CELEXA is indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies ( 14 )] . CELEXA is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder (MDD) in adults ( 1 ).
Contraindications
CELEXA is contraindicated in patients: taking, or within 14 days of stopping, MAOIs (including MAOIs such as linezolid or intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )] . taking pimozide because of risk of QT prolongation [ see Drug Interactions ( 7 )] . with known hypersensitivity to citalopram or any of the inactive ingredients in CELEXA.
Reactions have included angioedema and anaphylaxis [see Adverse Reactions ( 6.2 ) ]. Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing a MAOI ( 4 ). Concomitant use of pimozide ( 4 ) . Known hypersensitivity to citalopram or any of the inactive ingredients of CELEXA ( 4 ).
Warnings and precautions
QT-Prolongation and Torsade de Pointes : Dose-dependent QTc prolongation, Torsade de pointes, ventricular tachycardia, and sudden death have occurred. Avoid use of CELEXA in patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure and patients taking other drugs that prolong the QTc interval. Monitor electrolytes in patients at high risk for hypokalemia or hypomagnesemia.
Discontinue CELEXA in patients with persistent QTc measurements > 500 ms ( 5.2 , 7 ). Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If occurs, discontinue CELEXA and serotonergic agents and initiate supportive measures ( 5.3 ). In cr eased Risk of Bleeding : Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin and other anticoagulants may increase this risk ( 5.4 ).
Activation of Mania/Hypomania : Screen patients for bipolar disorder ( 5.5 ). Seizures: Use with caution in patients with seizure disorder ( 5.7 ). Angle-Closure Glaucoma: Avoid use of CELEXA in patients with untreated anatomically narrow angles ( 5.8 ). Hyponatremia : Can occur in association with syndrome of inappropriate antidiuretic hormone secretion ( 5.9 ). Sexual Dysfunction : CELEXA may cause symptoms of sexual dysfunction ( 5.10 ) .
5.1Suicidal Thoughts and Behavior in Adolescents and Young Adults
In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.
There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1 . Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range * Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo 25-64 years old 1 fewer patient ≥65 years old 6 fewer patients *CELEXA is not approved for use in pediatric patients.
It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes.
Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing CELEXA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
5.2 QT-Prolongation and Torsade de Pointes CELEXA 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 [see Adverse Reactions ( 6.2 ) ] . Because of the risk of QTc prolongation at higher CELEXA doses, it is recommended that CELEXA not be given at doses above 40 mg once daily [see Dosage and Administration ( 2.1 ) , Clinical Pharmacology ( 12.2 ) ] .
CELEXA should be avoided in patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure unless the benefits outweigh the risks for a particular patient. CELEXA should also be avoided in patients who are taking other drugs that prolong the QTc interval [see Drug Interactions ( 7 )] . 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 once daily in patients who are CYP2C19 poor metabolizers or those patients receiving concomitant cimetidine or another CYP2C19 inhibitor, since higher citalopram exposures would be expected. The maximum dose should also be limited to 20 mg once daily in patients with hepatic impairment and in patients who are greater than 60 years of age because of expected higher exposures [see Dosage and Administration ( 2.3 , 2.4 ) , Drug Interactions ( 7 ), Use in Specific Populations ( 8.5 ), Clinical Pharmacology ( 12.3 ) ] .
Electrolyte and/or ECG monitoring is recommended in certain circumstances. Patients being considered for treatment with CELEXA 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 CELEXA use is not recommended unless the benefits clearly outweigh the risks for a particular patient (see above). These include those patients with the cardiac conditions noted above, and those taking other drugs that may prolong the QTc interval. Discontinue CELEXA in patients who are found to have persistent QTc measurements >500 ms. If patients taking CELEXA 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.
5.3Serotonin Syndrome
SSRIs, including CELEXA, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4 ) , Drug Interactions ( 7 )] .
Serotonin syndrome can also occur when these drugs are used alone. Symptoms of serotonin syndrome were noted in 0.1% of MDD patients treated with CELEXA in premarketing clinical trials. Serotonin syndrome signs and 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of CELEXA with MAOIs is contraindicated. In addition, do not initiate CELEXA in a patient being treated with MAOIs such as linezolid or int
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Interactions
Table 5 presents clinically important drug interactions with CELEXA. Table 5: Clinically Important Drug Interactions with CELEXA Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of SSRIs, including CELEXA, and MAOIs increases the risk of serotonin syndrome. Intervention CELEXA is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2.5 ), Contraindications ( 4 ), Warnings and Precautions ( 5.3 )] .
Pimozide Clinical Impact: Concomitant use of CELEXA with pimozide increases plasma concentrations of pimozide, a drug with a narrow therapeutic index, and may increase the risk of QT prolongation and/or ventricular arrhythmias compared to use of CELEXA alone [see Clinical Pharmacology ( 12.2 )]. Intervention: CELEXA is contraindicated in patients taking pimozide [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )].
