FDA Label for Citalopram

Warning: Suicidal Thoughts And Behaviors

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short- term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions ( 5.1)]. Citalopram is not approved for use in pediatric patients [see Use in Specific Populations ( 8.4)].

1 Indications And Usage

Citalopram is indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies ( 14)] .

2 Dosage And Administration

2.1 Recommended Dosage

Administer Citalopram once daily, with or without food, at an initial dosage of 20 mg once daily, with an increase to a maximum dosage of 40 mg once daily at an interval of no less than one week.

Dosages above 40 mg once daily are not recommended due to the risk of QT prolongation [see Warnings and Precautions ( 5.2)] .

2.2 Screen For Bipolar Disorder Prior To Starting Citalopram

Prior to initiating treatment with Citalopram or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [See Warnings and Precautions ( 5.5)] .

2.3 Recommended Dosage For Specific Populations

The maximum recommended dosage of Citalopram for patients who are greater than 60 years of age, patients with hepatic impairment, and for CYP2C19 poor metabolizers is 20 mg once daily [see Warnings and Precautions ( 5.2), Clinical Pharmacology ( 12.3)] .

2.4 Dosage Modifications With Concomitant Use Of Cyp2c19 Inhibitors

The maxium recommended dosage of Citalopram when used concomitantly with a CYP2C19 inhibitor is 20 mg once daily [see Warnings and Precautions ( 5.2), Drug Interactions ( 7) ].

2.5 Switching Patients To Or From A Monoamine Oxidase Inhibitor Antidepressant

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of therapy with Citalopram. Conversely, at least 14 days must elapse after stopping Citalopram before starting an MAOI antidepressant [see Contraindications ( 4) and Warnings and Precautions ( 5.3)].

2.6 Discontinuing Treatment With Citalopram

Adverse reactions may occur upon discontinuation of Citalopram [see Warnings and Precautions ( 5.6)]. Gradually reduce the dosage rather than stopping Citalopram abruptly whenever possible.

3 Dosage Forms And Strengths

Citalopram tablets are available as:

Tablets:

• 10mg - Beige, oval, film‐coated. Imprint on one side with “FP”. Imprint on the other side with “10 mg”.
• 20 mg -10 x 10 Unit Dose -Pink, oval, scored, film‐coated. Imprint on scored side with “F” on the left side and “P” on the right side. Imprint on the non‐scored side with “20 mg”.
• 40 mg White, 10 x 10 Unit Dose - oval, scored, film‐coated. Imprint on scored side with “F” on the left side and “P” on the right side. Imprint on the non‐scored side with “40 mg”

4 Contraindications

Citalopram 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 Citalopram. Reactions have included angioedema and anaphylaxis [see Adverse Reactions ( 6.2)] .

5 Warnings And Precautions

5.1 Suicidal 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.

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 Citalopram, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Qt-Prolongation And Torsade De Pointes

Citalopram causes dose dependent QTc prolongation an ECG abnormality that has been associated with Torsade de Pointes (TdP), ventricular tachycardia, and sudden death, all of which have been observed in post marketing reports for citalopram [see Adverse Reactions 6.2)] .

Because of the risk of QTc prolongation at higher citalopram doses, it is recommended that citalopram not be given at doses above 40 mg once daily [see Dosage and Administration ( 2.1), Clinical Pharmacology ( 12.2)] .

Citalopram 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. Citalopram 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 Citalopram 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 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 Citalopram 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.

5.3 Serotonin Syndrome

SSRIs, including Citalopram, 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, 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 Citalopram 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 Citalopram with MAOIs is contraindicated. In addition, do not initiate Citalopram in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Citalopram, discontinue Citalopram before initiating treatment with the MAOI [see Contraindications ( 4), Drug Interactions ( 7)] .

Monitor all patients taking Citalopram for the emergence of serotonin syndrome. Discontinue treatment with Citalopram and any concomitant serotonergic agents immediately if the above symptoms occur and initiate supportive symptomatic treatment. If concomitant use of Citalopram with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.4 Increased Risk Of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including Citalopram, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants may add to this 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 drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the increased risk of bleeding associated with the concomitant use of Citalopram and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Drug Interactions ( 7)] .

