DIRA 1.0: Atlas of Drug-induced Rhabdomyolysis

CITALOPRAM HYDROBROMIDE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Moderate-DIR concern

Severity Score:2

Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF

WARNINGS
QT- ProlongationandTorsadedePointes
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 postmarketing reports for citalopram.
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 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 C max for the dose of 40 mg is 12.6 (14.3) msec.
Because of the risk of QTc prolongation at higher citalopram doses, it is recommended that citalopram should not be given at doses above 40 mg/day.
It is recommended that citalopram should not be used in patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. Citalopram should also not be used in patients who are taking other drugs that prolong the QTc interval. 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/day in patients who are CYP2C19 poor metabolizers or those patients who may be taking concomitant cimetidine or another CYP2C19 inhibitor, since higher citalopram exposures would be expected. The maximum dose should also be limited to 20 mg/day in patients with hepatic impairment and in patients who are greater than 60 years of age because of expected higher exposures.
Electrolyte and/or ECG monitoring is recommended in certain circumstances. Patients being considered for citalopram treatment 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 (see above), but, nevertheless, considered essential. These include those patients with the cardiac conditions noted above, and those taking other drugs that may prolong the QTc interval.
Citalopram should be discontinued 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.
PRECAUTIONS
General
Use in Patients with Concomitant Illness
Clinical experience with citalopram in patients with certain concomitant systemic illnesses is limited. Due to the risk of QT prolongation, citalopram use should be avoided in patients with certain cardiac conditions, and ECG monitoring is advised if citalopram must be used in such patients. Electrolytes should be monitored in treating patients with diseases or conditions that cause hypokalemia or hypomagnesemia. (see WARNINGS).
[Drug Interactions]
Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant cimetidine because of the risk of QT prolongation (see WARNINGS and DOSAGE AND ADMINISTRATION)
Pimozide - In a controlled study, a single dose of pimozide 2 mg co-administered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or C max of pimozide. The mechanism of this pharmacodynamic interaction is not known.
CYP2C19 Inhibitors – Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant CYP2C19 inhibitors because of the risk of QT prolongation (see WARNINGS, DOSAGE AND ADMINISTRATION, and CLINICAL PHARMACOLOGY).
OVERDOSAGE
Human Experience
Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose.
DOSAGE AND ADMINISTRATION
Initial Treatment
Citalopram tablets (citalopram) should be administered at an initial dose of 20 mg once daily, with an increase to a maximum dose of 40 mg/day at an interval of no less than one week. Doses above 40 mg/day are not recommended due to the risk of QT prolongation. Additionally, the only study pertinent to dose response for effectiveness did not demonstrate an advantage for the 60 mg/day dose over the 40 mg/day dose.
ADVERSE REACTIONS
ECG Changes
In a thorough QT study, citalopram was found to be associated with a dose-dependent increase in the QTc interval (see WARNINGS - QT-Prolongation and Torsade de Pointes).
Electrocardiograms from citalopram (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 citalopram 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 citalopram group. The incidence of tachycardic outliers was 0.5% in the citalopram group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the citalopram group and 0.4% in the placebo group.
Other Events Observed During the Postmarketing Evaluation of Citalopram
It is estimated that over 30 million patients have been treated with citalopram since market introduction. Although no causal relationship to citalopram treatment has been found, the following adverse events have been reported to be temporally associated with citalopram treatment, and have not been described elsewhere in labeling: acute renal failure, akathisia, allergic reaction, anaphylaxis, angioedema, choreoathetosis, chest pain, delirium, dyskinesia, ecchymosis, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, angle closure glaucoma, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsades de pointes, and withdrawal syndrome.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Population Subgroups
Age - Citalopram pharmacokinetics in subjects 60 years of age were compared to younger subjects in two normal volunteer studies. In a single-dose study, citalopram AUC and half-life were increased in the subjects 60 years old by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age (see WARNINGSand DOSAGE AND ADMINISTRATION), due to the risk of QT prolongation.