Drugs that Prolong the QTc Interval Clinical Impact: Concomitant use of CELEXA with drugs that prolong QT can cause additional QT prolongation compared to the use of CELEXA alone [see Clinical Pharmacology ( 12.2 )]. Intervention: Avoid concomitant use of CELEXA with drugs that prolong the QT interval (CELEXA is contraindicated in patients taking pimozide) [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )].
CYP2C19 Inhibitors Clinical Impact: Concomitant use of CELEXA with CYP2C19 inhibitors increases the risk of QT prolongation and/or ventricular arrhythmias compared to the use of CELEXA alone [see Clinical Pharmacology ( 12.2 )]. Intervention: The maximum recommended dosage of CELEXA is 20 mg daily when used concomitantly with a CYP2C19 inhibitor [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.2 )].
Other Serotonergic Drugs Clinical Impact: Concomitant use of CELEXA and other serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during CELEXA initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of CELEXA and/or concomitant serotonergic drugs [ see Warning and Precautions ( 5.3 )] .
Drugs That Interfere With Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact: Concomitant use of CELEXA and an antiplatelet or anticoagulant may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding associated with the concomitant use of CELEXA and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [ see Warning and Precautions ( 5.4 )] .
CYP2C19 Inhibitors: CELEXA 20 mg daily is the maximum recommended dosage for patients taking concomitant CYP2C19 inhibitors ( 5.2 , 7.1).
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants . Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.4 ) and Clinical Considerations] .
Available data from published epidemiologic studies and postmarketing reports with citalopram use in pregnancy have not established an increased risk of major birth defects or miscarriage. Published studies demonstrated that citalopram levels in both cord blood and amniotic fluid are similar to those observed in maternal serum. There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including CELEXA, during pregnancy .
There also are risks associated with untreated depression in pregnancy (see Clinical Considerations) . In animal reproduction studies, citalopram caused adverse embryo/fetal effects at doses that caused maternal toxicity (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy.
Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of CELEXA in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.4 )] . Fetal/Neonatal Adverse Reactions Neonates exposed to CELEXA and other SSRIs late in 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 findings are consistent with either a direct toxic effect of SSRIs or possibly, a drug discontinuation syndrome.
It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions ( 5.3 )] . Data Human Data Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1- 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality.
Animal Data Citalopram was administered orally to pregnant rats during the period of organogenesis at doses of 32, 56, and 112 mg/kg/day, which are approximately 8, 14, and 27 times the Maximum Recommended Human Dose (MRHD) of 40 mg, based on mg/m 2 body surface area. Citalopram caused maternal toxicity of CNS clinical signs and decreased weight gain at 112 mg/kg/day, which is 27 times the MRHD. At this maternally toxic dose, citalopram decreased embryo/fetal growth and survival and increased fetal abnormalities (including cardiovascular and skeletal defects).
The no observed adverse effect level (NOAEL) for maternal and embryofetal toxicity is 56 mg/kg/day, which is approximately 14 times the MRHD. Citalopram was administered orally to pregnant rabbits during the period of organogenesis at doses up to 16 mg/kg/day, which is approximately 8 times the MRHD of 40 mg, based on mg/m 2 body surface area. No maternal or embryofetal toxicity was observed. The NOAEL for maternal and embryofetal toxicity is 16 mg/kg/day, which is approximately 8 times the MRHD.
Citalopram was administered orally to pregnant rats during late gestation and lactation periods at doses of 4.8, 12.8, and 32 mg/kg/day, which are approximately 1, 3, and 8 times the MRHD of 40 mg, based on mg/m 2 body surface area. Citalopram increased offspring mortality during the first 4 days of birth and decreased offspring growth at 32 mg/kg/day, which is approximately 8 times the MRHD. The NOAEL for developmental toxicity is 12.8 mg/kg/day, which is approximately 3 times the MRHD.
In a separate study, similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, which is approximately 6 times the MRHD. A NOAEL was not determined in that study.
Adverse reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling: Hypersensitivity reactions [see Contraindications ( 4 )] Suicidal thoughts and behaviors in adolescents and young adults [see Warnings and Precautions ( 5.1 )] QT-prolongation and torsade de pointes [see Warnings and Precautions ( 5.2 )] Serotonin syndrome [see Warnings and Precautions ( 5.3 )] Increased risk of bleeding [see Warnings and Precautions ( 5.4 )] Activation of mania or hypomania [see Warnings and Precautions ( 5.5 )] Discontinuation syndrome [see Warnings and Precautions ( 5.6 )] Seizures [see Warnings and Precautions ( 5.7 )] Angle-closure glaucoma [see Warnings and Precautions ( 5.8 )] Hyponatremia [see Warnings and Precautions ( 5.9 )] Sexual Dysfunction [see Warnings and Precautions ( 5.10 )] Most common adverse reaction (incidence ≥ 5% and twice placebo) is ejaculation disorder (primarily ejaculation delay) ( 6.1 ) .