5.5 Activation Of Mania Or Hypomania

In patients with bipolar disorder, treating a depressive episode with Citalopram or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were excluded; however, symptoms of mania or hypomania were reported in 0.1% of undiagnosed patients treated with Citalopram. Prior to initiating treatment with Citalopram, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration ( 2.2)] .

5.6 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration ( 2.6)] .

5.7 Seizures

Citalopram has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. 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). Citalopram should be prescribed with caution in patients with a seizure disorder.

5.8 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs, including Citalopram, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Citalopram, in patients with untreated anatomically narrow angles.

5.9 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs, including Citalopram. Cases of serum sodium lower than 110 mmol/L have been reported. 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 many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue Citalopram and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs [see Use in Specific Populations ( 8.5)] .

5.10 Sexual Dysfunction

Use of SSRIs, including Citalopram, may cause symptoms of sexual dysfunction [ see Adverse Reactions ( 6.1)] . In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of Citalopram and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

6 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)]

6.1 Clinical 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 Citalopram 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 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.

6.2 Post Marketing Experience

The following adverse reactions have been identified during postapproval use of citalopram, the racemate, or escitalopram, the S-enantiomer of citalopram. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: hemolytic anemia, thrombocytopenia, prothrombin decreased

Cardiac Disorders: torsade de pointes, ventricular arrhythmia, QT prolonged

Endocrine Disorders: hyperprolactinemia

Eye Disorders: angle-closure glaucoma

Gastrointestinal Disorders: gastrointestinal hemorrhage, pancreatitis General Disorders and Administrative Site Conditions: withdrawal syndrome Hepatobiliary Disorders: hepatic necrosis

Immune System Disorders: anaphylaxis, allergic reaction

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Nervous System Disorders: grand mal convulsion(s), myoclonus, choreoathetosis, dyskinesia, akathisia, nystagmus

Pregnancy, Puerperium and Perinatal Conditions: spontaneous abortion

Psychiatric Disorders: delirium

Renal and Urinary Disorders: acute renal failure

Reproductive System and Breast Disorders: priapism

Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, epidermal necrolysis, angioedema, erythema multiforme, ecchymosis

Vascular Disorders: thrombosis

7 Drug Interactions

Table 5 presents clinically important drug interactions with Citalopram.

8 Use In Specific Populations

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healhcare providers are encouraged to register patients 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

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 Citalopram, 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.

Fetal/Neonatal Adverse Reactions

Neonates exposed to Citalopram 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/m2 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/m2 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.

8.2 Lactation

Risk Summary

Data from the published literature report the presence of citalopram in human milk at relative infant doses ranging between 0.7 to 9.4% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.78 to 4.3. There are reports of breastfed infants exposed to citalopram experiencing irritability, restlessness, excessive somnolence, decreased feeding, and weight loss (see Clinical Considerations) . There is no information about effects of citalopram on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Citalopram and any potential adverse effects on the breastfed child from Citalopram or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding infants for adverse reactions, such as irritability, restlessness, excessive somnolence, decreased feeding, and weight loss.

8.4 Pediatric Use

The safety and effectiveness of Citalopram have not been established in pediatric patients. Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with Citalopram, and the data were not sufficient to support use in pediatric patients.

Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions ( 5.1)] . Decreased appetite and weight loss have been observed in association with the use of SSRIs in pediatric patients.

8.5 Geriatric Use

Of 4422 patients in clinical studies of Citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. In two pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in subjects ³ 60 years of age as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively [see Clinical Pharmacology ( 12.3)]. Therefore, the maximum recommended dosage in patients 60 years of age and older is lower than younger patients [see Dosage and Administration ( 2.3),Warnings and Precautions ( 5.2)] .

SSRIs, including Citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions ( 5.9)] .

8.6 Hepatic Impairment

Increased citalopram exposure occurs in patients with hepatic impairment. The maximum recommended dosage of Citalopram is lower in patients with hepatic impairment [see Dosage and Administration ( 2.3), Clinical Pharmacology ( 12.3)].

9 Drug Abuse And Dependence

9.1 Controlled Substance

Citalopram (citalopram HBr) is not a controlled substance.

