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Instructions / Instruction for use: Citalopram

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Latin name of substance Citalopram

Citalopramum (genus. Citaloprami)

Chemical name

1- [3- (Dimethylamino) propyl] -1- (p-fluorophenyl) -5-phthalanecarbonitrile (as the hydrobromide)

Gross formula

C20H21FN2O∑HBr

Pharmacological group:

Antidepressant

The nosological classification (ICD-10)

F32 Depressive episode: Adynamic subdepression; Astheno-adynamic subdepressive states; Asthenoadressive disorder; Astheno-depressive disorder; Asthenodepressive state; Astheno-depressive state; Major Depressive Disorder; Vyaloapatichesky depression with retardation; Double Depression; Depressive pseudodement; Depressive illness; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive disorders; Depressive syndrome; Depressive syndrome larviated; Depressive syndrome in psychoses; Depressed masks; Depression; Depression Depletion; Depression with the phenomena of inhibition within the framework of cyclothymia; Depression is smiling; Involutional depression; Involutionary melancholy; Involutional depression; Manic-depressive disorder; Masked Depression; Melancholic Attack; Neurotic depression; Neurotic depression; Shallow Depression; Organic depression; Organic depressive syndrome; Simple depression; Simple melancholic syndrome; Psychogenic depression; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Reactive depression; Recurrent depression; Seasonal depressive syndrome; Severostatic depression; Senile Depression; Symptomatic Depression; Somatogenic depression; Cyclotymic depression; Exogenous depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome

F33 Recurrent depressive disorder: Major depressive disorder; Secondary depression; Double Depression; Depressive pseudodement; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive syndrome; Depressed masks; Depression; Depression is smiling; Involutional depression; Involutional depression; Masked Depression; Melancholic Attack; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Exogenous depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome

F40.0 Agoraphobia: Fear of open space; Fear of being in a crowd

F41.0 Panic disorder [episodic paroxysmal anxiety]: Panic state; Panic attack; Panic; Panic disorders

F42 Obsessive-compulsive disorder: Obsessive-compulsive syndrome; Obsessive compulsive states; Obsessive-compulsive syndrome; The Obsession Syndrome; The obsession neurosis; Obsessive-compulsive neurosis; Obsessions

CAS code

59729-32-7

Characteristics of the substance Citalopram

Antidepressant group SSRIs.

Citalopram hydrobromide is a white or almost white powder. It is soluble in water, soluble in ethanol. Molecular weight 405.35.

Pharmacology

Pharmacological action - antidepressant.

In animal studies in vitro and in vivo, the ability to selectively inhibit reverse neuronal capture of serotonin in the CNS with a minimal effect on the reuptake of norepinephrine and dopamine has been shown to be highly selective. Tolerance to inhibition of the capture of serotonin does not develop with prolonged (14 days) administration of rats. Does not interact or has a very weak ability to bind to 5-HT1A, 5-HT2A, dopamine D1 and D2, alpha1, alpha2 and beta adrenoreceptors, histamine H1 receptors, GABA and benzodiazepine receptors, muscarinic cholinergic receptors.

The antidepressant effect develops after 2-4 weeks of treatment. When ingestion Cmax is achieved in 2-4 hours Bioavailability - about 80% (does not depend on food intake). Pharmacokinetics has a linear dose-dependent character with single and multiple doses (doses in the range of 10-60 mg / day). When taking 1 time per day, the equilibrium concentration in the plasma is established after 1-2 weeks of therapy and 2.5 times higher than the concentration in the blood after taking a single dose. The volume of distribution is about 12 l / kg. Penetrates into breast milk. Metabolized mainly in the liver by demethylation, deamination, oxidation with the formation of demethyl citalopram (DCT) and didemethylcitalopram (DDTST), citalopram-N-oxide and deaminated derivative of propionic acid. The binding of citalopram and its two metabolites (DCT and DDTST) to plasma proteins is less than 80%. In human plasma, citalopram is predominant in unchanged form. In an equilibrium state, the concentrations of metabolites in the plasma are approximately 1/2 (DCT) and 1/10 (DDTST) from the concentration of citalopram. In vitro studies have shown that the pharmacological activity of citalopram (inhibition of serotonin reuptake) is 8 times that of its metabolites. In vitro studies using human liver microsomes indicate the involvement of CYP3A4 and CYP2C19 isoenzymes in the process of N-demethylation of citalopram. The final T1 / 2 is 35 hours. It is excreted by the kidneys and through the intestine. It is shown that after intravenous administration it is determined in urine in unchanged form (about 10%) and in the form of demethylcitalopram (5%). The systemic clearance of citalopram is 330 ml / min, of which approximately 20% is renal.

