Generic Name: CITALOPRAM HYDROBROMIDE
Brand Name: Citalopram Hydrobromide
- Substance Name(s):
- CITALOPRAM HYDROBROMIDE
Drug Interactions Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs including citalopram HBr, and the potential for serotonin syndrome, caution is advised when citalopram HBr is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see WARNINGS-Serotonin Syndrome ). The concomitant use of citalopram HBr with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS – Drug Interactions ). Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of citalopram HBr with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS – Serotonin Syndrome ). CNS Drugs Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs. Alcohol Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram HBr is not recommended. Monoamine Oxidase Inhibitors (MAOIs) See CONTRAINDICATIONS and WARNINGS . Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when citalopram HBr is initiated or discontinued. Cimetidine In subjects who had received 21 days of 40 mg/day citalopram HBr, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical significance of these findings is unknown. Digoxin In subjects who had received 21 days of 40 mg/day citalopram HBr, combined administration of citalopram HBr and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin. Lithium Coadministration of citalopram HBr (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram HBr and lithium are coadministered. Pimozide In a controlled study, a single dose of pimozide 2 mg co-administered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known. Theophylline Combined administration of citalopram HBr (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated. Sumatriptan There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate observation of the patient is advised. Warfarin Administration of 40 mg/day citalopram HBr for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown. Carbamazepine Combined administration of citalopram HBr (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered. Triazolam Combined administration of citalopram HBr (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam. Ketoconazole Combined administration of citalopram HBr (40 mg) and ketoconazole (200 mg) decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram. CYP3A4 and 2C19 Inhibitors In vitro studies indicated that CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram. However, coadministration of citalopram (40 mg) and ketoconazole (200 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance. Metoprolol Administration of 40 mg/day citalopram HBr for 22 days resulted in a two-fold increase in the plasma levels of the beta-adrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of citalopram HBr and metoprolol had no clinically significant effects on blood pressure or heart rate. Imipramine and Other Tricyclic Antidepressants (TCAs) In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of citalopram HBr (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with citalopram HBr.. Electroconvulsive Therapy (ECT) There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and citalopram HBr.
Human Experience In clinical trials of citalopram, there were reports of citalopram overdose, including overdoses of up to 2000 mg, with no associated fatalities. During the postmarketing evaluation of citalopram, citalopram HBr 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. Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose. Management of Overdose Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for citalopram HBr. 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 HBr is an orally administered selective serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant agents. Citalopram HBr is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, HBr with the following structural formula: The molecular formula is C20H22BrFN2O and its molecular weight is 405.35. Citalopram HBr occurs as a fine, white to off-white powder. Citalopram HBr is sparingly soluble in water and soluble in ethanol. Citalopram HBr is available as tablets. Citalopram HBr 10 mg tablets are oval shaped biconvex, film-coated tablets containing citalopram HBr in strengths equivalent to 10 mg citalopram base. Citalopram HBr 20 mg and 40 mg tablets are, oval shaped, biconvex, film-coated, scored tablets containing citalopram HBr in strengths equivalent to 20 mg or 40 mg citalopram base. The tablets also contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film-coating contains: hydroxyethyl cellulose, polyethylene glycol, red ferric oxide (10mg and 20mg), titanium dioxide, and yellow ferric oxide (10mg). Formula
Comparison of Clinical Trial Results Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated.
Citalopram HBr Tablets 10 mg are beige-pink, oval shaped, biconvex, film-coated tablets, engraved “APO” on one side and “CI 10” on the other side. They are supplied as follows: Bottles of 30 NDC 60505-2518-4 Bottles of 100 NDC 60505-2518-1 Bottles of 1000 NDC 60505-2518-8 100 Unit Dose NDC 60505-2518-3 Citalopram HBr Tablets, 20mg are pink, oval shaped, biconvex, film-coated tablets, engraved “APO” on one side and scored and engraved “CI 20” on the other side. They are supplied as follows: Bottles of 30 NDC 60505-2519-4 Bottles of 100 NDC 60505-2519-1 Bottles of 1000 NDC 60505-2519-8 100 Unit Dose NDC 60505-2519-3 Citalopram HBr Tablets, 40mg are white, oval shaped, biconvex, film-coated tablets, engraved “APO” on one side and scored and engraved “CI 40” on the other side. They are supplied as follows: Bottles of 30 NDC 60505-2520-4 Bottles of 100 NDC 60505-2520-1 Bottles of 1000 NDC 60505-2520-8 100 Unit Dose NDC 60505-2520-3 Store at 20º to 25°C (68º to 77°F); excursions permitted to 15 – 30°C (59-86°F). [See USP Controlled Room Temperature].
