Pr
phl-CITALOPRAM
(Citalopram Hydrobromide Tablets) 10 mg, 20 mg and 40 mg Citalopram, as Citalopram Hydrobromide
6111 Royalmount Ave., Suite 100 November 18, 2005 Montreal, Quebec H4P 2T4
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 14 DOSAGE AND ADMINISTRATION 16 OVERDOSAGE 17 ACTION AND CLINICAL PHARMACOLOGY 18 STORAGE AND STABILITY 20 DOSAGE FORMS, COMPOSITION AND PACKAGING 20
PHARMACEUTICAL INFORMATION 21 DETAILED PHARMACOLOGY 24 TOXICOLOGY 27 REFERENCES 30
Pr
phl-CITALOPRAM
(Citalopram Hydrobromide Tablets) 10 mg, 20 mg and 40 mg Citalopram, as Citalopram Hydrobromide Antidepressant
| Route of Administration | Dosage Form/ Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | tablet 10, 20 and 40 mg | None. For a complete listing see Dosage Forms, Composition and Packaging section. |
phl-CITALOPRAM (citalopram hydrobromide) is indicated for the symptomatic relief of depressive illness. The relapse rate was significantly lower in citalopram-treated patients than in placebo-treated patients in two placebo-controlled studies, that were conducted over a 24-week period in patients who responded to 6 or 8 weeks of acute treatment with citalopram (see Clinical Trials under ACTION AND CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use citalopram for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
Geriatrics (> 65 years of age):
Lower doses and lower maximum doses are recommended for elderly patients (see Warnings and Precautions).
Pediatrics (0 to 18 years of age):
No data is available.
Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. Patients should not take citalopram in combination with a monoamine oxidase inhibitor (MAOI) or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should elapse after discontinuing citalopram treatment before starting a MAOI (see DRUG-DRUG INTERACTIONS). Citalopram should not be used in combination with the anti-psychotic drug pimozide, as results from a controlled study with racemic citalopram indicate that concomitant use is associated with an increased risk of Qtc prolongation compared to pimozide alone. This apparent pharmacodynamic interaction occurred in the absence of a clinically significant pharmacokinetic interaction; the mechanism is unknown (see PRECAUTIONS, Drug Interactions).
Pediatrics: Placebo-Controlled Clinical Trial Data
Adults and Pediatrics: Additional data
Discontinuation Symptoms
Cardiovascular
Citalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical trials during the drug's premarketing assessment. However, the electrocardiograms of patients, who received citalopram in clinical trials, indicate that citalopram was not associated with the development of clinically significant ECG abnormalities. In clinical trials, citalopram caused small but statistically significant decreases in heart rate (see ECG under ADVERSE REACTIONS). Consequently, caution should be observed when citalopram is initiated in patients with pre-existing slow heart rate.
Dependence/Tolerance
When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation (e.g. dizziness, abnormal dreams, sensory disturbances [including paresthesias and electric shock sensations], agitation, anxiety, emotional indifference, impaired concentration, headache, migraine, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance. (See ADVERSE REACTIONS). A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. 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. (See ADVERSE REACTIONS and DOSAGE and ADMINISTRATION).
Endocrine and Metabolism
Citalopram has not been systematically evaluated in diabetic patients since diabetes constituted an exclusion criterion. Although 13 patients did receive insulin during the studies, this number is too small to determine whether citalopram affects the response to insulin. Rare events of hypoglycemia were reported. Citalopram should be used with caution in diabetic patients on insulin or other antidiabetic drugs.
Hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported as a rare adverse event with use of citalopram as with other SSRIs. Elderly female patients in particular seem to be a group at risk.
Hematologic
There have been reports of cutaneous bleeding abnormalities such as ecchymosis and purpura with SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g., atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, and non-steroidal anti-inflammatory drugs (NSAIDS)) as well as in patients with a history of bleeding disorders.
Hepatic/biliary/Pancreatic
In subjects with hepatic impairment, citalopram clearance was significantly decreased and plasma concentrations, as well as elimination half-life significantly increased (see PHARMACOKINETICS). Consequently, the use of citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see DOSAGE AND ADMINISTRATION).