Gender - In three pharmacokinetic studies (total N=32), citalopram AUC in women was one and a half to two times that in men. This difference was not observed in five other pharmacokinetic studies (total N=114). In clinical studies, no differences in steady state serum citalopram levels were seen between men (N=237) and women (N=388). There were no gender differences in the pharmacokinetics of DCT and DDCT. No adjustment of dosage on the basis of gender is recommended.
Reduced hepatic function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 20 mg/day is the maximum recommended dose for hepatically impaired patients (see WARNINGS and DOSAGE AND ADMINISTRATION), due to the risk of QT prolongation.
CYP2C19 poor metabolizers – In CYP2C19 poor metabolizers, citalopram steady state C max and AUC was increased by 68% and 107%, respectively. Citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation (see WARNINGS and DOSAGE AND ADMINISTRATION).
[Drug-Drug Interactions]
CYP3A4 and CYP 2C19 inhibitors: Since CYP3A4 and CYP 2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of citalopram. However, coadministration of citalopram and the potent CYP3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. Citalopram 20 mg/day is the maximum recommended dose in patients taking concomitant cimetidine or another CYP2C19 inhibitor, because of the risk of QT prolongation (see WARNINGS and DOSAGE AND ADMINISTRATION).
MEDICATION GUIDE
Changes in the electrical activity of your heart (QT prolongation and Torsade de Pointes).
This condition can be life threatening.
The symptoms may include:
Chest pain
fast or slow heartbeat
shortness of breath
dizziness or fainting
have a heart problem including congenital long QT syndrome
Do not take citalopram tablets with Orap® (pimozide) because taking these two drugs together can cause serious heart problems.
take the antipsychotic medicine pimozide because this can cause serious heart problems.
have a heart problem including congenital long QT syndrome
ANIMAL TOXICOLOGY
Cardiovascular Changes in Dogs
In a one-year toxicology study, 5 of 10 beagle dogs receiving oral doses of 8 mg/kg/day (4 times the maximum recommended daily human dose of 60 mg on a mg/m 2 basis) died suddenly between weeks 17 and 31 following initiation of treatment. Although appropriate data from that study are not available to directly compare plasma levels of citalopram (CT) and its metabolites, demethylcitalopram (DCT) and didemethylcitalopram (DDCT), to levels that have been achieved in humans, pharmacokinetic data indicate that the relative dog-to-human exposure was greater for the metabolites than for citalopram. Sudden deaths were not observed in rats at doses up to 120 mg/kg/day, which produced plasma levels of CT, DCT, and DDCT similar to those observed in dogs at doses of 8 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs. This effect occurred in dogs at doses producing peak DDCT plasma levels of 810 to 3,250 nM (39 to 155 times the mean steady state DDCT plasma level measured at the maximum recommended human daily dose of 60 mg). In dogs, peak DDCT plasma concentrations are approximately equal to peak CT plasma concentrations, whereas in humans, steady state DDCT plasma concentrations are less than 10% of steady state CT plasma concentrations. Assays of DDCT plasma concentrations in 2,020 citalopram-treated individuals demonstrated that DDCT levels rarely exceeded 70 nM; the highest measured level of DDCT in human overdose was 138 nM. While DDCT is ordinarily present in humans at lower levels than in dogs, it is unknown whether there are individuals who may achieve higher DDCT levels. The possibility that DCT, a principal metabolite in humans, may prolong the QT interval in dogs has not been directly examined because DCT is rapidly converted to DDCT in that species.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

Rhabdomyolysis

124

42788

Other ADRs

23289

14093990

Odds Ratio = 1.754

Drug Property Information

ATC Code(s):

N06AB04 - citalopram hydrobromide

N06AB - Selective serotonin reuptake inhibitors
N06A - ANTIDEPRESSANTS
N06 - PSYCHOANALEPTICS
N - NERVOUS SYSTEM

Active Ingredient:citalopram hydrobromide

Active Ingredient UNII:I1E9D14F36

Drugbank ID:DB00215

PubChem Compound:2771

CAS Number:59729-33-8

Dosage Form(s):tablet

Route(s) Of Administrator:oral

Daily Dose:

20.0 mg/day N06AB04

Chemical Structure:

SMILE Code:
CN(C)CCCC1(C2=C(CO1)C=C(C=C2)C#N)C3=CC=C(C=C3)F

Reference

COHORT STUDY:

N/A

OTHER REFERENCE(S):

1: Adult respiratory distress syndrome and renal failure associated with citalopram overdose.

[Kelly C A,Upex A,Spencer E P,Flanagan R J,Bateman D N]
Hum Exp Toxicol.2003 Feb;22(2):103-5. PMID: 12693836

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