Dependence of pharmacokinetics parameters on some factors

Age. In 2 studies on healthy volunteers it was shown that the pharmacokinetic parameters of citalopram in young people and people over 60 years old are comparable. With the introduction of a single dose in elderly people, AUC (by 30%) and T1 / 2 (by 50%) were increased, against the background of repeated intake the same parameters were increased by 23 and 30%, respectively.

Floor. In 3 pharmacokinetic studies (N = 32), the AUC of citalopram in women was 1.5-2 times higher than in men. This difference was not observed in 5 other pharmacokinetic studies (N = 114). In clinical studies, there was no difference in the values of the equilibrium concentration of citalopram in the serum in men (N = 237) and in women (N = 388). The pharmacokinetics of metabolites of DCT and DDTST for men and women does not differ.

Violation of the function of the liver. In patients with impaired hepatic function, citalopram clearance was reduced by 37%, plasma concentration and T1 / 2 (2-fold) were increased in comparison with these parameters in healthy people.

Impaired renal function. In patients with mild to moderate renal impairment, citalopram clearance was reduced by 17% compared to healthy individuals. There is no information on the pharmacokinetic parameters of citalopram in patients with severe renal insufficiency (with creatinine clearance less than 20 mL / min).

In vitro studies, no inhibitory effect of citalopram on CYP3A4, CYP2S9, CYP2E1 was detected, and a weak inhibition of CYP1A2, CYP2D6 and CYP2S19 was detected. It is assumed that in vivo citalopram has a weak effect on the cytochrome P450 enzyme group, but data on this issue are limited.

Since CYP3A4 and CYP2S19 are involved in the metabolism of citalopram, strong inhibitors of CYP3A4 (including ketoconazole, itraconazole, macrolides) and strong inhibitors of CYP2C19 (including omeprazole) can reduce the clearance of citalopram. However, the combined use of citalopram and ketoconazole did not reveal a significant change in the pharmacokinetics of citalopram (perhaps because citalopram is metabolized not only by this enzyme and inhibition of only one enzyme does not significantly reduce clearance).

The equilibrium concentrations of citalopram do not significantly differ in weak and strong metabolizing agents, which indicates a low probability of a clinically significant interaction of citalopram with CYP2D6 inhibitors.

Toxicological studies in animals

Chronic toxicity. Two-year studies of the carcinogenicity of citalopram in albino rats have revealed pathological changes in the retina (degeneration / atrophy). An increase in both the frequency and severity of the retinal pathology was observed in males and females who received 80 mg / kg / day (13 times higher than MPDM - 60 mg / day, calculated in mg / m2). Similar changes were not observed when citalopram was administered to rats at doses of 24 mg / kg / day for 2 years, mice - 240 mg / kg / day for 18 months, dogs - 20 mg / kg / day for 1 year (4, 20 and 10 times higher than MPDH). Additional studies to study the mechanism of development of this pathology have not been carried out, the potential significance of the data obtained for humans has not been established.