Neurologic
In studies in normal volunteers, citalopram in doses of 40 mg/day did not impair cognitive function or psychomotor performance. However, psychotropic medications may impair judgement, thinking or motor skills. Consequently, patients should be cautioned against driving a car or operating hazardous machinery until they are reasonably certain that citalopram does not affect them adversely.
The safety and efficacy of the concurrent use of citalopram and ECT have not been studied.
Rarely, the occurrence of serotonin syndrome has been reported in patients receiving SSRIs. A combination of symptoms, possibly including agitation, confusion, tremor, myoclonus and hyperthermia, may indicate the development of this condition.
Citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the premarketing testing of citalopram. In clinical trials, seizures occurred in 0.25% of patients treated with citalopram and in 0.23% patients treated with placebo. Like other antidepressants, citalopram should be used with caution in patients with a history of seizure disorder. The drug should be discontinued in any patient who develops seizures.
Psychiatric
In placebo-controlled trials with citalopram, some of which included patients with bipolar disorder, mania/hypomania was reported in 0.1% of 1027 patients treated with citalopram versus none of the 426 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed antidepressants. If a patient enters a manic phase, citalopram should be discontinued.
The possibility of a suicide attempt is inherent in depression and may persist until remission occurs. Therefore, high risk patients should be closely supervised throughout therapy with citalopram and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescription for citalopram should be written for the smallest quantity of drug consistent with good patient management (see WARNINGS AND PRECAUTIONS: POTENTIAL ASSOCIATION WITH BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).
Renal
No dosage adjustment is needed in patients with mild to moderate renal impairment. Since, no information is available on the pharmacokinetic or pharmacodynamic effects of citalopram in patients with severely reduced renal function (creatinine clearance <20 mL/min), citalopram should be used with caution in these patients.
Special Population
The safety of citalopram during pregnancy and has not been established. Therefore, citalopram should not be used during pregnancy, unless, in the opinion of the physician, the expected benefits to the patient markedly outweigh the possible hazards to the fetus. Post-marketing reports indicate that some neonates exposed to SSRIs such as CITALOPRAM and other newer antidepressants 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, hyperreflexia, tremor jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants, 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, Neurologic, Serotonin Syndrome). When treating a pregnant woman with CITALOPRAM during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. (See DOSAGE AND ADMINISTRATION).
The safety of citalopram during lactation has not been established. Citalopram is excreted in human milk.Therefore, citalopram should not be administered to nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the child.
Safety and effectiveness in children under 18 years of age have not been established.
In premarketing clinical trials, 800 elderly patients ($65 years of age) have been treated with citalopram. Of these patients 298 were $75 years old. In a pharmacokinetic study (N=11, age 73 to 90 years), clearance was substantially decreased and half-life prolonged (see PHARMACOKINETICS). In a 6-week placebo-controlled study, approximately equal numbers of patients received citalopram at 20 or 30 mg per day, as the final dose. In about 5% of patients, the final dose was 10 mg per day (see CLINICAL TRIALS under ACTION AND CLINICAL PHARMACOLOGY ). Consequently, elderly patients should be administered lower doses and a lower maximum dose (see DOSAGE AND ADMINISTRATION).
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 are in general mild and transient. They usually attenuate during the first one or two weeks of treatment.
Most Frequent Adverse Events
Adverse events that occurred in citalopram -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 1).
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 Associated with Discontinuation of Treatment
From the short-term (4 to 6 weeks) placebo-controlled, Phase III clinical trials, 15.9% (163/1027) of the citalopram -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 in 1% or more of patients at a rate of at least twice that of placebo, were as follows: Nausea (4.1% versus 0.0%), insomnia (2.4% versus 1.2%), somnolence (2.4% versus 1.2%), dizziness (2.3%
versus 0.7%), vomiting (1.3% versus 0.0%), agitation (1.2% versus 0.0%), asthenia (1.1% versus 0.5%), and dry mouth (1.1% versus 0.2%).
