pms-Citalopram Adverse Reactions

Adverse Drug Reaction Overview: During the premarketing clinical development, 3652 patients received citalopram hydrobromide for the treatment of depression. Of these patients, 66% were females and 34% were males. The mean age of the patients was 50 years, with 70% being <60 years old (30% <40 years old, 40% 40 to 59 years old) and 30% being ≥60 years old. Adverse events observed with citalopram hydrobromide are in general mild and transient. They usually attenuate during the first one or two weeks of treatment.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Adverse Findings Observed in Short-term, Placebo-controlled Trials: Adverse Reactions Leading to Discontinuation of Treatment: From the short-term (4 to 6 weeks) placebo-controlled, Phase III clinical trials, 15.9% (163/1027) of the citalopram hydrobromide treated patients discontinued treatment due to an adverse event. The discontinuation rate in the placebo-treated patients was 7.7% (33/426).
The events associated with discontinuation of citalopram hydrobromide in 1% or more of patients at a rate of at least twice that of placebo, were as follows: nausea (4.1% vs. 0.0%), insomnia (2.4% vs. 1.2%), somnolence (2.4% vs. 1.2%), dizziness (2.3% vs. 0.7%), vomiting (1.3% vs. 0.0%), agitation (1.2% vs. 0.0%), asthenia (1.1% vs. 0.5%), and dry mouth (1.1% vs. 0.2%).
Incidence of Adverse Events in Placebo-controlled Studies: Table 6 enumerates the incidence of treatment emergent adverse events that occurred in 1027 depressed patients who received citalopram hydrobromide at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration. Events included are those occurring in 2% or more of patients treated with citalopram hydrobromide, and for which the incidence in patients treated with citalopram hydrobromide was greater than the incidence in placebo-treated patients. Reported adverse events were classified using the standard World Health Organization (WHO)-based dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. (See Table 6.)

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The following events had a higher incidence in the placebo group compared to the citalopram group: asthenia, back pain, headache, dizziness, constipation, palpitation, insomnia, abnormal vision.
Most Frequent Adverse Events: Adverse events that occurred in citalopram hydrobromide treated patients in the course of the short-term, placebo-controlled trials with an incidence greater than, or equal to, 10% were: nausea, dry mouth, somnolence, and increased sweating (Table 6).
Dose Dependency of Adverse Events: The potential relationship between the dose of citalopram hydrobromide and the incidence of an adverse event was examined in a fixed dose short-term, placebo-controlled study in which patients received citalopram hydrobromide at doses of 10, 20, 40 or 60 mg per day. The incidence of diarrhea, dry mouth, fatigue, insomnia, increased sweating, nausea and somnolence was dose-related.
Male and Female Sexual Dysfunction with SSRIs: While sexual dysfunction is often part of depression and other psychiatric disorders, there is increasing evidence that treatment with SSRIs may induce sexual side effects. This is a difficult area to study because patients may not spontaneously report symptoms of this nature, and therefore, it is thought that sexual side effects with SSRIs may be underestimated.
In placebo-controlled, short-term clinical trials, the reported incidence of decreased libido, ejaculation disorders (primarily ejaculation delay and ejaculation failure), and impotence in male depressed patients receiving citalopram hydrobromide (N=404) was 3.7%, 6.2%, and 3.2%, respectively. In female depressed patients receiving citalopram hydrobromide (N=623), the reported incidence of decreased libido and anorgasmia was 1.3% and 1.1%, respectively. The reported incidence of each of these adverse events was ≤1% among male and female depressed patients receiving placebo.
Weight Changes: Patients treated with citalopram hydrobromide in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.
ECG: Retrospective analyses of electrocardiograms in citalopram hydrobromide treated (N=779 <60 years and N=313 ≥60 years) and placebo-treated (N=74 <60 years and N=43 ≥60 years) patients indicated that citalopram hydrobromide decreases heart rate. In patients <60 years old, the mean decrease was approximately 5 bpm, while in patients ≥60 years old, mean decreases ranged between 5 to 10 bpm. Following the initial drop, heart rate remained decreased but stable over prolonged periods of time (up to one year in over 100 younger and over 50 elderly patients). The effect was reversible within approximately a week after stopping treatment.
