(Citalopram Hydrobromide Tablets) 20 and 40 mg as citalopram Antidepressant Rhoxalpharma Inc. Date of Preparation: 4600 boul. Thimens November 7, 2003 St-Laurent, (Quebec) Date of Revision: H4R 2B2 May 20, 2004 Control No. : 091245
(Citalopram Hydrobromide Tablets) 20 and 40 mg as citalopram
Antidepressant
ACTION AND CLINICAL PHARMACOLOGY
Rhoxal-citalopram (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 hydrobromide 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 hydrobromide. Citalopram hydrobromide has no or very low affinity for a series of receptors including serotonin 5-HT1A, 5-HT2, dopamine D1, and D2, "1-, "2-, $-adrenergic, histamine H1, muscarinic cholinergic, benzodiazepine, gamma aminobutyric acid (GABA) and opioid receptors.
Comparative Bioavailability
A single dose cross-over comparative bioavailability study was performed to assess the bioequivalence of citalopram hydrobromide 40 mg film-coated tablets in healthy male volunteers under fasting conditions. The summary of the comparative bioavailability study is presented in the following table: Summary table of the comparative bioavailability data Rhoxal-citalopram (1x40 mg) film coated tablets versus Celexa(r) (1x40 mg) From measured data (fasting conditions)
TMAX
T1/2
| PARAMETER | Rhoxal-citalopram TEST 40 mg tablets (A) | Celexa(r) * * * REFERENCE 40 mg tablets (A) | % RATIO OF GEOMETRIC LS MEANS (A/B) | 90 % CONFIDENCE INTERVALS |
| AUC T | 1200.186 | 1229.119 | 97.65 | 94.89-100.48 |
| (ng.h/mL) | 1217.127 (22.9) | 1249.576 (23.1) | ||
| AUC I | 1643.512 | 1679.666 | 97.85 | 94.33-101.50 |
| (ng.h/mL) | 1686.120 (26.5) | 1725.424 (28.4) | ||
| C MAX | 37.113 | 36.068 | 97.49 | 93.48-101.68 |
| (ng/mL) | 37.563 (21.9) | 38.663 (22.4) | ||
| * (h) | 4.25 (2.5 - 8) | 4.75 (1.5 - 7) | -- | -- |
| * * (h) | 38.92 (15.6) | 38.31 (18.1) | -- | -- |
* expressed as median (minimum to maximum) only.
* * expressed as arithmetic mean (CV%) only * * * Lundbeck Canada Inc. reference product
Following the administration of a single oral dose of citalopram hydrobromide (40 mg) to healthy male volunteers, peak blood levels occurred at about 4 hours (range 1 to 6 hours). The absolute bioavailability of citalopram hydrobromide was about 80% (range 52 to 93%) relative to an intravenous dose. Absorption was not affected by food.
After intravenous infusion in healthy male volunteers the apparent volume of distribution (Vd)$ was about 12 L/kg (range 9-17 L/kg), indicating a pronounced tissue distribution; (Vd)$ oral was about 17 L/kg (range 14-17 L/kg). The binding of citalopram hydrobromide and its demethylated metabolites to human plasma proteins is about 80%.
The single- and multiple dose pharmacokinetics of citalopram hydrobromide 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 hydrobromide does not accumulate during long term treatment. A clear relationship between citalopram hydrobromide plasma levels and therapeutic response or side effects has not been established.
Citalopram hydrobromide is metabolized in the liver to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide and a deaninated 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 hydrobromide is the predominant compound in plasma.
In vitro
studies indicated that the biotransformation of citalopram hydrobromide to its demethyl metabolites depends on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6.
The elimination half-life of citalopram hydrobromide (t1/2$) is approximately 37 hours (range: 30-42 hours) which allows recommendation of once-daily dosing. The systemic citalopram hydrobromide plasma clearance (Cls) is 0.33 L/min. Citalopram hydrobromide 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 hydrobromide.
Special Populations
Elderly patients (4 male and 7 female aged 73-90 years), received a 20 mg/day dose of citalopram hydrobromide 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 hydrobromide plasma levels occurred at an earlier age in females than in males. In this population, lower doses and a lower maximum dose of citalopram hydrobromide are recommended (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
The pharmacokinetics of citalopram hydrobromide 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 hydrobromide was approximately doubled (83 hours versus 37 hours), steady state citalopram hydrobromide concentrations increased by 61% and oral clearance decreased by 37%. Consequently the use of citalopram hydrobromide 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, aged 30-55 years), citalopram hydrobromide 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 hydrobromide. At present, no information is available for chronic treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min). (See PRECAUTIONS.)