Incidence of Adverse Events in Placebo-controlled Studies
Table 1 enumerates the incidence of treatment emergent adverse events that occurred in 1027 depressed patients who received citalopram 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, and for which the incidence in patients treated with citalopram 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. TABLE 1 Common Side Effects (>1%)
TREATMENT-EMERGENT ADVERSE EVENTS * INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS
| Body System/Adverse Event | Percentage of Patients Reporting | |
| Citalopram (N = 1027) | Placebo (N = 426) | |
| Autonomic Nervous System | 19.4 | 12.2 |
| Dry mouth 1 | ||
| Sweating increased | 10.5 | 8.0 |
| Body as a Whole | 5.2 | 3.1 |
| Fatigue | ||
| Fever 1 | 2.4 | 0.2 |
| Central and Peripheral Nervous System Tremor | 8,4 | 6,3 |
| Gastrointestinal System | 20.6 | 13.4 |
| Nausea 1 | ||
| Diarrhea | 8.1 | 5.4 |
| Dyspepsia | 4.3 | 3.5 |
| Vomiting | 3.9 | 2.6 |
| Abdominal pain | 3.1 | 2.1 |
| Psychiatric | 17.3 | 9.9 |
| Somnolence 1 | ||
| Anorexia 1 | 4.2 | 1.6 |
| Nervousness | 3.6 | 3.5 |
| Anxiety | 3.3 | 2.1 |
| Agitation 1 | 2.4 | 0.7 |
| Libido decreased 1 | 2.2 | 0.2 |
| Yawning 1 | 2.1 | 0 |
| Reproductive, Female 2 Dysmenorrhea (<50 years) | 2,7 | 1,6 |
| Reproductive, Male 3 | 6.2 | 1.1 |
| Ejaculation disorder 1 | ||
| Impotence 3 | 3.2 | 0.6 |
| Respiratory System | 5.1 | 4.7 |
| Upper respir. tract infection | ||
| Rhinitis | 4.9 | 3.3 |
| Pharyngitis | 3.4 | 2.8 |
| Sinusitis 1 | 2.4 | 0.2 |
| Urinary System Micturition disorder | 2,3 | 2,1 |
| Body System/Adverse Event | Percentage of Patients Reporting | |
| Citalopram (N = 1027) | Placebo (N = 426) | |
| * Events included are those occurring in 2% or more of patients treated with citalopram, and for which the incidence in patients treated with citalopram was greater than the incidence in placebo-treated patients. 1 Statistically significantly higher incidence in the citalopram group (p <0.05). 2 Denominator used was for females only (N=623 for citalopram; N=245 for Placebo). 3 Denominator used was for males only (N=404 for citalopram; N=181 for Placebo). | ||
The following events had an incidence on placebo $ citalopram: asthenia, back pain, headache, dizziness, constipation, palpitation, insomnia, abnormal vision.
Dose Dependency of Adverse Events
The potential relationship between the dose of citalopram and the incidence of an adverse event was examined in a fixed dose short-term, placebo-controlled study in which patients received citalopram 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.
Cardiovascular
ECG
Retrospective analyses of electrocardiograms in citalopram -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 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- and placebo-treated patients were statistically significant. ECG parameters, including QT interval, remained unaffected.
Endocrine and Metabolism
Weight Changes
Patients treated with citalopram in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.
Sexual Function
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 selective serotonin reuptake inhibitors (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 (N=404) was 3.7%, 6.2%, and 3.2%, respectively. In female depressed patients receiving citalopram (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.
Adverse Reactions following Discontinuation of Treatment (or Dose Reduction)
There have been reports of adverse reactions upon the discontinuation of citalopram (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation, anxiety, emotional indifference, impaired concentration, headache, migraine, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance, (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Patients should be monitored for these or any other symptoms. A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. 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. These events are generally self-limiting. Symptoms associated with discontinuation have been reported for other selective serotonin re-uptake inhibitors. (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Frequent Clinical Trial Adverse Drug Reactions ($1%)
Body as a Whole - General Disorders:
Influenza-like symptoms, non-pathological trauma, pain.
Cardiovascular Disorders
: Postural hypotension, tachycardia.
Central and Peripheral Nervous System Disorders
: Migraine, paraesthesia.
Gastrointestinal System Disorders:
Flatulence.
Metabolic and Nutritional DisordersPsychiatric Disorders
: Appetite decreased, Weight decrease, weight increase.
: Abnormal dreaming, aggravated depression, amnesia, apathy, confusion, depression, impaired concentration, increased appetite, sleep disorder, suicide attempt.
Reproductive Disorders, Female
: Abnormal orgasm.
Skin and Appendage Disorders
: Pruritus, rash.
