Cipramil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYPRAMIL (CIPRAMIL®)

Composition:

Active substance: citalopram;

1 tablet contains citalopram hydrobromide equivalent to citalopram 20 mg;

Excipients: maize starch; lactose monohydrate; copovidone; glycerol (85 %); microcrystalline cellulose; sodium croscarmellose; magnesium stearate;

Coating: hypromellose, polyethylene glycol 400, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: oval, with a dividing line, film-coated, white tablets, with "C" and "N" imprinted symmetrically on either side of the line.

Pharmacotherapeutic group.

Antidepressants. Selective serotonin reuptake inhibitors.

ATC code N06AB04.

Pharmacological Properties.

Mechanism of Action

Citalopram is a potent inhibitor of serotonin (5-HT) reuptake.

Tolerance to 5-HT reuptake blockade does not develop during prolonged treatment with citalopram.

Citalopram is a highly selective serotonin reuptake inhibitor, with no or minimal effect on the reuptake of noradrenaline, dopamine, or γ-aminobutyric acid (GABA).

In contrast to many tricyclic antidepressants and some other SSRIs, citalopram has no or very low affinity for other receptor types, including serotonin 5-HT1A, 5-HT2 receptors, dopamine D1 and D2 receptors, α1-, α2-, β-adrenergic receptors, histamine H1, muscarinic cholinergic, benzodiazepine, and opioid receptors. The main metabolites of citalopram are also selective serotonin reuptake inhibitors (SSRIs), although their potency and selectivity ratios are lower than those of citalopram. However, the metabolites' selectivity is higher than that of many newer SSRIs. Metabolites do not contribute significantly to the overall antidepressant effect.

Pharmacodynamics.

Suppression of rapid eye movement (REM) sleep is considered a marker of antidepressant activity. Like tricyclic antidepressants, other SSRIs, and MAO inhibitors, citalopram suppresses REM sleep and enhances deep slow-wave sleep.

Although citalopram does not bind to opioid receptors, it enhances the antinociceptive effect of opioid analgesics.

In humans, citalopram does not impair cognitive or psychomotor performance and has no or minimal sedative properties, even when combined with alcohol.

In a double-blind, placebo-controlled ECG study in healthy volunteers, the change from baseline in QTc (Fridericia-corrected) interval was 7.5 (90% CI: 5.9–9.1) ms at a dose of 20 mg/day and 16.7 (90% CI: 15.0–18.4) ms at a dose of 60 mg/day.

Pharmacokinetics.

Absorption

Absorption is nearly complete and independent of food intake. Maximum plasma concentration is reached within 3 hours after administration. The bioavailability of escitalopram is approximately 80%.

Distribution

The apparent volume of distribution (Vd) β is approximately 12–17 L/kg. Plasma protein binding is less than 80% for citalopram and its main metabolites.

Biological Transformation

Citalopram is metabolized into active desmethylcitalopram, didesmethylcitalopram, citalopram-N-oxide, and inactive deaminated propionic acid derivatives. All active metabolites are also SSRIs, although less potent than the parent compound. Unchanged citalopram is the main component in blood plasma. Concentrations of desmethylcitalopram and didesmethylcitalopram typically amount to 30–50% and 5–10% of citalopram concentration, respectively. Citalopram biotransformation is mediated by CYP2C19 (approximately 38%), CYP3A4 (approximately 31%), and CYP2D6 (approximately 31%).

Elimination

The elimination half-life is approximately 1.5 days, and the systemic plasma clearance (Cls) of citalopram is approximately 0.3–0.4 L/min, with oral plasma clearance (Cloral) being about 0.4 L/min.

Citalopram is primarily eliminated via the liver (85%), with the remainder (15%) excreted by the kidneys; 12–23% of the daily dose is excreted unchanged in urine. Hepatic (residual) clearance is approximately 0.3 L/min, and renal clearance is about 0.05–0.08 L/min.