9.2 Abuse

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, health care providers 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).

10 Overdosage

The following have been reported with Citalopram tablet overdosage:

• Seizures, which may be delayed, and altered mental status including coma.
• Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, and torsade de pointes. Hypertension most commonly seen, but rarely can see hypotension alone or with co‐ingestants including alcohol.
• Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk).

Prolonged cardiac monitoring is recommended in Citalopram overdosage ingestions due to the arrhythmia risk. Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a Citalopram overdose. Consider contacting a Poison Center (1‐800‐221‐2222) or a medical toxicologist for additional overdosage management recommendations.

11 Description

Citalopram tablet contains citalopram hydrobromide, 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 hydrobromide is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3- dihydroisobenzofuran-5-carbonitrile, hydrobromide with the following structural formula:

Image - structure

The molecular formula is C ₂₀H ₂₂BrFN ₂O and its molecular weight is 405.35.

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

Citalopram is available only in tablet dosage form.

Citalopram tablets, USP 10 mg are film-coated, round tablets containing citalopram hydrobromide in strengths equivalent to 10 mg citalopram base. Citalopram hydrobromide, USP 20 mg and 40 mg tablets are film-coated, round, scored tablets containing citalopram hydrobromide in strengths equivalent to 20 mg or 40 mg citalopram base. Their strengths reflect their citalopram base equivalent content. The 10 mg, 20 mg and 40 mg strength tablets contain 12.49 mg, 24.98 mg and 49.96 mg of citalopram hydrobromide, respectively. The tablets also contain the following inactive ingredients: copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, opadry beige (HPMC 2910/hypromellose 6cp, titanium dioxide, macrogol/Peg400, iron oxide yellow and iron oxide red), opadry pink (HPMC 2910/hypromellose 6cP, titanium dioxide, macrogol/ Peg400 and iron oxide red) and opadry white (titanium dioxide, HPMC 2910/hypromellose 3cp, HPMC 2910/ hypromellose 6cp, Macrogol/Peg400 and Polysorbate 80) are used as coloring agents in the beige (10 mg) and pink (20 mg) and white (40 mg) tablets.

12.1 Mechanism Of Action

The mechanism of action of citalopram is unclear, but is presumed to be related to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).

12.2 Pharmacodynamics

In vitro and in vivo studies in animals suggest that citalopram is a selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake.

Citalopram has no or very low affinity for 5-HT1A, 5-HT2A, dopamine D1 and D2, α1-, α2-, and β-adrenergic, histamine H1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors.

Cardiac Electrophysiology

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 (1.5 times the maxium recommended dosage) 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 [see Warnings and Precautions ( 5.2)] .

12.3 Pharmacokinetics

The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 40 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Citalopram increased the incidence of small intestine carcinoma in rats treated for 24 months at doses of 8 and 24 mg/kg/day in the diet, which are approximately 2 and 6 times the Maximum Recommended Human Dose (MRHD) of 40 mg, respectively, based on mg/m2 body surface area. A no-effect level (NOEL) for this finding was not established.

Citalopram did not increase the incidence of tumors in mice treated for 18 months at doses up 240 mg/kg/day in the diet, which is approximately 30 times the MRDH of 40 mg based on mg/m2 body surface area.

Mutagenesis

Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.

Impairment of Fertility

Citalopram was administered orally to female and male rats at doses of 32, 48, and 72 mg/kg/day prior to and throughout mating and continuing to gestation. These doses are approximately 8, 12, and 17 times the MRHD of 40 mg based on mg/m2 body surface area. Mating and fertility were decreased at doses ≥ 32 mg/kg/day, which is approximately 8 times the MRHD. Gestation duration was increased at 48 mg/kg/day, which is approximately 12 times the MRHD

13.2 Animal Toxicology And/Or Pharmacology

Retinal Changes in Rats

Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with citalopram. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day, which is approximately 19 times the MRHD of 40 mg based on mg/m2 body surface area. Similar findings were not present in rats treated for two years at the dose of 24 mg/kg/day, 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, which are approximately 6, 29, and 17 times the MRHD, respectively, based on mg/m2 body surface area.

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.

