Citalopram Hydrobromide: Package Insert and Label Information (Page 3 of 5)

6.2 Postmarketing 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.

Table 5: Clinically Important Drug Interactions with Citalopram

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact

Concomitant use of SSRIs, including citalopram, and MAOIs increases the risk of serotonin syndrome.

Intervention

Citalopram 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 citalopram 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 citalopram alone [see Clinical Pharmacology ( 12.2 )].

Intervention:

Citalopram 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 citalopram with drugs that prolong QT can cause additional QT prolongation compared to the use of citalopram alone [see Clinical Pharmacology ( 12.2 )].

Intervention:

Avoid concomitant use of citalopram with drugs that prolong the QT interval (citalopram is contraindicated in patients taking pimozide) [see Contraindications ( 4 ) , Warnings and Precautions ( 5.2 )].

CYP2C19 Inhibitors

Clinical Impact:

Concomitant use of citalopram with CYP2C19 inhibitors increases the risk of QT prolongation and/or ventricular arrhythmias compared to the use of citalopram alone [see Clinical Pharmacology ( 12.2 )].

Intervention:

The maximum recommended dosage of citalopram is 20 mg daily when used concomitantly with a CYP2C19 inhibitor [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.2)].

Serotonergic Drugs

Clinical Impact:

Concomitant use of citalopram and other serotonergic drugs increases the risk of serotonin syndrome.

Intervention:

Monitor patients for signs and symptoms of serotonin syndrome, particularly during citalopram initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of citalopram 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 citalopram 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 citalopram and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warning and Precautions ( 5.4 )].

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/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.

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 4,422 patients in clinical studies of citalopram, 1,357 were 60 and over, 1,034 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 ≥ 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.

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