Citalopram caused a change in the function of the cardiovascular system in dogs: in a one-year toxicological study, 5 out of 10 beagle dogs ingested 8 mg / kg / day of citalopram (4 times higher than the MPDR - 60 mg / day, calculated in mg / m2), suddenly died between 17 and 31 weeks from the start of treatment. The data of this study do not allow direct comparison of plasma levels of citalopram and its metabolites (DCT and DDTST) in dogs and humans, but it is established that in dogs the level of these metabolites prevails over the level of citalopram itself. There were no cases of sudden death in rats receiving doses up to 120 mg / kg / day, at which levels of citalopram, DCT and DDTST were similar to those in dogs receiving 8 mg / kg / day. Subsequent studies using intravenous administration showed that in beagle dogs, DDTST causes QT prolongation, which is a known risk factor for the observed outcome in dogs. This effect was observed at doses giving the peak of the levels (Cmax) of DDTST in plasma 810-3250 nM (39-155 times higher than the equilibrium level of DDTST, measured with the reception of MPDH). In Cmax dogs, DDTST in plasma and Cmax of citalopram are approximately equal, whereas in humans the equilibrium Cmax of DDTST was less than 10% of the equilibrium Cmax of citalopram. The results of the determination of the concentration of DDTST in plasma in 2020 patients taking citalopram showed that the level of DDTST exceeds 70 nM; the highest value of the level of DDTST in humans with an overdose was 138 nM. Although DDTST in human plasma is usually contained in smaller quantities than in dogs, the existence of individuals that can have a high level of DDCR is not excluded. The possibility of DCT - the main metabolite of citalopram in humans, to elongate the QT interval in dogs is not investigated, because DTST in these animals quickly turns into DDTST.

Carcinogenicity, mutagenicity, effects on fertility

Carcinogenicity. The evaluation of the carcinogenicity of citalopram was performed in NMRI / BOM line mice and COBS WI rats treated with food for 18 and 24 months, respectively. In mice receiving doses up to 240 mg / kg / day (20 times greater than MPDM 60 mg / day, calculated in mg / m2), there was no carcinogenic effect. In rats treated with doses of 8 or 24 mg / kg / day (approximately 1.3 and 4 times higher than MPDT in mg / m2), small-cell bowel cancer has been reported (the significance of the data obtained is not known to humans).

Mutagenicity. Citalopram showed mutagenic activity in an in vitro bacterial mutation test (Ames test) in two of the five strains of bacteria (Salmonella TA98 and TA1537) in the absence of metabolic activation. The clastogenic effect in an in vitro test for the detection of chromosomal aberrations in lung cells of Chinese hamsters in the presence and absence of metabolic activation was noted. No mutagenic activity was detected in the in vitro test on mouse lymphoma cells and in a double in vitro / in vivo DNA synthesis test in rat hepatocytes. It was shown that citalopram did not exhibit clastogenic activity in the in vitro test for the detection of chromosomal aberrations in human peripheral blood lymphocyte culture and in two micronucleus tests in mice (in vivo).

Violation of fertility. In males and female rats receiving citalopram inside before and during mating and pregnancy at doses of 16/24 (males / females), 32, 48 and 72 mg / kg / day, mating was reduced at all doses studied. Fertility decreased at doses ≥ 32 mg / kg / day (about 5 times the MPDM - 60 mg / day, calculated in mg / m2). The duration of the gestation period increased at a dose of 48 mg / kg / day (about 8 times higher than MPDH).

Clinical trials

The efficacy of citalopram in the treatment of depression was established in 2 placebo-controlled studies lasting 4-6 weeks in adult outpatients (age 18-66 years) with a large depressive episode (DSM-IV). Severity of symptoms in patients was recorded using the Hamilton scales, Montgomery-Asberg scales, and the scale of the overall clinical impression.

Adequate controlled studies of the efficacy of citalopram in the treatment of hospitalized patients with depression were not conducted.

The effectiveness of citalopram for maintenance therapy for 24 weeks after 6-8 weeks of acute treatment was demonstrated in 2 long-term placebo-controlled trials.

Application of the substance Citalopram

According to the State Register1, citalopram is indicated for the treatment of depression of various genesis, panic disorders (including agoraphobia), obsessive-compulsive disorders.

According to the Physicians Desk Reference (2009) 2, citalopram is indicated for the treatment of depression.

Contraindications

Hypersensitivity, incl. to escitalopram, simultaneous administration of MAO inhibitors.

Update of information

Contraindications (optional)

Congenital syndrome of prolongation of the QT interval.

Restrictions on the use

Pregnancy, breast-feeding, children's age (safety and effectiveness of use in children are not defined).