Special Senses, Vision, Hearing and Vestibular Disorders:
Abnormal accommodation.
Urinary System Disorders:
Polyuria
Less Common Clinical Trial Adverse Drug Reactions (<1%)
The events listed below include all adverse events that were reported in the overall development program of citalopram (N=3652). All reported events are included except those already listed in Table 1 and those events which occurred in only one patient. It is important to emphasize that, although the events reported occurred during treatment with citalopram, they were not necessarily caused by it. The events are enumerated using the following criteria: 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
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
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
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
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 SGPT. Rare:Bilirubinemia, increased SGOT, jaundice.
Metabolic and Nutritional Disorders
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
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
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
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
Infrequent:Conjunctivitis, earache, eye pain, mydriasis, taste perversion, tinnitus. Rare:Eye abnormality, keratitis, photophobia.
Urinary System Disorders
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 Reaction
Adverse events which have been reported to be temporally (but not necessarily) associated with citalopram treatment in at least 3 patients since its market introduction include: Abnormal hepatic function, acute renal failure, aggravated condition, aggravated migraine, akathisia, anaphylaxis, angioedema, asthma, choreoathetosis, convulsion NOS, decreased drug level, decreased prothrombin time, delirium, dyskinesia, ecchymosis, eosinophilia, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, gynecological problems, hemolytic anemia, hepatitis, hypersensitivity NOS, hyperprolactinemia, hypomania, hyponatremia, increased drug level, increased prothrombin time, menometrorrhagia, myoclonic jerks, neuroleptic malignant syndrome, neuropathy, nystagmus, pancreatitis, pancytopenia, purpura NOS, rhabdomyolysis, serotonin syndrome, SIADH, spontaneous abortion/fetal death, suicide ideation, thrombocytopenia, vasodilatation, ventricular arrhythmia, Torsades de pointes, withdrawal syndrome.
SERIOUS DRUG-DRUG INTERACTIONS
Drug-Drug Interactions
General
The studies described in this section were carried out in young, healthy, mostly male volunteers. In addition, some of the studies, namely interactions with metoprolol, warfarin, digoxin, imipramine, and levomepromazine, utilized only single doses of these drugs, although citalopram was given repeatedly to attain steady state. Thus, data are not available in patients who would be receiving these drugs on an ongoing basis at therapeutic doses.
Carbamazepine, titrated to 400 mg/day, was given for 21 days alone and then in combination with citalopram (40 mg/day) for an additional 14 days. Citalopram did not affect the plasma levels of either carbamazepine, a CYP3A4 substrate, or its metabolite, carbamazepine-epoxide. However, since carbamazepine is a microsomal enzyme inducer, the possibility that carbamazepine may increase the clearance of citalopram should be considered if the two drugs are given concomitantly.
Citalopram 40 mg/day was administered for 29 days. During the last 8 days of treatment, cimetidine (400 mg bid) was added to the treatment regimen. In the presence of cimetidine, a potent inhibitor of hepatic cytochrome P450 enzymes, the Cmax and AUC of citalopram was increased by 39% and 41%, respectively. Thus, caution should be exercised at the upper end of the dose range of citalopram when it is used concomitantly with high doses of cimetidine.
Using in vitro models of human liver microsomes, the biotransformation of citalopram to its demethyl metabolites was shown to depend on both CYP 2C19 and CYP 3A4, with a small contribution from CYP 2D6. Studies have also indicated that citalopram is a weak inhibitor of CYP 2D6 and CYP 2C19 and a weak or negligible inhibitor of CYP 3A4 and CYP 1A2. One in vitro study using human liver microsomes has shown that ketoconazole and omeprazole reduced the rate of formation of the demethylcitalopram metabolite of citalopram to 45-60% and 75-85% of control, respectively. As data are not available from clinical pharmacokinetic studies, the possibility that the clearance of citalopram will be decreased when citalopram is administered with a potent inhibitor of CYP 3A4 (e.g., ketoconazole, itraconazole, fluconazole or erythromycin), or a potent inhibitor of CYP 2C19 (e.g., omeprazole), should be considered.
Administration of citalopram (40 mg/day for 21 days) did not affect the pharmacokinetics of digoxin (single dose of 1 mg), although the serum levels of citalopram were slightly lower in the presence of digoxin.