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The safety for CELEXA included citalopram exposures in patients and/or healthy subjects from 3 different groups of studies: 429 healthy subjects in clinical pharmacology/pharmacokinetic studies; 4,422 exposures from patients in controlled and uncontrolled clinical trials, corresponding to approximately 1,370 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 CELEXA 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 Associated with Discontinuation of Treatment Among 1,063 patients with MDD who received CELEXA at doses ranging from 10 mg to 80 mg once daily in placebo-controlled trials of up to 6 weeks duration, 16% discontinued treatment due to an adverse reaction, as compared to 8% of 446 patients receiving placebo.
The adverse reactions associated with discontinuation (i.e., associated with discontinuation in at least 1% of CELEXA-treated patients at a rate at least twice that of placebo) are shown in Table 2 . Table 2: Adverse Reactions Associated with Discontinuation of CELEXA Treatment in Short-Term, Placebo-Controlled MDD Trials Body System/Adverse Reaction CELEXA Placebo (N=1,063) % (N=446) % 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 * A patient can report more than one reason for discontinuation and be counted more than once in this table.
Table 3 enumerates the incidence of adverse reactions that occurred among 1,063 patients with MDD who received CELEXA at doses ranging from 10 mg to 80 mg once daily in placebo-controlled trials of up to 6 weeks duration. The most common adverse reaction that occurred in CELEXA-treated 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: Adverse Reactions (≥2% and Greater than Placebo) Among CELEXA-Treated Patients* CELEXA Placebo Body System/Adverse Reaction (N=1,063) % (N=446) % Gastrointestinal Disorders Nausea 21 14 Diarrhea 8 5 Dyspepsia 5 4 Vomiting 4 3 Abdominal Pain 3 2 Autonomic Nervous System Disorders Dry Mouth 20 14 Sweating Increased 11 9 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 Central & Peripheral Nervous System Disorders Tremor 8 6 Urogenital Ejaculation Disorder 2,3 6 1 Impotence 3 3 <1 Respiratory System Disorders Upper Respiratory Tract Infection 5 4 Rhinitis 5 3 Sinusitis 3 <1 General Fatigue 5 3 Fever 2 <1 Musculoskeletal System Disorders Arthralgia 2 1 Myalgia 2 1 *Adverse reactions reported by at least 2% of patients treated with CELEXA are reported, except for the following adverse reactions which had an incidence on placebo ≥ CELEXA: headache, asthenia, dizziness, constipation, palpitation, vision abnormal, sleep disorder, nervousness, pharyngitis, micturition disorder, back pain. 1 Denominator used was for females only (N=638 CELEXA; N=252 placebo). 2 Primarily ejaculatory delay. 3 Denominator used was for males only (N=425 CELEXA; N=194 placebo).
Dose Dependen t Adverse Reactions The potential relationship between the dosage of CELEXA and the incidence of adverse reactions was examined in a fixed-dose study in patients with MDD receiving placebo or CELEXA 10 mg, 20 mg 40 mg, or 60 mg (1.5 times the maximum recommended dosage). A positive dose response (p<0.05) was revealed for the following adverse reactions: fatigue, impotence, insomnia, increased sweating, somnolence, and yawning.
Male and Female Sexual Dysfunction with SSRIs 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 SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them.
Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence. Table 4 displays the incidence of sexual adverse reactions reported by at least 2% of male patients taking CELEXA in a pool of placebo-controlled clinical trials in patients with depression. Table 4: Adverse Reactions (≥2%) Related to Sexual Dysfunction in CELEXA-Treated Male Patients in Pooled Placebo-Controlled Clinical Trials of MDD CELEXA Placebo n (males) 425 ( % ) 194 ( % ) Abnormal ejaculation (mostly ejaculatory delay) 6.1 1 Decreased libido 3.8 <1 Impotence 2.8 <1 In female depressed patients receiving CELEXA, the reported incidence of decreased libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252 females), respectively.
Weight Changes Patients treated with CELEXA in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients. ECG Changes In a thorough QT study, CELEXA was found to be associated with a dose-dependent increase in the QTc interval. Electrocardiograms from CELEXA (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 CELEXA 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 CELEXA group. The incidence of tachycardic outliers was 0.5% in the CELEXA group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the CELEXA group and 0.4% in the placebo group.
Other Adverse Reactions Observed During the Premarketing Evaluation of CELEXA The following list of adverse reactions does not include reactions that are: 1) included in Table 3 or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformativ
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Composition
Active ingredients
CITALOPRAM HYDROBROMIDE EQ 20MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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