Update of information

Restrictions on use (optional)

Bradycardia, hypokalemia, hypomagnesemia, recently transferred myocardial infarction, decompensated heart failure.

Application in pregnancy and lactation

When pregnancy is possible, if the expected effect of therapy exceeds the potential risk for the fetus (adequate and strictly controlled studies of safety of use in pregnant women have not been conducted).

In experimental studies of reproduction in animals (rats, rabbits), unfavorable effect of citalopram on embryo / fetal and postnatal development was revealed, including. teratogenic effects (in rats), when administered at doses exceeding therapeutic values for humans.

Based on the results of two studies, the administration of citalopram to pregnant rats inside at doses of 32, 56 and 112 mg / kg / day during organogenesis was accompanied at high doses (about 18 times higher than in MPD) by decreased embryo / fetal growth and survival of offspring, fetal disorders (including violations of the development of the cardiovascular system and skeleton), toxicity for the mother's body (clinical signs, reduction in weight gain). At a dose of 56 mg / kg / day (approximately 9 times higher than MPDH), no adverse effects were observed.

In the study, rabbits showed no adverse effect on embryo / fetal development at doses up to 16 mg / kg / day (approximately 5 times the MRDD).

Administration of citalopram to pregnant rats at doses of 4.8, 12.8 and 32 mg / kg / day, from late gestation to weaning, resulted in an increase in mortality of offspring within 4 days after birth and sustained growth retardation at the highest doses approximately 5 times higher than the MPD). At a dose of 12.8 mg / kg / day (approximately 2 times higher than MPDR), no adverse effects were observed. Similar effects on the effect on mortality and growth of offspring were observed when females received doses ≥ 24 / mg / kg / day (about 4 times the MPDR) during pregnancy and in the early lactation period, the dose-response relationship was not revealed in this study.

The action category for fetus by FDA is C.

Lactation. There are 2 reports of cases of excessive drowsiness, reduced intake of food and body weight in infants breastfed by women taking citalopram. In one case, the baby completely recovered after citalopram was stopped by the mother.

Breastfeeding women should stop breastfeeding or taking citalopram.

Side effects of the substance Citalopram

Side effects associated with discontinuation of treatment in short-term placebo-controlled trials. Based on placebo-controlled trials of up to 6 weeks, 16% of the 1063 patients who received citalopram at doses of 10 to 80 mg per day interrupted treatment due to side effects, compared to 8% of the 446 patients who received the placebo. The side effects associated with cessation of treatment and those recognized by citalopram (ie, observed in at least 1% of patients receiving citalopram, 2 times more likely than placebo) include the following: asthenia 1% (<1%), nausea 4% (0%), dry mouth 1% (<1%), vomiting 1% (0%), dizziness 2% (<1%), insomnia 3% (1%), drowsiness 2% (1%), agitation 1% (<1%).

Side effects observed in placebo-controlled clinical trials. The table shows the side effects observed in patients who received citalopram at doses of 10 to 80 mg per day for 6 weeks (adverse effects noted in at least 2% of patients and exceeding the placebo frequency were indicated).

Body Systems / Side Effects Percent (%) of patients
Citalopram (N=1063) Placebo (N=446)
Disorders of the autonomic nervous system
Dry mouth 20 14
Increased sweating 11 9
Disorders of the central and peripheral nervous system
Tremor 8 6
Gastrointestinal disorders
Nausea 21 14
Diarrhea 8 5
Dyspepsia 5 4
Vomiting 4 3
Abdominal pain 3 2
common
Fatigability 5 3
Fever 2 <1
Musculo-skeletal system disorders
Arthralgia 2 1
Myalgia 2 1
Psychiatric Disorders
Drowsiness 18 10
Insomnia 15 14
Anxiety 4 3
Anorexia 4 2
Agitation 3 1
Dysmenorrhea * 3 2
Lowering the libido 2 <1
Yawn 2 <1
Disorders of the respiratory system
Upper respiratory tract infection 5 4
Rhinitis 5 3
Sinusitis 3 <1
Urogenital disorders
Violation of ejaculation ** (mainly delay) 6 1
Impotence** 3 <1

* Fixed only in women: N = 638 (citalopram), N = 252 (placebo).
** Fixed only in men: N = 425 (citalopram), N = 194 (placebo)

Adverse effects observed in these clinical trials in 2% of patients and observed less frequently than placebo: headache, asthenia, dizziness, constipation, palpitation, pharyngitis, urination disorder, back pain.