Linearity

The kinetics are linear. Steady-state plasma concentrations are reached within 1–2 weeks after initiation of treatment. A mean concentration of 300 nmol/L (165–405 nmol/L) is achieved at a daily dose of 40 mg.

Elderly Patients (>65 years)

In elderly patients, the elimination half-life is prolonged (1.5–3.75 days) due to reduced metabolic rate, and steady-state concentrations are approximately twice as high compared to younger patients receiving the same dose.

Impaired Liver Function

In patients with impaired liver function, citalopram is eliminated more slowly. Elimination half-life and steady-state concentration values are approximately twice as high as those in patients with normal liver function receiving the same dose.

Impaired Renal Function

In patients with mild to moderate renal impairment, citalopram is eliminated more slowly, but without significant impact on pharmacokinetics. Information on treatment of patients with severe renal impairment (creatinine clearance <30 mL/min) is currently unavailable.

Polymorphism

In vivo studies in humans with reduced CYP2D6 enzyme activity showed no significant changes in plasma citalopram concentrations.

In individuals with reduced CYP2C19 enzyme activity, plasma citalopram concentrations were twice as high. Therefore, as a precautionary measure, in patients identified as poor metabolizers of CYP2C19, it is recommended that the initial dose should not exceed 10 mg.

Clinical characteristics.

Indications.

Treatment of depression of various etiologies and types, prevention of relapses.

Treatment of panic disorders, with or without agoraphobia.

Obsessive-compulsive disorder (OCD).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Concomitant use of monoamine oxidase inhibitors (MAOIs).

Symptoms resembling those of serotonin syndrome have been reported in some cases.

Citalopram must not be used in patients concurrently receiving monoamine oxidasi inhibitors (MAOIs), including the selective MAO-B inhibitor selegiline at daily doses exceeding 10 mg/day.

Citalopram is contraindicated during the first two weeks after discontinuation of irreversible MAOIs. After discontinuation of reversible MAO inhibitors, e.g. moclobemide, citalopram must not be administered during the time period specified in the reversible MAOI product information. MAOI treatment must not be initiated earlier than 7 days after discontinuation of citalopram.

Citalopram is contraindicated in combination with linezolid if adequate means for careful monitoring of blood pressure are not available.

Concomitant use with pimozide is contraindicated.

Citalopram is contraindicated in patients with documented QT interval prolongation or congenital long QT syndrome.

Citalopram is contraindicated in combination with medicinal products known to prolong the QT interval.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Cases of serotonin syndrome have been reported with the use of citalopram together with moclobemide and buspirone.

Contraindicated combinations

Concomitant administration of citalopram and MAOIs may result in severe adverse effects, including serotonin syndrome. Cases of serious and sometimes fatal reactions have been observed with the use of SSRIs in combination with MAOIs, including selegiline, linezolid, and moclobemide, as well as in patients who started MAOI treatment shortly after discontinuation of SSRIs. Some cases presented with symptoms resembling serotonin syndrome. Symptoms of adverse interaction between citalopram and MAOIs include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes ranging from confusion and agitation to delirium and coma.

QT interval prolongation

Pharmacokinetic and pharmacodynamic studies of citalopram administered together with other medicinal products that prolong the QT interval have not been conducted. An additive effect of citalopram and these medicinal products cannot be excluded.

Therefore, concomitant use of citalopram with medicinal products that prolong the QT interval, such as class IA and III antiarrhythmics, antipsychotics (phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (sparfloxacin, moxifloxacin, erythromycin, pentamidine, antimalarials, particularly halofantrine), certain antihistamines (astemizole, mizolastine), etc., is contraindicated.

Pimozide

Single-dose administration of 2 mg pimozide to subjects receiving racemic citalopram at a dose of 40 mg/day for 11 days resulted in increased AUC and Cmax of pimozide, although not systematically throughout the study. Concomitant administration of pimozide and citalopram led to an average increase in QTc interval of approximately 10 msec.

Due to the interaction between citalopram and low doses of pimozide, concomitant use is contraindicated.

