Citing increased risk of cardiac arrhythmias and a lack of therapeutic benefit associated with high doses of the selective serotonin reuptake inhibitor (SSRI) citalopram hydrobromide (Celexa), the FDA has reduced the recommended maximum to 40 mg/day.
Previously, the agency had approved a 60-mg/day dose of the antidepressant for certain patients.
The new dosing instruction was prompted by postmarketing surveillance reports and a prospective trial linking the 60-mg dose to unacceptable QT interval prolongations and Torsade de Pointes.
The trial -- a randomized, placebo-controlled, crossover study in 119 adults -- examined citalopram's effects on QT intervals at doses of 20 mg and 60 mg, the FDA said.
Relative to the placebo phase, the 20-mg dose produced mean QT prolongation of 8.5 msec (90% CI 6.2 to 10.8). At 60 mg, QT intervals were extended by an average of 18.5 msec (90% CI 16.0 to 21.0).
By interpolating these results, the FDA estimated that a 40-mg dose would prolong QT intervals by an average of 12.6 msec (90% CI 10.9 to 14.3), which it deemed marginally acceptable.
"As a result of this thorough QT study, FDA has determined that citalopram causes dose-dependent QT interval prolongation and should no longer be used at doses above 40 mg per day," the agency said in a drug safety communication.
Congestive heart failure, bradyarrhythmias, and predispositions to potassium or magnesium deficiencies are risk factors for Torsade de Pointes, the FDA noted.
Consequently, the agency recommended that patients with these conditions should undergo regular electrocardiography if given citalopram, and hypokalemia and hypomagnesemia should be corrected before starting patients on the drug.
Patients currently taking citalopram at doses higher than 40 mg/day should not stop the drug abruptly, but should talk to their doctors about lowering the dose, and should seek treatment immediately for irregular heartbeats, shortness of breath, fainting, or dizziness.
Package inserts for citalopram, which is also available in generic forms, will be rewritten to include the new information, the agency said.
The FDA did not indicate that the cardiac effects were an issue with escitalopram (Lexapro), which is the S-enantiomer of citalopram -- suggesting that the arrhythmias stem from the latter's R-enantiomer.