The efficacy of citalopram hydrobromide in the treatment of depression was established in five placebo-controlled studies in patients who met the DSM-III or DSM-III-R criteria for major depression. Response to treatment was evaluated by the Hamilton Depression Rating Scale (HAMD) and/or the Montgomery Asberg Depression Rating Scale (MADRS), as well as the Clinical Global Impression (CGI) Severity Scale. On the HAMD and MADRS, total scores, selected single items, and percentage of responders (defined as patients whose HAMD/MADRS total score decreased by at least 50% versus baseline) were assessed. In a 6-week fixed dose, dose-response study, patients received citalopram hydrobromide at doses of 10, 20, 40, or 60 mg/day or placebo (n=129 to 131 per group). The 40 and 60 mg/day doses were titrated, with patients reaching these designated doses within 4 and 8 days, respectively. The study showed that the 40 and 60 mg/day doses were significantly more effective than placebo, although the 60 mg/day dose was not more effective than the 40 mg/day dose. The lower doses did not show statistically significant superiority over placebo, except on the MADRS; on this scale the percent of 'responders' was significantly higher in all the citalopram hydrobromide-treated groups than in the placebo-treated group. The second study was a 4-week flexible dose study in which 85% of the depressed patients met the criteria for melancholia. At entry, 89 and 91 patients were randomized to the citalopram hydrobromide and placebo groups, respectively. This was the only study in which more male than female patients participated (64% versus 36%). The initial dose of citalopram hydrobromide, 20 mg/day, could be titrated to the maximal tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram hydrobromide showed significantly greater improvement than patients treated with placebo. At week 4, the average daily dose was 63 mg, with 52% of patients receiving the 80 mg/day dose. In a 6-week fixed-dose study, patients received citalopram hydrobromide, 20 or 40 mg/day, or placebo (n=64 to 70 per group). Patients treated with citalopram hydrobromide 40 mg/day, showed significantly greater improvement than placebo-treated patients. The difference between the lower dose of citalopram hydrobromide and placebo was not significant. In another 6-week fixed-dose study, patients received citalopram hydrobromide, 20 or 40 mg/day or placebo (n=88 to 97 per group). Although citalopram hydrobromide-treated patients improved to a somewhat greater degree than the placebo-treated patients, the differences between drug and control groups did not reach statistical significance due to a high placebo response, i.e., substantial improvement in the placebo group. A 6-week, flexible dose study was conducted in elderly, depressed patients (the mean age of male and female patients was 75 and 77 years, respectively) to determine the antidepressant effect and safety of citalopram hydrobromide in this subpopulation. The number of patients who received citalopram hydrobromide and placebo was 98 and 51, respectively. The study allowed patients to enter with lower baseline HAMD scores than are usually acceptable ($18 in clinical trials). However, only a small percentage of patients had HAMD scores of less than 18 at entry. The dose of citalopram hydrobromide was titrated from a starting dose of 10 mg/day to a maximum dose of 30 mg/day. Patients treated with citalopram hydrobromide showed significantly greater improvement than patients treated with placebo. The final dose of citalopram hydrobromide was 10, 20 and 30 mg/day in 5%, 51% and 44% of patients, respectively. The effectiveness of citalopram hydrobromide in preventing relapse was assessed in two long-term studies. Depressed patients who responded to citalopram hydrobromide during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20-60 mg/day in the second study) were randomized to continue on citalopram hydrobromide or receive placebo. The number of patients who received citalopram hydrobromide and placebo was 257 and 116, respectively. In both studies, patients who continued on citalopram hydrobromide experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the relapse rates were similar at the 20 and 40 mg/day doses, namely 10% and 12%, respectively. Of the placebo-treated patients, 31% experienced relapse. In the flexible- dose study, the relapse rates were 14% and 24% in the citalopram hydrobromide and placebo-treated patients, respectively. While the majority of patients (76%) were maintained on 20 or 40 mg/day of citalopram hydrobromide during most of the study, some patients received 60 mg/day, while a few patients were maintained on less than 20 mg/day.
Rhoxal-citalopram (citalopram hydrobromide) is indicated for the symptomatic relief of depressive illness. The relapse rate was significantly lower in citalopram hydrobromide-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 hydrobromide (see Clinical Trials under ACTION). Nevertheless, the physician who elects to use citalopram hydrobromide for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
WARNINGS
POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.
Pediatrics: Placebo-Controlled Clinical Trial Data
Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer anti-depressants suggests that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.
The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs
Adults and Pediatrics: Additional data
There are clinical trial and post-marketing reports with SSRIs and other newer anti- depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.
Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type
emotional and behavioural changes.
Discontinuation Symptoms
Patients currently taking rhoxal-sertraline should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer anti-depressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.
SPECIAL WARNING:
This product is not approved for any indication other than depression. It must not be prescribed or dispensed for any other condition.
In particular, this drug must not be prescribed or dispensed for any of the following conditions:
Cognitive disorders or amnesia associated with dementia; Cerebrovascular disorders; Cerebrovascular disorders caused by cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoid hemorrhage, cerebral thrombosis or cerebral embolism; Ischemia; Amnesia associated with ischemia; Dementia; Vascular or multi-infarct dementia; or Dementia of the Alzheimer's type.
Rhoxal-citalopram (citalopram hydrobromide) is contraindicated in patients with known hypersensitivity to citalopram hydrobromide or the excipients of the drug product.
In patients, receiving selective serotonin reuptake inhibitors (SSRIs) in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes, including extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on a MAOI. Some cases presented with features resembling serotonin syndrome. Therefore, citalopram hydrobromide should not be used in combination with a MAOI or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should elapse after discontinuing citalopram hydrobromide treatment before starting a MAOI.