Coadministration of citalopram (40 mg/day for 10 days) and the tricyclic antidepressant, imipramine (single dose of 100 mg), did not affect the pharmacokinetics of either drug. However, in the presence of citalopram, the concentration of desipramine, the metabolite of imipramine, increased by approximately 50% and its half- life was prolonged. The results indicate that citalopram does not interfere with the demethylation of imipramine to desipramine but does inhibit the metabolism of desipramine to its 2-hydroxy metabolite. Consequently, concomitant treatment with citalopram and imipramine/desipramine should be undertaken with caution.
Coadministration of citalopram (40 mg/day for 10 days) and levomepromazine (single dose of 50 mg), did not affect the pharmacokinetics of either drug.
Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days), did not affect the pharmacokinetics of either drug. However, since lithium may increase serotonergic neurotransmission, concomitant treatment with these two drugs should be undertaken with caution.
Coadministration of citalopram (40 mg/day for 22 days) and the $-adrenergic blocking agent metoprolol (single dose of 150 mg), resulted in a twofold increase in the plasma levels of metoprolol. However, the effect of metoprolol on blood pressure and heart rate was not affected.
In a double-blind crossover study in healthy young adults, a single dose of pimozide 2 mg coadministered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values at Tmax of approximately 12 msec compared to pimozide when given with placebo. The mechanism of this apparent pharmacodynamic interaction is not known
No pharmacodynamic interactions have been noted in clinical trials where citalopram has been given concomitantly with benzodiazepines (anxiolytics/hypnotics), analgesics (NSAIDs, non-NSAIDs), antihistamines, antihypertensives or other cardiovascular drugs. Pharmacokinetic interactions between citalopram and these drugs were not specifically studied.
There have been rare postmarketing reports describing patients with weakness, hyperreflexia and incoordination, following the concomitant use of a SSRI and the antimigraine drug sumatriptan, a 5-HT1 agonist. Such interaction should be considered if citalopram is to be used in combination with a 5-HT1 agonist.
Administration of citalopram (40 mg/day for 21 days), did not affect either the pharmacokinetics or the pharmacodynamics (prothrombin time) of a single, 25 mg dose of warfarin.
Drug-Lifestyle Interactions
Alcohol Although citalopram did not potentiate the cognitive and psychomotor effects of alcohol in volunteers, the concomitant use of alcohol and citalopram should be avoided.
Drug-Herb Interactions
St. John's Wort: In common with other SSRI's, pharmacodynamic interactions between citalopram and the herbal remedy St. John's Wort may occur and may result in undesirable effects.
Drug-Laboratory Test Interactions
There are no known interactions of citalopram with commonly used laboratory tests.
Dosing Considerations
Adult patients Elderly patients Hepatic impairment Renal impairment Maintenance treatment Switching patients to or from a monoamine oxidase inhibitor Discontinuation of phl-CITALOPRAM treatment Children
At least 14 days should elapse between discontinuation of a MAOI and initiation of therapy with phl- CITALOPRAM. Similarly, at least 14 days should be allowed after stopping phl-CITALOPRAM before starting a MAOI (see CONTRAINDICATIONS).
Recommended Dose and Dosage Adjustment
phl-CITALOPRAM (citalopram hydrobromide) should be administered once daily, in the morning or evening, with or without food.
Adults
phl-CITALOPRAM should be administered as a single oral dose of 20 mg/day. In patients who do not respond adequately, an increase of dosage to 40 mg/day should be considered. Certain patients may require 60 mg/day. However, in a dose-response study, the 60 mg/day dose did not demonstrate an advantage regarding effectiveness over the 40 mg/day dose. Dose increases should usually occur in increments of 20 mg, at intervals of no less than one week.
Post-marketing reports indicate that some neonates exposed to SSRIs such as CITALOPRAM and other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS AND PRECAUTIONS). When treating a pregnant woman with CITALOPRAM during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering CITALOPRAM in the third trimester.
Elderly Patients
A single oral dose of 20 mg/day is the recommended dose for most elderly patients. Some patients may respond to a 10 mg/day dose (see Clinical Trials under ACTION AND CLINICAL PHARMACOLOGY). The dose may be titrated to a maximum of 40 mg/day if needed and tolerated. As with other SSRIs, caution should be exercised in treating elderly female patients who may be more susceptible to adverse events such as hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion). (See PRECAUTIONS).
