Citalopram Hydrobromide (Page 5 of 9)

Carcinogenesis, Mutagenesis, Impairment of Fertility


Citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which is equivalent to 20 times the maximum recommended human daily dose (MRHD) of 60 mg on a surface area (mg/m ) basis. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day, doses which are approximately 1.3 and 4 times the MRHD, respectively, on a mg/m basis. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown. 2 2


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

Impairment of Fertility

When citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48 and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses ≥ 32 mg/kg/day, approximately 5 times the MRHD of 60 mg/day on a body surface area (mg/m ) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8 times the MRHD. 2


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/m ) 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/m 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/m basis. Thus, teratogenic effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit. 2 2 2

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/m basis. The no-effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m 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/m basis. A no effect dose was not determined in that study. 2 2 2

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.

Pregnancy- Nonteratogenic Effects

Neonates exposed to Citalopram Hydrobromide 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:Serotonin Syndrome

Infants exposed to SSRIs in pregnancy 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. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including Citalopram Hydrobromide tablet) in pregnancy and PPHN. Other studies do not show a significant statistical association.

Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.

When treating a pregnant woman with Citalopram Hydrobromide tablet, the physician should carefully consider both the potential risks of taking an SSRl, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see ). DOSAGE AND ADMINISTRATION

Labor and Delivery

The effect of Citalopram HBr tablets on labor and delivery in humans is unknown.

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 tablets therapy should take into account the risks of citalopram exposure for the infant and the benefits of Citalopram HBr tablets treatment for the mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see and ). Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with Citalopram, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Citalopram in a child or adolescent must balance the potential risks with the clinical need. BOXED WARNINGWARNINGS—Clinical Worsening and Suicide Risk

Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with Citalopram.

Geriatric Use

Of 4422 patients in clinical studies of Citalopram HBr tablets, 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 tablets in clinical trials received daily doses between 20 and 40 mg (see ). DOSAGE AND ADMINISTRATION

SSRIs and SNRIs, including Celexa, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see , ). PRECAUTIONSHyponatremia

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

20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age (see ). and WARNINGSDOSAGE AND ADMINISTRATION

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