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 hydrobromide and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescription for citalopram hydrobromide should be written for the smallest quantity of drug consistent with good patient management. (See WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM)
In placebo-controlled trials with citalopram hydrobromide, some of which included patients with bipolar disorder, mania/hypomania was reported in 0.1% of 1027 patents treated with citalopram hydrobromide 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 hydrobromide should be discontinued.
Citalopram hydrobromide has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the premarketing testing of citalopram hydrobromide. In clinical trials, seizures occurred in 0.25% of patients treated with citalopram hydrobromide and in 0.23% patients treated with placebo. Like other antidepressants, citalopram hydrobromide should be used with caution in patients with a history of seizure disorder.
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).
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.
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 hydrobromide is to be used in combination with a 5-HT1 agonist. St. John's Wort: In common with other SSRI's pharmacodynamic interaction between Rhoxal- citalopram (citalopram hydrobromide) and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.
Hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported as rare adverse event with use of citalopram hydrobromide.
The safety of citalopram hydrobromide during pregnancy and lactation has not been established. Therefore, citalopram hydrobromide 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. Citalopram hydrobromide is excreted in human milk. Citalopram hydrobromide 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 patients below the age of 18 have not been established.
In premarketing clinical trials, 800 elderly patients ($65 years of age) have been treated with citalopram hydrobromide. 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 hydrobromide 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). Consequently, elderly patients should be administered lower doses and a lower maximum dose (see DOSAGE AND ADMINISTRATION).
In subjects with hepatic impairment, citalopram hydrobromide clearance was significantly decreased and plasma concentrations, as well as elimination half-life significantly increased (see PHARMACOKINETICS). Consequently, the use of citalopram hydrobromide in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see DOSAGE AND ADMINISTRATION).
No dosage adjustment is needed in patients with mild to moderate renal impairment. To date, no information is available on the pharmacokinetic or pharmacodynamic effects of citalopram hydrobromide in patients with severely reduced renal function (creatinine clearance <20 mL/min).
Citalopram hydrobromide 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 drugs premarketing assessment. However, the electrocardiograms of patients, who received citalopram hydrobromide in clinical trials, indicate that citalopram hydrobromide was not associated with the development of clinically significant ECG abnormalities. In clinical trials, citalopram hydrobromide caused small but statistically significant decreases in heart rate (see ECG under ADVERSE REACTIONS). Consequently, caution should be observed when citalopram hydrobromide is initiated in patients with pre-existing slow heart rate.
Citalopram hydrobromide 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 hydrobromide affects the response to insulin. Rare events of hypoglycemia were reported. Citalopram hydrobromide should be used with caution in diabetic patients on insulin or other antidiabetic drugs.
In studies in normal volunteers, citalopram hydrobromide 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 hydrobromide does not affect them adversely.
The safety and efficacy of the concurrent use of citalopram hydrobromide and ECT have not been studied.
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.
DRUG INTERACTIONS:
For interactions between citalopram hydrobromide and MAOI, see CONTRAINDICATIONS.
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 hydrobromide 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.
Coadministration of citalopram hydrobromide (40 mg/day for 22 days) and the $-adrenergic blocking agent metoprolol (single dose of 150 mg), resulted in a two-fold increase in the plasma levels of metoprolol. However, the effect of metoprolol on blood pressure and heart rate was not affected.
Administration of citalopram hydrobromide (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.
Administration of citalopram hydrobromide (40 mg/day for 21 days) did not affect the pharmacokinetics of digoxin (single dose of 1 mg), although the serum levels of citalopram hydrobromide were slightly lower in the presence of digoxin.
Coadministnation of citalopram hydrobromide (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 hydrobromide, the concentration of desipramine, the metabolite of imipramine, increased by approximately 50% and its half-life was prolonged. The results indicate that citalopram hydrobromide 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 hydrobromide and imipramine/desipramine should be undertaken with caution.
Coadministration of citalopram hydrobromide (40 mg/day for 10 days) and levomepromazine (single dose of 50 mg), did not affect the pharmacokinetics of either drug.
Coadministration of citalopram hydrobromide (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.
Citalopram hydrobromide 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 hydrobromide was increased by 39% and 41%, respectively. Thus, caution should be exercised at the upper end of the dose range of citalopram hydrobromide when it is used concomitantly with high doses of cimetidine.
Carbamazepine, titrated to 400 mg/day, was given for 21 days alone and then in combination with citalopram hydrobromide (40 mg day) for an additional 14 days. Citalopram hydrobromide 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 hydrobromide should be considered if the two drugs are given concomitantly.
Using in vitro models of human liver microsomes, the biotransformation of citalopram hydrobromide to its demethyl metabolites was shown to depend on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6. Studies have also indicated that citalopram hydrobromide is a weak inhibitor of CYP2D6 and CYP2C19 and a weak or negligible inhibitor of CYP3A4 and CYP1A2. As data are not available from clinical pharmacokinetic studies, the possibility that the clearance of citalopram hydrobromide will be decreased when citalopram hydrobromide is administered with a potent inhibitor of CYP3A4 (e.g., ketoconazole, itraconazole, fluconazole or erythromycin), or a potent inhibitor of CYP2C19 (e.g., omeprazole), should be considered.
