckless behavior
• unusually grand ideas
• excessive happiness or irritability
• talking more or faster than usual
  

8. Changes in appetite or weight.

Children and adolescents should have height and weight monitored during treatment.

. Elderly people may be at greater risk for this. Symptoms may include: 9. Low salt (sodium) levels in the blood

• headache
• weakness or feeling unsteady
• confusion, problems concentrating or thinking or memory problems
  

Do not stop Citalopram without first talking to your healthcare provider.

Stopping Citalopram Oral Solution too quickly may cause serious symptoms including:

• anxiety, irritability, high or low mood, feeling restless or changes in sleep habits
• headache, sweating, nausea, dizziness
• electric shock-like sensations, shaking, confusion
  

Citalopram Oral Solution is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Citalopram Oral Solution is also used to treat: What is Citalopram Oral Solution?

• Major Depressive Disorder (MDD)

Talk to your healthcare provider if you do not think that your condition is getting better with Citalopram treatment.

• Who should not take Citalopram Oral Solution?

Do not take Citalopram Oral Solution if you:

• are allergic to citalopram hydrobromide or escitalopram oxalate or any of the ingredients in Citalopram Oral Solution. See the end of this Medication Guide for a complete list of ingredients in Citalopram Oral Solution.
• take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
• • Do not take an MAOI within 14 days of stopping Citalopram Oral Solution.
  • Do not start Citalopram Oral Solution if you stopped taking an MAOI in the last 14 days.
    

People who take Citalopram Oral Solution close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:

• high fever
• uncontrolled muscle spasms
• stiff muscles
• rapid changes in heart rate or blood pressure
• confusion
• loss of consciousness (pass out)
  

-take the antipsychotic medicine pimozide because this can cause serious heart problems.

-have a heart problem including congenital long QT syndrome

What should I tell my healthcare provider before taking Citalopram Oral Solution? Ask if you are not sure.

Before starting Citalopram Oral Solution, tell your healthcare provider if you

• Are taking certain drugs such as:
• • Medicines for heart problems
  • Medicines that lower your potassium or magnesium levels in your body
  • Cimetidine
  • Triptans used to treat migraine headache
  • Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, or antipsychotics
  • Tramadol
• • Over-the-counter supplements such as tryptophan or St. John's Wort
  • have liver problems
  • have kidney problems
  • have heart problems
  • have or had seizures or convulsions
  • have bipolar disorder or mania
  • have low sodium levels in your blood
  • have a history of a stroke
  • have high blood pressure
  • have or had bleeding problems
  • are pregnant or plan to become pregnant. It is not known if Citalopram Oral Solution will harm your unborn baby. Talk to your health care provider about the benefits and risks of treating depression during pregnancy
  • are breast-feeding or plan to breastfeed. Some Citalopram may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Citalopram.
    

Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Citalopram Oral Solution and some medicines may interact with each other, may not work as well, or may cause serious side effects.

Your health care provider or pharmacist can tell you if it is safe to take Citalopram Oral Solution with your other medicines. Do not start or stop any medicine while taking Citalopram without talking to your health care provider first.

If you take Citalopram Oral Solution, you should not take any other medicines that contain citalopram hydrobromide or escitalopram oxalate.

How should I take Citalopram Oral Solution?

• Take Citalopram Oral Solution exactly as prescribed. Your healthcare provider may need to change the dose of Citalopram Oral Solution until it is the right dose for you.
• Citalopram Oral Solution may be taken with or without food.
• If you miss a dose of Citalopram Oral Solution, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Citalopram Oral Solution at the same time.
• If you take too much Citalopram Oral Solution, call your health care provider or poison control center right away, or get emergency treatment.
  

Citalopram Oral Solution can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how Citalopram Oral Solution affects you. Do not drink alcohol while using Citalopram. What should I avoid while taking Citalopram Oral Solution?

What are the possible side effects of Citalopram Oral Solution?
Citalopram Oral Solution may cause serious side effects, including:

Common possible side effects in people who take Citalopram Oral Solution include: See "What is the most important information I should know about Citalopram Oral Solution?"

• Nausea
• Sleepiness
• Weakness
• Dizziness
• Feeling anxious
• Trouble sleeping
• Sexual problems
• Sweating
• Shaking
• Not feeling hungry
• Dry mouth
• Constipation
• Diarrhea
• Respiratory Infections
• Yawning
  

Other side effects in children and adolescents include:

• increased thirst
• abnormal increase in muscle movement or agitation
• nose bleed
• urinating more often
• heavy menstrual periods
• possible slowed growth rate and weight change. Your child's height and weight should be monitored during treatment with Citalopram.
  

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Citalopram Oral Solution. For more information, ask your healthcare provider or pharmacist.

CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1- 800-FDA -1088.

• Store Citalopram Oral Solution at 25°C (77°F), between 15°C to 30°C (59°F to 86°F). • Keep Citalopram Oral Solution bottle closed tightly. How should I store Citalopram Oral Solution?

Keep Citalopram Oral Solution and all medicines out of the reach of children.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Citalopram Oral Solution for a condition for which it was not prescribed. Do not give Citalopram Oral Solution to other people, even if they have the same condition. It may harm them. General information about Citalopram Oral Solution

This Medication Guide summarizes the most important information about Citalopram Oral Solution. If you would like more information, talk with your healthcare provider. You may ask your health care provider or pharmacist for information about Citalopram Oral Solution that is written for healthcare professionals.

Active ingredient: citalopram hydrobromide Inactive ingredients: sorbitol, purified water, propylene glycol, methylparaben, peppermint flavor, propylparaben. This Medication Guide has been approved by the U.S. Food and Drug Administration. Silarx Pharmaceuticals, Inc. Carmel, NY 10512 USA What are the ingredients in Citalopram Oral Solution?

CITALOPRAM HYDROBROMIDE SOLUTION