The dose-response rate was evaluated at fixed doses in patients with depression receiving placebo or citalopram at doses of 10, 20, 40 and 60 mg. Using Jonckheer's test, a positive correlation (p <0.05) was found for the following effects: fatigue, impotence, insomnia, drowsiness, yawning.

Change of vital functions. There were no clinically significant changes in the indices of vital functions (pulse, SAD, DAD), incl. Orthostatic changes with a change in the position of the body on the background of citalopram treatment compared with placebo.

Change in body weight. In controlled trials, weight loss was about 0.5 kg (there was no change in the placebo group).

Change in laboratory indicators. Clinically significant changes in laboratory tests were not observed.

Changing ECG. Comparison of ECG in patients receiving citalopram (n = 802) and placebo (n = 241) showed that a statistically significant difference was only a decrease in heart rate with citalopram.

Interaction

Simultaneous use with MAO inhibitors can lead to increased pressure and excitation. Citalopram can enhance the effects of sumatriptan and other serotonergic drugs, increase the level of metoprolol in plasma (the result of the interaction is not clinically significant) and plasma concentration (by 50%) of the active metabolite of imipramine (the clinical significance of the effect is unknown).

Cimetidine increases AUC (by 43%) and Cmax (by 39%) citalopram. There was no clinically significant interaction with digoxin, warfarin, carbamazepine, triazolam, ketoconazole, lithium (with caution, since lithium may increase the serotonergic effect of citalopram) and alcohol.

Update of information

Interaction with drugs extending the QT interval

Due to the risk of prolonging the QT interval, citalopram should not be used in patients who take other drugs prolonging the QT interval. Such drugs include antiarrhythmic agents of class 1A (eg, quinidine, procainamide) and class III (eg, amiodarone, sotalol, some antipsychotics (eg, chlorpromazine, thioridazine), some antibacterial drugs (eg gatifloxacin, moxifloxacin), etc.

Overdose

In clinical trials with an overdose of citalopram (up to 2000 mg), no lethal cases were noted. In post-marketing reports of drug overdose, including citalopram, 12 deaths were recorded, 10 of which were combined with other drugs and / or alcohol, and 2 - with only citalopram (3920 mg and 2,800 mg); 1 case of an overdose without a lethal outcome with 6000 mg was also reported.

Symptoms: dizziness, increased sweating, nausea, vomiting, tremor, drowsiness, sinus tachycardia. In more rare cases - amnesia, confusion, coma, convulsions, hyperventilation of the lungs, cyanosis, rhabdomyolysis, ECG change (including QT lengthening with nodal rhythm and ventricular arrhythmia and 1 possible case of torsades de pointes).

Treatment: gastric lavage and the use of activated charcoal. Maintenance of airway patency for adequate ventilation and oxygenation. It is recommended to closely monitor and monitor vital functions, incl. heart function, symptomatic and supportive therapy. Due to the high volume of citalopram distribution, the effectiveness of such activities as forced diuresis, dialysis, hemoperfusion and exchange blood transfusion is unlikely. There is no specific antidote.

Routes of administration

Inside.

Precautions for the substance Citalopram

Clinical impairment and risk of suicide

In short-term studies of major depressive disorder according to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders (4th ed.) - Diagnostic and Statistical Manual of Mental Disorders, 4th edition) and other mental illnesses, there was an increased risk of suicidality (suicidal intentions or attempts at suicide) with antidepressants compared with placebo in children, adolescents and young people (18-24 years old). When appointing citalopram or any other antidepressant, patients of these age groups should assess the possible risk. In short-term studies in adults over 24 years of age, it has been shown that the risk of suicidality with antidepressants compared with placebo does not increase, and in patients over 65 years of age it decreases. Depression and some other mental illnesses are associated with an increased risk of suicide. When starting therapy with antidepressants, careful monitoring of patients of any age is necessary to detect clinical deterioration, suicidality or unusual behavior change in a timely manner. Relatives of patients and persons caring for them need to be aware of the need for close monitoring of patients and timely informing the doctor.