Although citalopram hydrobromide did not potentiate the cognitive and psychomotor effects of alcohol in volunteers, the concomitant use of alcohol and citalopram hydrobromide should be avoided.
In clinical trials, citalopram hydrobromide has been given concomitantly with benzodiazepines (anxiolytics/hypnotics), analgesics (NSAIDs, nonNSAIDs), lithium, antihistamines, antihypertensives or other cardiovascular drugs.
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 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 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% 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 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 favors to the adverse event incidence rate in the population studied.
TABLE 1
TREATMENT-EMERGENT ADVERSE EVENTS * INCIDENCE IN PLACEBO-CONTROLLED CLINICALTRIALS
| Percentage of Patients Reporting | ||
| Body System/Adverse Event | Citalopram (N = 1027) | Placebo (N = 426) |
| Body as a Whole | 5.2 | 3.1 |
| Fatigue | ||
| Fever 1 | 2.4 | 0.2 |
| Autonomic Nervous System | 19.4 | 12.2 |
| Dry mouth 1 | ||
| Sweating increased | 10.5 | 8.0 |
| 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 |
*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.
Statistically significantly higher incidence in the citalopram hydrobromide group (p<0.05).
Denominator used was for females only (n=623 for citalopram hydrobromide; n=245 for Placebo).
Denominator used was for males only (n=404 for citalopram; n=181 for Placebo).
The following events had an incidence on placebo $ citalopram hydrobromide: 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 1).
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 insomnia, increased sweating, and fatigue 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 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 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, 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 reuptake inhibitors. (see PRECAUTIONS and DOSAGE AND ADMINISTRATION)
ADDITIONAL ADVERSE EVENTS OBSERVED DURING THE PREMARKETING EVALUATION OF CITALOPRAM HYDROBROMIDE
The events listed below 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 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 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, nonpathological 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,
Hematopoietic and Lymphatic Disorders
Infrequent:Anemia, epistaxis, leukocytosis, purpura. Rare:Coagulation disorder, gingival bleeding, granuloytopenia, 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
Frequent: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,
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
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,
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.
Events Observed During the Post-Marketing Evaluation of Citalopram Hydrobromide
It is estimated that approximately 8 million patients have been treated with citalopram hydrobromide since market introduction. The following adverse events have been reported to be temporarily associated with citalopram hydrobromide treatment in at least 3 patients. Abnormal hepatic function, aggravated condition, aggravated migraine, angioedema, asthma, choreoathetosis, decreased drug level, decreased prothrombin time, dyskinesia, ecchymosis, eosinophilia, erythema multiforme, gynecological problems, hepatitis, hyperprolactinemia, hyponatremia, increased drug level, increased prothrombin time, mydriasis, neuroleptic malignant syndrome, neuropathy, pancreatitis, pancytopenia, postural hypotension, purpura NOS, serotonin syndrome, SIADH, spontaneous abortion/fetal death, thrombocytopenia, ventricular arrhythmia, Torsade de pointes, withdrawal syndrome.
Rhoxal citalopram (citalopram hydrobromide) has a wide margin of safety in overdose. Cases of overdoses involved the ingestion of citalopram hydrobromide either alone or in combination with other drugs and/or alcohol. In clinical trials, with overdoses of citalopram hydrobromide ranging from 180 mg to 2000 mg, all patients recovered. One patient, ingesting over 1500 mg citalopram hydrobromide, had reversible ECG abnormalities, the most important of which was prolongation of QTc. Of the cases reported postmarketing, six were fatal. The doses of citalopram hydrobromide in these patients ranged from 840 mg to 3920 mg. All but one of these patients had concomitant drugs and/or alcohol. Serum levels of citalopram hydrobromide in patients who ingested 2000 mg, 4000 mg and 5200 mg of the drug were 2900 ng/mL, 3800 ng/mL and 10,040 ng/mL citalopram, respectively. All these patients recovered. Three fatal cases of serotonin syndrome have been reported in patients who took overdoses of moclobemide and citalopram hydrobromide. The plasma concentrations of moclobemide were between 16 and 90 mg/L (therapeutic range: 1 to 3 mg/L) and those of citalopram hydrobromide between 0.3 and 1.7 mg (therapeutic concentration: 0.3 mg/L). This indicates that a relatively low dose of citalopram hydrobromide, given with an overdose of moclobemide represents a serious risk for the patient. Symptoms most often accompanying citalopram hydrobromide 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.
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 hydrobromide. Due to the large volume of distribution of citalopram hydrobromide, 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.
Rhoxal-citalopram (citalopram hydrobromide) should be administered once daily, in the morning or evening, with or without food.
Rhoxal-citalopram (citalopram hydrobromide) 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.
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). The dose may be titrated to a maximum of 40 mg/day if needed and tolerated.
The safety and effectiveness of fluvoxamine maleate in children under 18 years of age have not been established. (see WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM)
Patients with reduced hepatic function should receive dosages of no more than 30 mg/day.
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 hydrobromide in patients with severe renal impairment, Rhoxal-citalopram (citalopram hydrobromide) should be used with caution in these patients.
Evaluation of citalopram hydrobromide 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). 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.