Hepatic Impairment
Patients with reduced hepatic function should receive dosages of no more than 30 mg/day.
Renal Impairment
No dosage adjustment is necessary for patients with mild to moderate renal impairment. Since there is no information available on the pharmacokinetic or pharmacodynamic effects of citalopram in patients with severe renal impairment, citalopram should be used with caution in these patients.
Maintenance Treatment
Evaluation of citalopram in two placebo-controlled studies has shown that its antidepressant efficacy was maintained for periods of up to 24 weeks, following 6 or 8 weeks of initial treatment (total of 32 weeks) (See Clinical Trials under ACTION AND CLINICAL PHARMACOLOGY). In the flexible dose study, the great majority of patients were receiving 20 or 40 mg/day doses both at 12 and 24 weeks. During maintenance therapy, the dosage should be kept at the lowest effective level and patients should be periodically reassessed to determine the need for continued treatment.
Discontinuation of phl-CITALOPRAM Treatment
Symptoms associated with the discontinuation or dosage reduction of phl-CITALOPRAM have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction (See PRECAUTIONS and ADVERSE REACTIONS). A gradual reduction in the dose over several weeks rather than abrupt cessation is recommended whenever possible. 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. (See PRECAUTIONS and ADVERSE REACTIONS).
Citalopram hydrobromide has a wide margin of safety in overdose. Cases of overdoses involved the ingestion of citalopram either alone or in combination with other drugs and/or alcohol. Cases of overdoses of citalopram ranging from 180 mg to 2000 mg have been reported during the premarketing clinical development. All patients recovered. One patient, ingesting over 1500 mg citalopram, had reversible ECG abnormalities, the most important of which was prolongation of QTc. Citalopram is given to patients at potential risk of suicide and reports of attempted suicide have been received after its market introduction. Post-marketing reports of drug overdoses involving citalopram have included fatalities with citalopram alone as well as non-fatal overdoses of up to 5200 mg. In many cases, details regarding the precise dose of citalopram or combination with other drugs and/or alcohol are often lacking. Although most patients recovered without sequelae, fatalities have been reported at doses of citalopram up to 3920 mg. Fatal cases of serotonin syndrome have been reported in patients who took overdoses of moclobemide (Manerix) and citalopram . The plasma concentrations of moclobemide were between 16 and 90 mg/L (therapeutic range: 1 to 3 mg/L) and those of citalopram between 0.3 and 1.7 mg (therapeutic concentration: 0.3 mg/L). This indicates that a relatively low dose of citalopram, given with an overdose of moclobemide represents a serious risk for the patient. Symptoms most often accompanying citalopram overdose included dizziness, sweating, nausea, vomiting, tremor, and somnolence. In more rare cases, observed symptoms included confusion, loss of consciousness, convulsions, coma, sinus tachycardia, cyanosis, hyperventilation and rhabdomyolysis.
Management of Overdose
Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric lavage and use of activated charcoal should be considered. Cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive measures. There are no specific antidotes for citalopram. Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. In managing overdosage, the possibility of multiple drug involvement must be considered.
Citalopram hydrobromide is a highly selective and potent serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor with minimal effects on the neuronal reuptake of norepinephrine (NE) and dopamine (DA). The ability of Citalopram to potentiate serotonergic activity in the central nervous system via inhibition of the neuronal reuptake of serotonin is thought to be responsible for its antidepressant action. Tolerance to the inhibition of serotonin reuptake is not induced by long-term (14 days) treatment of rats with Citalopram. Citalopram has no or very low affinity for a series of receptors including serotonin 5-HT1A, 5-HT2, dopamine D1 and D2, "1-, "2-, $-adrenergic, histamine H1, muscarinic cholinergic, benzodiazepine, gamma aminobutyric acid (GABA) and opioid receptors.
Pharmacokinetics
Following the administration of a single oral dose of citalopram (40 mg) to healthy male volunteers, peak blood levels occurred at about 4 hours (range 1 to 6 hours). The absolute bioavailability of citalopram was about 80% (range 52 to 93%) relative to an intravenous dose. Absorption was not affected by food.