In the 6-week, fixed dose, dose-response study, the mean decreases in heart rate ranged between 2-6 bpm in the 20-60 mg/day dose range, but the effect did not seem to be dose-related and was independent of gender. In placebo-treated patients heart rates remained unaffected. The differences in heart rates between citalopram hydrobromide and placebo-treated patients were statistically significant. ECG parameters, including QT interval, remained unaffected.
Adverse Reactions following Discontinuation of Treatment (or Dose Reduction): There have been reports of adverse reactions upon the discontinuation of citalopram hydrobromide (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation or anxiety, emotional indifference, impaired concentration, headache, migraine, tremor, nausea and/or vomiting, sleep disturbances (including insomnia and intense dreams), confusion, diarrhoea, palpitations, irritability, visual disturbances and sweating or other symptoms which may be of clinical significance (see Recommended Dose and Dosage Adjustment: Discontinuation of pms-CITALOPRAM Treatment under Dosage & Administration and General: Discontinuation Symptoms under Precautions).
Patients should be monitored for these or any other symptoms. A gradual reduction in the dosage over a period of at least one to two weeks, rather than abrupt cessation is recommended to reduce the risk of withdrawal reactions. Generally these events are mild to moderate and are self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when citalopram treatment is no longer required, gradual discontinuation by dose tapering should be carried out. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. Symptoms associated with discontinuation have been reported for other selective serotonin reuptake inhibitors (see Recommended Dose and Dosage Adjustment: Discontinuation of pms-CITALOPRAM Treatment under Dosage & Administration and General: Discontinuation Symptoms under Precautions).
Additional Adverse Events Observed During the Premarketing Evaluation of Citalopram Hydrobromide: The events listed as follows include all adverse events that were reported in the overall development program of citalopram hydrobromide (N=3652). All reported events are included except those already listed in Table 6 and those events which occurred in only one patient. It is important to emphasize that, although the events reported occurred during treatment with citalopram hydrobromide, they were not necessarily caused by it. The events are enumerated using the following criteria: Frequent: adverse events that occurred on one or more occasions in at least 1/100 patients.
Infrequent: adverse events that occurred in less than 1/100 patients but at least in 1/1000 patients.
Rare: adverse events that occurred in fewer than 1/1000 patients.
Body as a Whole - General Disorders: Frequent: influenza-like symptoms, non-pathological trauma, pain.
Infrequent: alcohol intolerance, allergic reaction, allergy, chest pain, edema, hot flushes, leg pain, malaise, rigors, syncope.
Rare: peripheral edema, sudden death, traumatic injury.
Cardiovascular Disorders: Frequent: postural hypotension, tachycardia.
Infrequent: angina pectoris, arrhythmia, bradycardia, cardiac failure, cerebrovascular disorders, edema dependent, extrasystoles, flushing, hypertension, hypotension, myocardial infarction, myocardial ischemia, peripheral ischemia.
Rare: aggravated hypertension, bundle branch block, cardiac arrest, coronary artery disorder, ECG abnormal, heart disorder, phlebitis, supraventricular extrasystoles.
Central and Peripheral Nervous System Disorders: Frequent: migraine, paraesthesia.
Infrequent: abnormal gait, ataxia, convulsions, dysphonia, dystonia, extrapyramidal disorder, hyperkinesia, hypertonia, hypoesthesia, hypokinesia, involuntary muscle contractions, leg cramps, neuralgia, speech disorder, vertigo.
Rare: abnormal coordination, convulsions grand mal, hyperesthesia, ptosis, sensory disturbance, stupor.
Collagen Disorders: Rare: rheumatoid arthritis.
Endocrine Disorders: Rare: goiter, gynecomastia, hypothyroidism.
Gastrointestinal System Disorders: Frequent: flatulence.