At least 14 days should elapse between discontinuation of a MAOI and initiation of therapy with citalopram hydrobromide. Similarly, at least 14 days should be allowed after stopping citalopram hydrobromide before starting a MAOI (see CONTRAINDICATIONS).
Symptoms associated with the discontinuation or dosage reduction of citalopram hydrobromide 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
5-Isobenzofurancarbonitrile, 1-[3-(dimethylamino)propyl] -
1-(4-fluorophenyl)-1,3-dihydro-, monohydrobromide
O
CH2CH2CH2N(CH3)2 . HBr
NC
Molecular Formulas: C20H21FN2O %HBr
405.30
White or almost white, crystalline powder
185degC-186degC
5.5-6.5 (0.5% w/v in water)
8.84
Water (sparingly soluble) Ethanol (soluble) Chloroform (freely soluble)
Diethylether (very slightly soluble)
13 at pH 7
Rhoxal-citalopram tablets contain citalopram hydrobromide
corresponding to 20 mg or 40 mg citalopram, and the following non-medicinal ingredients: maize starch, lactose monohydrate, povidone (K64), glycerol 85%, microcrystalline cellulose, magnesium stearate, sodium starch glycollate, hypromellose, macrogol 6000, titanium dioxide E171 and talc.
Rhoxal-citalopram tablets should be stored in a dry place at room temperature between 15/ and 30/C.
Rhoxal-citalopram (citalopram hydrobromide) is available as film-coated, white tablets.
Each white, oblong, biconvex film-coated tablet, embossed "C20" on one side and scored on the other contains 20 mg citalopram (as citalopram hydrobromide).
Blister packages of 30 and bottles of 100.
Each white, oblong, biconvex film-coated tablet, embossed "C40" on one side and scored on the other contains 40 mg citalopram (as citalopram hydrobromide).
Blister packages of 30 and bottles of 100. Please read this information before you start to take your medicine. Keep the leaflet while you are taking Rhoxal-citalopram; you may want to read it again. This leaflet does not contain all the information about this medicine. For further information or advice please see your doctor or pharmacist.
Always keep medicines out of the reach of children.
Rhoxal-citalopram belongs to the family of medicines called SSRIs (Selective Serotonin Reuptake Inhibitors). Rhoxal-citalopram has been prescribed to you by your doctor to relieve your symptoms of depression. Treatment with these types of medications is most safe and effective when you and your doctor have good communication about how you are feeling.
All your medical conditions, including heart problems, history of seizures, liver or kidney disease, diabetes, bleeding disorders. Any medications (prescription or non-prescription) which you are taking or have taken within the last 14 days, especially a monoamine oxidase inhibitor (e.g., phenelzine, tranylcypromine, moclobemide or selegiline), or any other antidepressant, lithium, tryptophan, or cimetidine, as well as any herbal product such as St. John's Wort, which may interact with citalopram. If you ever had an allergic reaction to any medication. If you are pregnant or thinking of becoming pregnant, or if you are breast feeding. Your habits of alcohol consumption.
You should not be taking Rhoxal-citalopram if you are pregnant or breast feeding. Do not take Rhoxal-citalopram if you are allergic to it, or to any of the components of its formulation (for list of components see the section on "What does Rhoxal-citalopram contain"). Stop taking Rhoxal-citalopram and contact your doctor immediately if you experience an allergic reaction or any severe side effect.
It is important that you take Rhoxal-citalopram exactly as your doctor has instructed. Usually your doctor will prescribe 20 mg per day, which you will take as a single dose either in the morning or in the evening. This dose may be increased. Never change the dose of Rhoxal-citalopram unless your doctor tells you to. You should continue to take Rhoxal-citalopram even if you do not feel better, as it may take several weeks for your medication to work. Improvement may be gradual. Continue to take Rhoxal-citalopram for as long as your doctor recommends it. Do not stop taking your tablets even if you begin to feel better, unless you are told to do so by your doctor. Your doctor may tell you to continue to take Rhoxal-citalopram for several months. Continue to follow your doctor's instructions. Swallow the tablets whole with a drink of water. Do not chew them. Rhoxal-citalopram can be taken with or without food. If you miss a dose, do not worry. Do not take the missed tablet(s) - just take the next dose when it is due.
Rhoxal-citalopram may cause unwanted effects (side-effects). These may include nausea, dry mouth, drowsiness, increased sweating, tremor, diarrhea and sexual problems. Other effects include dizziness and sleep disturbance.
Contact your doctor before stopping or reducing your dosage of Rhoxal-citalopram. Symptoms such as dizziness, abnormal dreams, electric shock sensations, agitation, anxiety, emotional indifference, difficulty concentrating, headache, migraine, tremor (shakiness), nausea, vomiting, sweating or other symptoms may occur after stopping or reducing the dosage of Rhoxal-citalopram. Such symptoms may also occur if a dose is missed. These symptoms usually disappear without needing treatment. Tell your doctor immediately if you have these or any other symptoms. Your doctor may adjust the dosage of Rhoxal-citalopram to reduce the symptoms. Side-effects are often mild and may disappear after a few days. If they are troublesome or persistent, or if you develop any other unusual side-effects while taking Rhoxal-citalopram, please consult your doctor. Usually Rhoxal-citalopram does not affect patients' ability to carry out normal daily activities. However, you should not drive a car or operate machinery until you are reasonably certain that Rhoxal-citalopram does not affect you adversely. Avoid drinking alcohol while taking Rhoxal-citalopram.