14 Clinical Studies

The efficacy of Citalopram as a treatment for major depressive disorder was established in two placebo-controlled studies (of 4 to 6 weeks duration) in adult outpatients (ages 18-66) meeting DSM-III or DSM-III-R criteria for major depressive disorder (MDD) (Studies 1 and 2).

Study 1, a 6-week trial in which patients received fixed Citalopram doses of 10 mg, 20 mg, 40 mg, and 60 mg daily, showed that Citalopram 40 daily and 60 mg daily (1.5 times the maximum recommended daily dosage) was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the primary efficacy endpoint. The HAMD-17 is a 17-item, clinician-rated scale used to assess severity of depressive symptoms. Scores on the HAMD-17 range from 0 to 52, with higher scores indicating more severe depression. This study showed no clear effect of the 10 mg and 20 mg daily doses, and the 60 mg daily dose was not more effective than the 40 mg daily dose. Due to the risk of QTc prolongation and ventricular arrhythmias, the maximum recommended dosage of Citalopram is 40 mg once daily.

In study 2, a 4-week, placebo-controlled trial in patients with MDD, the initial dose was 20 mg daily, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg daily (2 times the maximum recommended daily dosage).

Patients treated with Citalopram showed statistically significantly greater improvement than placebo patients on the HAMD total score, the primary efficacy endpoint. In three additional placebo-controlled trials in patients with MDD, the difference in response to treatment between patients receiving Citalopram and patients receiving placebo was not statistically significant.

In two long-term studies, patients with MDD who had responded to Citalopram during an initial 6 or 8 weeks of acute treatment were randomized to continuation of Citalopram or placebo. In one study, patients received fixed doses of Citalopram 20 mg or 40 mg daily and in the second study, patients received flexible doses of Citalopram 20 mg daily to 60 mg daily (1.5 times the maximum recommended daily dosage). In both studies, patients receiving continued Citalopram treatment experienced statistically significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 mg or 40 mg daily of Citalopram. Due to the risk of QTc prolongation and ventricular arrhythmias, the maximum recommended dosage of Citalopram is 40 mg once daily.

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

16 How Supplied/Storage And Handling

Citalopram Tablets, USP

40 mg. They are supplied in Bottle of 30 NDC # 51655-209-52 and Bottle of 90 NDC # 51655-209-26

White, film coated, round, bi-convex tablets debossed with I on the left side of bisect and G on right side of bisect on one side and “208” on the other.

Store at 20°C to 25° C (68° F to 77° F) [see USP Controlled Room Temperature]

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling ( Medication Guide).

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning, Warnings and Precautions ( 5.1)] .

QT Prolongation and Torsade de Pointes

Advise patients to consult their health care provider immediately if they feel faint, lose consciousness, or have heart palpitations. Instruct patients to inform their health care provider that they are taking Citalopram before taking any new medications [see Warnings and Precautions ( 5.2), Drug Interactions ( 7)] .

Serotonin Syndrome

Caution patients about the the risk of serotonin syndrome, particularly with the concomitant use of Citalopram with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, 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). Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions ( 5.3), Drug Interactions ( 7)] .

Increased Risk of Bleeding

Inform patients about the concomitant use of Citalopram with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the counter medications that increase the risk of bleeding [see Warnings and Precautions ( 5.4)] .

Activation of Mania or Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions ( 5.5)] .

Discontinuation SyndromeAdvise patients not to abruptly discontinue Citalopram and to discuss any tapering regimen with their healthcare provider. Inform patients that adverse reactions can occur when Citalopram is discontinued [see Warnings and Precautions( 5.6)] .

Sexual Dysfunction

Advise patients that use of Citalopram may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions ( 5.10)] .

Pregnancy

• Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Citalopram [see Use in Specific Populations ( 8.1)] .
• Advise patients that Citalopram use late in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN) [see Use in Specific Populations ( 8.1)] .
• Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to citalopram during pregnancy [see Use in Specific Populations ( 8.1)] .

Lactation

Advise breastfeeding women to monitor infants for excess sedation, restlessness, agitation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2)] .

Package Label.Principal Display Panel

NDC: 51655-209-52

Label - 51655 209 52