The combination with MAO inhibitors

With the simultaneous administration of drugs from the group of serotonin reuptake inhibitors in combination with MAO inhibitors, patients reported serious, sometimes fatal reactions, including hyperthermia, rigidity, unstable vital signs with possible rapid fluctuations, changes in mental state (including agitation, up to and including delirium and coma). Similar reactions were reported in patients who started taking MAO inhibitors shortly after discontinuation of citalopram treatment. Therefore, you should not combine citalopram with MAO inhibitors or prescribe it within the first two weeks after they are discontinued. At the end of the course of citalopram treatment, you should also take a break 2 weeks before taking MAO inhibitors.

The possibility of developing hyponatremia (several reported cases), as well as the syndrome of inadequate secretion of ADH, that occur after discontinuation of treatment and / or medical intervention should be considered.

Based on placebo-controlled trials, some of which included patients with bipolar disorder, 0.2% of the 1063 patients who received citalopram (compared with 446 patients receiving placebo) had an activation of mania / hypomania. Citalopram (like other antidepressants) should be cautiously prescribed to patients with a history of mania.

Caution is necessary, as with other antidepressants, if there is an epileptic seizure in the history.

In studies on healthy volunteers receiving doses of 40 mg / day, there was no decrease in mental activity and the rate of psychomotor reactions. However, patients should be warned about the need to be cautious when working with potentially dangerous mechanisms, incl. when driving a car.

Clinical experience with citalopram in patients with concomitant diseases is limited. Care must be taken in cases of diseases accompanied by a disturbance in metabolism or hemodynamics.

There were no systematic observations in patients with myocardial infarction or unstable cardiac diseases, these patients were excluded from clinical premarketing studies. However, ECG analysis in 1116 patients receiving citalopram showed that citalopram was not associated with the development of clinically significant ECG abnormalities.

Care should be taken when taking other drugs with a central effect at the same time.

In the experimental, as well as in clinical studies, there were no cases of abuse, tolerance, physical dependence. However, these observations were not systematic, and careful monitoring of patients with a history of drug abuse is required.

Update of information

The prolongation of the QT interval is associated with high doses of citalopram

The FDA (Food and Drug Administration) notified medical professionals and patients in the US that the citalopram antidepressant should no longer be used at doses exceeding 40 mg per day, as this can cause abnormal changes in the electrical activity of the heart (prolongation of the QT interval on the ECG) and lead to disturbance of the heart rhythm (including the development of torsade de pointes), which can be fatal.

Especially at risk of such changes (prolongation of the QT interval and the development of heart rhythm disturbances) patients with low levels of potassium and magnesium in the blood.

According to the FDA, studies have not revealed the benefits of taking citalopram in doses above 40 mg per day in the treatment of depression. Previously, the instructions for use indicated that some patients may take this antidepressant at a daily dose of 60 mg.

Serotonin syndrome

There are reports of the development of a potentially life-threatening serotonin syndrome with the use of SSRIs and SSRIs, incl. citalopram, especially with the combined use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium preparations, tramadol, tryptophan, buspirone and St. John's Wort preparations), as well as drugs that disrupt serotonin metabolism (in particular, MAO inhibitors, linezolid, methylthioninium chloride IV).

Elongation of the QT interval and torsade de pointes

Since citalopram causes a dose-dependent lengthening of the QT interval, it should not be used at doses above 40 mg / day. Postmarketing reports on the development of torsade de pointes in patients receiving citalopram have been noted. Citalopram is contraindicated in patients with congenital syndrome of QT interval prolongation. Hypokalemia and hypomagnesemia should be corrected before treatment with citalopram. It is recommended ECG-control in patients with heart failure, bradyarrhythmia, as well as with simultaneous reception of drugs that can prolong the QT interval. It is not recommended to exceed the dose of 20 mg / day in weak metabolizers for the isoenzyme CYP2C9 and in patients taking concomitantly inhibitors of CYP2C9.