If you have accidentally taken too much Rhoxal-citalopram contact your doctor or nearest hospital emergency department immediately, even if you do not feel sick. If you go to the doctor or the hospital, take the Rhoxal-citalopram container with you.
Rhoxal-citalopram is available as white 20 mg and 40 mg tablets. Citalopram is the active ingredient. The non-medicinal ingredients in the tablets are maize starch, lactose monohydrate, povidone (K64), glycerol 85%, microcrystalline cellulose, magnesium stearate, sodium starch glycollate, hypromellose, macrogol 6000, titanium dioxide E171 and talc.
As with all medicines, keep Rhoxal-citalopram out of the reach of children. Store your tablets at room temperature (15/-30/C) in a dry place. Keep the container tightly closed. If your doctor tells you to stop taking your medicine you should return any left-over tablets to the pharmacist, unless the doctor tells you to keep them at home.
Rhoxal-citalopram tablets are made by: Rhoxal Pharma Inc. 4600 boul. Thimens St-Laurent, (Quebec) H4R 2B2
Citalopram is a racemic mixture with the S (+) enantiomer mediating the pharmacological effects. The R (-) enantiomer contributes little to the activity of citalopram.
IN VITRO
EXPERIMENTS
The primary pharmacological effect of citalopram is inhibition of the 5-HT reuptake mechanism. Citalopram was shown to inhibit 5-HT uptake in rabbit blood platelets, with an IC50 of 14 nM. Similarly, the drug inhibits 5-HT uptake in rat brain synaptosomal preparations.
| 5-HT | NE | DA | NE/5-HT | |
| citalopram | 1.8 | 8800 | 41 000 | 4889 |
| demethylcitalopram | 7.4 | 780 | 26 000 | 105 |
| didemethylcitalopram | 24 | 1500 | 12 000 | 63 |
| citalopram-N-oxide | 56 | 3200 | >100 000 | 57 |
The data indicate that citalopram is a potent and specific 5-HT uptake inhibitor with no activity on the neuronal reuptake of norepinephrine (NE) or dopamine (DA). The metabolites of citalopram are also specific inhibitors of 5-HT reuptake, albeit less active than the parent drug. The ratio between the concentrations inhibiting the in vitro uptake of NE and 5-HT determine the selectivity of a SSRI. According to this criterion citalopram is a highly selective SSRI.
Citalopram has no or very low affinity for a series of receptors including 5-HT IS, 5-HT2, dopamine D1 and D2 receptors, "1-, "2-, $-adrenoreceptors, histamine H1, muscarinic cholinergic, benzodiazepine, and opioid receptors. A series of functional in vitro tests in isolated organs as well as functional in vivo tests have confirmed the lack of receptor affinity.
In a 'behavioral despair paradigm', mice, trained to swim in a glass jar, eventually exhibit immobility. This behavior was dose-dependently reversed by citalopram. The 5-HT precursors, tryptophan and 5-HTP, induce in mice and rats the 5-HT syndrome, characterized by tremor, hyperactivity, abnormal gait, lordosis, and abduction of the hind limbs. Citalopram potentiated these behavioral manifestations. The demethyl, didemethyl, and N-oxide metabolites were less potent than the parent drug. The characteristic head twitches, induced by a combined treatment with a MAOI and 5-HTP, were potentiated by citalopram. However, head twitches induced by quipazine, a direct 5-HT mimetic, were not affected by citalopram, indicating that the drug has no anti-5-HT activity. Although citalopram has no antinociceptive activity per se, it potentiated the antinociceptive effect of morphine. In a food reinforcement paradigm, delivered under a multiple schedule, citalopram did not affect the responding in pigeons but potentiated the 5-HTP-induced decrease in responding. In rats, citalopram did not facilitate self-stimulation, did not substitute for d-amphetamine, d-LSD, or 8-OHDPAT in a drug discrimination paradigm and did not increase ethanol consumption in an ethanol/water preference test. In the latter experiment, citalopram actually decreased ethanol consumption. These experiments indicate that citalopram would not be abused and would not cause dependence. Citalopram had a slight protective effect against maximal electroshock-induced convulsions, isoniazide-induced convulsions and audiogenic seizure. However, in toxicity studies convulsions have been observed at very high plasma levels of citalopram (see TOXICOLOGY).
In conscious dogs, single oral doses of 5 mg/kg of citalopram caused pronounced fluctuation of the blood pressure and heart rate. A 10 mg/kg dose caused tachycardia and elevated blood pressure. The ECG was unchanged. In anaesthetized cats, single oral doses of 35 mg/kg decreased the following parameters: mean arterial blood pressure, left ventricular end diastolic pressure, contractility, cardiac performance, stroke volume, and cardiac output. Peripheral resistance was increased. ECG abnormalities included alterations in conduction, changes in rhythm and T-wave inversion in 2 of 6 cats. Additional cardiovascular effects of citalopram and a metabolite are described under TOXICOLOGY.