Geriatric Use Of 4422 patients in clinical studies of citalopram HBr, 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 HBr in clinical trials received daily doses between 20 and 40 mg (see DOSAGE AND ADMINISTRATION ). SSRIs and SNRIs, including citalopram HBr, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia). 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 ).
INDICATIONS AND USAGE
Citalopram HBr is indicated for the treatment of depression. The efficacy of citalopram HBr 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 HBr in hospitalized depressed patients has not been adequately studied. The efficacy of citalopram HBr 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 HBr for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk ). Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with citalopram HBr, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of citalopram HBr in a child or adolescent must balance the potential risks with the clinical need.
Pregnancy Pregnancy Category C In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses. In two rat embryo/fetal development studies, oral administration of citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the MRHD of 60 mg/day on a body surface area (mg/m2) basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental, no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on a mg/m2 basis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/m2 basis. Thus, teratogenic effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit. When female rats were treated with citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD on a mg/m2 basis. The no-effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m2 basis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the MRHD on a mg/m2 basis. A no-effect dose was not determined in that study. There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Neonates exposed to citalopram HBr and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS ). Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective, case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman with citalopram HBr during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION ). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
Nursing Mothers As has been found to occur with many other drugs, citalopram is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or citalopram HBr therapy should take into account the risks of citalopram exposure for the infant and the benefits of citalopram HBr treatment for the mother.
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Citalopram HBr or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Citalopram HBr is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
INFORMATION FOR PATIENTS
Information for Patients Physicians are advised to discuss the following issues with patients for whom they prescribe citalopram HBr. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of citalopram HBr and triptans, tramadol or other serotonergic agents. Although in controlled studies citalopram HBr has not been shown to impair psychomotor performance, any psychoactive drug may impair judgment, thinking, or motor skills, so patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram HBr therapy does not affect their ability to engage in such activities. Patients should be told that, although citalopram HBr 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 HBr 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 HBr and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has 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 breastfeeding an infant. While patients may notice improvement with citalopram HBr 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 HBr and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for citalopram HBr. 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 contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text 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 HBr. Clinical Worsening and Suicide Risk 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 look 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.
DOSAGE AND ADMINISTRATION
Initial Treatment Citalopram HBr 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 HBr should be administered once daily, in the morning or evening, with or without food. Special Populations 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 HBr should be used with caution in patients with severe renal impairment. Treatment of Pregnant Women During the Third Trimester Neonates exposed to citalopram HBr 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 HBr during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering citalopram HBr in the third trimester. Maintenance Treatment It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Systematic evaluation of citalopram HBr 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 HBr (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 HBr 20 or 40 mg/day, or placebo, for maintenance treatment. In the latter study, the rates of relapse to depression were similar for the two dose groups (see Clinical Trials under CLINICAL PHARMACOLOGY ). Based on these limited data, it is not known whether the dose of citalopram needed to maintain euthymia is identical to the dose needed to induce remission. If adverse reactions are bothersome, a decrease in dose to 20 mg/day can be considered. Discontinuation of Treatment with Citalopram HBr Symptoms associated with discontinuation of citalopram HBr and other SSRIs and SNRIs have been reported (see PRECAUTIONS ). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Switching Patients To or From a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of citalopram HBr therapy. Similarly, at least 14 days should be allowed after stopping citalopram HBr before starting an MAOI (see CONTRAINDICATIONS and WARNINGS ).