After intravenous infusion in healthy male volunteers, the apparent volume of distribution (Vd)$ was about 12 L/kg (range 9-17 L/kg), indicating a pronounced tissue distribution; (Vd)$ oral was about 17 L/kg (range 14-21 L/kg). The binding of citalopram and its demethylated metabolites to human plasma proteins is about 80%.
The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 60 mg/day. Steady-state plasma levels are achieved in patients in 1-2 weeks. At a daily dose of 40 mg, the average plasma concentration is about 83 ng/mL (n=114) with a range from 30 to 200 ng/mL. Citalopram does not accumulate during long-term treatment. A clear relationship between citalopram plasma levels and therapeutic response or side effects has not been established.
Citalopram is metabolized in the liver to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In vitro studies show that DCT, DDCT and citalopram-N-oxide also inhibit the neuronal reuptake of serotonin but are less selective and less potent than the parent compound and are of minor clinical importance. Unchanged citalopram is the predominant compound in plasma.
In vitro
studies indicated that the biotransformation of citalopram to its demethyl metabolites depends on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6.
The elimination half-life of citalopram (t1/2$) is approximately 37 hours (range: 30-42 hours) which allows recommendation of once-daily dosing. The systemic citalopram plasma clearance (ClS) is 0.33 L/min. Citalopram is eliminated primarily via the liver (85%) and the remainder via the kidneys; approximately 12% (range 6-21%) of the daily dose is excreted in urine as unchanged citalopram.
Special Populations and Conditions
Elderly patients (4 males and 7 females aged 73-90 years), received a 20 mg/day dose of citalopram for 3-4 weeks. In the elderly, steady state plasma levels were elevated (106 ng/mL), half-life prolonged (1.5-3.75 days) and clearance decreased (0.08-0.3 L/min). Elevation of citalopram plasma levels occurred at an earlier age in females than in males. In this population, lower doses and a lower maximum dose of citalopram are recommended (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
The pharmacokinetics of citalopram were compared in patients with reduced hepatic function (3 female and 6 male patients aged 41-60 years) to those seen in 12 healthy male volunteers (aged 21-43 years). In patients with reduced hepatic function the half-life of citalopram was approximately doubled (83 hours versus 37 hours), steady state citalopram concentrations increased by 61% and oral clearance decreased by 37%. Consequently the use of citalopram in patients with reduced hepatic function should be approached with caution and lower maximal doses should be prescribed (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
In patients with mild to moderate reduction of the renal function (4 female and 3 male patients aged 30-55 years), citalopram was being eliminated more slowly than in 12 healthy male volunteers (aged 21-43 years); half-lives being 49 hours versus 37 hours. However, mild to moderate renal impairment had no major influence on the kinetics of citalopram. At present, no information is available for chronic treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min). (See PRECAUTIONS.)
phl-CITALOPRAM tablets should be stored in a dry place at room temperature between 15o and 30oC.
Availability of Dosage Forms
phl-CITALOPRAM (citalopram hydrobromide) is available as film-coated, white tablets. Tablets are supplied as:
Each White, oval, coated tablets, imprinted "10" on one side and nothing on the other side. contains 10 mg citalopram (as citalopram hydrobromide). HDPE bottles of 100 tablets.
Each white to off-white, oval, film-coated tablet, scored on one side and imprinted "20" on the unscored side, contains 20 mg citalopram (as citalopram hydrobromide). Blister packages 30 tablets and HDPE bottles of 100 and 500 tablets.
Each white to off-white, oval, film-coated tablet, scored on one side and imprinted "40" on the unscored side, contains 40 mg citalopram (as citalopram hydrobromide). Blister packages 30 tablets and HDPE bottles of 100 and 500 tablets.
Composition
phl-CITALOPRAM tablets contain citalopram hydrobromide corresponding to 10mg, 20 mg, or 40 mg citalopram, and the following non-medicinal ingredients: Colloidal Silicon Dioxide, Lactose Monohydrate, Magnesium Stearate, Microcrystalline Cellulose, Hydroxypropyl Methylcellulose, Hydroxypropyl Cellulose, Titanium Dioxide, Polyethylene Glycol and Sodium Starch Glycolate. Product Monograph available upon request. Pharmel Inc. Montreal, Quebec H4P 2T4