The kinetics of citalopram in mouse, rat, and dog are characterized by rapid absorption, with Tmax ranging from 0.5 to 4 hours. In contrast to man, reduced systemic bioavailability due to extensive
Pharmacokinetic analysis of single dose i.v. data suggests two-compartment distribution characteristics. High levels of drug and demethylated metabolites were found in the lungs, liver, and kidneys, and lower levels in the heart and brain. Citalopram and the demethylated metabolites were shown to pass the placental barrier and were excreted in small amounts in milk. The plasma protein binding of citalopram has been estimated to be 70-80%. The binding protein(s) has not been identified. Both in mice and dogs, tissue concentrations of parent drug as well as those of the demethylated metabolites increased with increasing doses, although not necessarily in a dose-related manner. Levels of the didemethylated metabolites were higher in dogs than in mice in relation to the parent drug, resulting in smaller citalopram/didemethylcitalopram ratios in the dog, particularly in the heart and kidneys.
There are no major qualitative differences in the metabolism of citalopram between animals and man. Citalopram is metabolized to demethylcitalopram, didemethylcitalopram, citalopram-N-oxide, and the deaminated propionic acid. Demethylcitalopram and didemethylcitalopram levels are more prominent in mouse, rat, and dog than in man.
Elimination of citalopram after a single dose is rapid, the half-life ranging from 1.5-2 hours in the mouse to 3.5-8 hours in the dog. In the dog, the half-life is prolonged with increasing doses due to Following the administration of 14C-labelled citalopram to rats, at a dose of 20 mg/kg, approximately equal amounts of the dose were excreted in the urine and feces, with total recovery being about 80%.
Plasma levels were determined in several long-term toxicity studies. The table below summarizes the results seen in some of these studies.
| Species | Study | Dose mg/kg | CT a ng/mL | DCT b ng/mL | DDCT c ng/mL |
| Rat d | 12-month tox po (diet) | 32 | male 330334 female | 474391 | 246204 |
| 60 | male 690826 female | 989862 | 497290 | ||
| 120 | male 1e+07 female | 19471655 | 758577 | ||
| Dog e | 12-month tox po (in capsules) | 1 | 19 | 22 | 95 |
| 3 | 350 | 170 | 314 | ||
| 8 | 1218 | 586 | 574 | ||
| Man | multiple dose po 6 weeks | 0.3 | 39 | 13 | 3.7 |
| 0.6 | 83 | 28 | 5.2 | ||
| 0.9 | 121 | 41 | 6.3 |
a: citalopram; b: demethylcitalopram; c: didemethylcitalopram; d: average value at Week 52; e: 2 hours postdose -Week 52 (1 and 3 mg/kg dose groups), Week 57 (8 mg/kg dose group).
The data indicate that the plasma levels of citalopram, as well as those of the demethylated metabolites, are considerably higher in animals than in man. The approximate 0.9 mg/kg dose in man corresponds to the highest recommended dose (60 mg/day). The plasma levels of the parent drug, seen in rats and dogs at the highest doses, are approximately 10 times higher in animals than in man, while the levels of the didemethyl metabolites are almost 100 fold higher. In the rat, a NOEL could not be established in this study; at the low dose minimal vacuolization of hepatocytes with fatty infiltration, and foam cell accumulation in lungs were noted. The changes were
The LD50 values of citalopram ranged between 900-1700 mg/kg after oral administration and 38-74 mg/kg after intravenous administration. However, some mortality was also seen in the 400-600 mg/kg dose range, indicating a very flat dose-response curve regarding mortality. Signs of toxicity were sedation and tremor, while convulsions occurred at doses close to or above the LD50 values.
| Species | Sex | i.v. p.o. | Route of Administration i.p. s.c. | i.m. | ||
| Mouse | Male | 72 +- 9 | 1140 +- 190 | 220 +- 9 | 534 +- 71 | >400 |
| Female | 74 +- 10 | 900 +- 120 | 207 +- 20 | - | - | |
| Rat | Male | 40 +- 4 | 1710 +- 292 | 157 +- 27 | 1950 +- 364 | >400 |
| Female | 38 +- 7 | 1426 +-554 | 133 +- 17 | - | - | |
A number of single dose toxicity studies have been carried out in dogs to investigate the potential cardiovascular toxicity of citalopram. In these studies, cardiotoxicity was not observed, but tonic- clonic convulsions were seen after oral administration of 20-40 mg/kg, as well as after slow intravenous infusion of 20-24 mg/kg. The critical plasma concentration for convulsions was about 1950 ng/mL.