Infrequent: colitis, dental abscess, dysphagia, eructation, gastritis, gastroenteritis, gastrointestinal disorder (not specified), hemorrhoids, increased saliva, teeth-grinding, toothache.
Rare: appendicitis, esophagitis, gastric ulcer, gastroesophageal reflux, gingivitis, stomatitis, tooth disorder, ulcerative stomatitis.
Hematopoietic and Lymphatic Disorders: Infrequent: anemia, epistaxis, leukocytosis, purpura.
Rare: coagulation disorder, gingival bleeding, granulocytopenia, hematoma, leukopenia, lymphadenopathy, lymphocytosis, pulmonary embolism.
Liver and Biliary System Disorders: Infrequent: cholecystitis, cholelithiasis, increased gamma-GT, increased ALT.
Rare: bilirubinemia, increased AST, jaundice.
Metabolic and Nutritional Disorders: Frequent: appetite decreased, weight decrease, weight increase.
Infrequent: leg edema, xerophthalmia.
Rare: dehydration, edema, hypoglycemia, hypokalemia, increased alkaline phosphatase, obesity, thirst.
Musculo-Skeletal System Disorders: Infrequent: arthralgia, arthritis, arthrosis, dystonia, muscle weakness, myalgia.
Rare: bone disorder, bursitis, osteoporosis, tendon disorder.
Neoplasm: Rare: breast neoplasm malignant female.
Psychiatric Disorders: Frequent: abnormal dreaming, aggravated depression, amnesia, apathy, confusion, depression, impaired concentration, increased appetite, sleep disorder, suicide attempt.
Infrequent: abnormal thinking, aggressive reaction, delusion, depersonalization, drug abuse, drug dependence, emotional lability, euphoria, hallucination, increased libido, manic reaction, neurosis, paranoid reaction, paroniria, psychosis, psychotic depression.
Rare: catatonic reaction, hysteria, personality disorder.
Reproductive Disorders, Female: Frequent: Abnormal orgasm.
Infrequent: amenorrhea, breast pain, lactation nonpuerperal, menorrhagia, menstrual disorder, premenstrual syndrome, salpingitis, unintended pregnancy, vaginal dryness, vaginitis.
Rare: breast enlargement, vaginal hemorrhage.
Reproductive Disorders, Male: Infrequent: penis disorder, prostatic disorder, testis disorder.
Resistance Mechanism Disorders: Infrequent: abscess, fungal infection, herpes simplex infection, otitis media, viral infection.
Rare: bacterial infection, moniliasis, sepsis.
Respiratory System Disorders: Infrequent: bronchitis, coughing, dyspnea, pneumonia.
Rare: asthma, bronchospasm, increased sputum, laryngitis, pneumonitis, respiratory disorder.
Skin and Appendage Disorders: Frequent: pruritus, rash.
Infrequent: acne, alopecia, dermatitis, dry skin, eczema, photosensitivity reaction, psoriasis, rash erythematous, rash maculo-papular, skin discoloration, urticaria.
Rare: cellulitis, decreased sweating, hypertrichosis, melanosis, pruritus ani.
Special Senses, Vision, Hearing and Vestibular Disorders: Frequent: abnormal accommodation.
Infrequent: conjunctivitis, earache, eye pain, mydriasis, taste perversion, tinnitus.
Rare: eye abnormality, keratitis, photophobia.
Urinary System Disorders: Frequent: polyuria.
Infrequent: abnormal urine, cystitis, hematuria, micturition frequency, urinary incontinence, urinary retention, urinary tract infection.
Rare: dysuria, facial edema, oliguria, renal calculus, renal pain.
Post-Market Adverse Drug Reactions: During the 22 year of post marketing experience, it is estimated that more than 138 million patients have been treated with citalopram, which corresponds to more than 34 million patient-years of treatment.
The following adverse events have been identified during post-approval use of citalopram. These events are reported voluntarily from a population of uncertain size, and it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. (See Table 7.)

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