Toxicological studies, including daily dosing for periods up to 26 weeks in mice and 52 weeks in rats and dogs, have been carried out. Plasma drug monitoring in the long-term safety studies documented that animals have been exposed to average citalopram levels of up to about 1200 ng/mL (dogs and rats) and 2900 ng/mL (mice), as well as substantial levels of demethylcitalopram [up to about 1800 ng/mL (rats), 600 ng/mL (dogs), 1150 ng/mL (mice)] and didemethylcitalopram [up to about 650 ng/mL (rats), 600 ng/mL (dogs), 300 ng/mL (mice)]. Apart from behavioral and functional characteristics of exaggerated 5-HT stimulation (e.g., hyperactivity, tremor, tail rigidity, mydriasis, reduced food consumption, and reduced body weight gain), two treatment-related findings have been demonstrated in rodents, namely fatty infiltration of the liver and lipidosis (vacuolization of lymphocytes). Both of the findings were reversible. In addition, retinal degeneration and testicular atrophy were also observed in rats. In dogs, two treatment-related effects were found. Firstly, convulsions and death when plasma citalopram levels exceeded 1950 ng/mL (p.o. or i.v. ). Secondly, fatal ventricular arrhythmias at combined high levels of the didemethyl metabolite (about 300 ng/mL) and citalopram (about 1950 ng/mL) were seen following i.v. infusion.
Fatty infiltration in the liver was first observed in a 3-month gavage study in rats given 8-32 mg/kg/day of citalopram. This administration resulted in dose-related hepatic fatty infiltration in all male rats but not in female rats at any of the doses. The fatty infiltration in male rats was also observed in a 4-week study, however, only at considerably higher doses (>160 mg/kg). In female rats only minimal fatty infiltration was seen at a 200 mg/kg/day dose.
Phospholipidosis, which has been seen in rodents, is an abnormal accumulation of phospholipids in phagocytic cells and cells which catabolize biomembranes, such as pulmonary alveolar macrophages and circulating leucocytes (especially lymphocytes). Phospholipidosis developed in rats receiving citalopram at daily doses of 120 rng/kg and slight vacuolization of peripheral lymphocytes was observed in mice at daily doses of 100 mg/kg, in the 52-week and 26-week studies, respectively. Both conditions were reversible within 3-4 weeks.
In the rat carcinogenicity study, a slight, dose-related increase in lens opacity was seen, affecting males only. In addition, increased incidence/severity of retinal degeneration/atrophy was seen in the high-dose group (80 mg/kg/day). The incidence was higher in females, however, more female than male rats survived the study. It was concluded by an independent pathologist that the retinal changes were most likely related to drug-induced pupillary dilatation (mydriasis) which increased the risk of retinal damage in the already light-sensitive albino rat.
In the 52-week rat toxicity study, testicular atrophy was seen at the 60 and 120 mg/kg/day doses of citalopram.
Toxicity studies in dogs revealed that citalopram administration led to fatal ventricular arrhythmias. Consequently, studies were undertaken to elucidate the mechanism of this effect and to determine its relevance to humans. The studies have shown that (1) i.v. infusion of citalopram, at a dose of 20 mg/kg, led to convulsions. The blood levels of citalopram were 1950 ng/mL at this dose. In the presence of diazepam, also infused intravenously, higher doses of citalopram could be infused, namely up to 70 mg/kg (6800 ng/mL). (2) Intravenous infusion of the didemethyl metabolite of citalopram caused QT prolongation in a dose range of 5 to 22 mg/kg. The blood levels of the metabolite were 300 ng/mL at the 5 mg/kg dose. The QT prolongation was dose-dependent. (3) When citalopram, 20 mg/kg, and didemethylcitalopram, 5 mg/kg, were infused concomitantly (in the presence of diazepam in order to prevent convulsions), 5 out of 9 dogs died due to ventricular fibrillation. At these doses, the plasma levels of citalopram and didemethylcitalopram were 1950 ng/mL and 300 ng/mL, respectively. As shown in the table below, there is a substantial difference in the plasma levels of citalopram and its metabolite in dogs and in humans at the recommended therapeutic doses.
| Treatment | Dog ventricular fibrillation | Patients at steady state after a 60 mg/day dose of citalopram |
| citalopram, 20 mg/kg plus didemethylcitalopram, 5 mg/kg | 1950 ng/mL 300 ng/mL | 121 ng/mL 6.3 ng/mL |
Citalopram did not affect the reproductive performance of rats at dosages up to 16 mg/kg/day (males) and 32 mg/kg/day (females). In the teratology studies in rats, effects were observed in the conceptuses at dosages that were toxic to the dams. Minimal developmental toxicity was evident at 32 mg/kg/day: manifested as low incidences of resorptions, slightly reduced fetal and pup weights, and small reversible delays in ossification and postnatal development. In rabbits, dosages of 4.8 mg/kg/day and above were toxic to the dams, and 16 mg/kg/day and above caused deaths. There were no effects on embryo-fetal development at the highest dose that could be assessed (16 mg/kg/day).
Citalopram did not have mutagenic activity in most of the in vitro tests (Ames Salmonella assay; chromosome aberration assay in cultured human lymphocytes; gene mutation assay in cultured mouse lymphoma L5178Y) and in vivo tests (micronucleus test; unscheduled DNA synthesis). However, citalopram was mutagenic in some in vitro studies (Ames Salmonella assay and Chinese hamster lung cell assay).
Citalopram did not show any carcinogenic potential in mice at daily doses of 40-240 mg/kg (1.5 years) and in rats at 8-80 mg/kg (2 years). There was an increased incidence of small intestine carcinoma in rats treated with 8 and 24 mg/kg/day of citalopram but not in rats treated with an 80 mg/kg/day dose.
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