Combinations requiring caution

MEDICINAL PRODUCTS CAUSING HYPOKALEMIA/HYPOMAGNESEMIA

Concomitant use of medicinal products that induce hypokalemia/hypomagnesemia should be done with caution, as this may increase the risk of developing malignant arrhythmias.

Selegiline (selective MAO-B inhibitor)

A pharmacokinetic/pharmacodynamic interaction study with concomitant administration of citalopram (20 mg daily) and selegiline (10 mg daily) (a selective MAOI inhibitor) did not show clinically significant interactions.

Concomitant use of citalopram and selegiline at daily doses exceeding 10 mg is contraindicated.

Serotonergic medicinal products

Concomitant use with serotonergic medicinal products (e.g., opioids (including tramadol) and triptans (including sumatriptan and oxitriptan)) may lead to enhanced effects related to 5-hydroxytryptamine.

Until additional information is available, concomitant use of citalopram and 5-hydroxytryptamine agonists such as sumatriptan and other triptans is not recommended (see section "Special precautions for use").

Lithium and tryptophan

No pharmacodynamic interactions were observed in studies of concomitant use of citalopram with lithium. However, cases of enhanced effects have been reported with the use of SSRIs together with lithium and tryptophan; therefore, the combination of citalopram with these agents should be used with caution. Routine monitoring of lithium levels should be continued.

Hypericum perforatum (St. John's wort)

Dynamic interactions between SSRIs and herbal products containing Hypericum perforatum may occur, increasing the risk of adverse effects. Pharmacokinetic interactions have not been studied.

MEDICINAL PRODUCTS AFFECTING BLOOD COAGULATION

Caution is required in patients receiving concomitant anticoagulants, medicinal products affecting platelet function such as nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, dipyridamole, and ticlopidine, or other agents (e.g. atypical antipsychotics, phenothiazines, tricyclic antidepressants) that may increase the risk of bleeding.

ECT (electroconvulsive therapy)

There are no clinical studies assessing the risks or benefits of combined use of ECT and citalopram.

Alcohol

Studies have not demonstrated adverse pharmacodynamic interactions between citalopram and alcohol; however, combination of SSRIs with alcohol is not recommended.

MEDICINAL PRODUCTS THAT LOWER THE SEIZURE THRESHOLD

SSRIs may lower the seizure threshold. Combinations with other agents that lower the seizure threshold (e.g. antidepressants (tricyclics, SSRIs), neuroleptics (phenothiazines, thioxanthenes, and butyrophenones), mefloquine, bupropion, and tramadol) should be used with caution.

Neuroleptics

Experience with citalopram has not revealed clinically significant interactions with neuroleptics. However, as with other SSRIs, pharmacodynamic interactions cannot be excluded.

Pharmacokinetic interactions

The biotransformation of citalopram to demethylcitalopram is mediated by the cytochrome P450 system: isoenzymes CYP2C19 (approximately 38%), CYP3A4 (approximately 31%), and CYP2D6 (approximately 31%). The fact that citalopram is metabolized by more than one cytochrome implies a lower likelihood of inhibition of its biotransformation; therefore, pharmacokinetic interactions with other medicinal products are unlikely.

Food intake

There are no reports on the effect of food intake on the absorption and other pharmacokinetic properties of citalopram.

Effect of other agents on the pharmacokinetics of citalopram

Combination with ketoconazole (a strong CYP3A4 inhibitor) does not alter the pharmacokinetics of citalopram.

A pharmacokinetic interaction study between lithium and citalopram did not reveal any pharmacokinetic interactions.

Cimetidine (a strong inhibitor of CYP2D6, 3A4, and 1A2) causes a moderate increase in mean steady-state levels of citalopram. Caution is recommended when citalopram is used concomitantly with cimetidine, and dose adjustment may be necessary.

Concomitant administration of escitalopram (the active enantiomer of citalopram) and omeprazole (a CYP2C19 inhibitor) at a dose of 30 mg once daily resulted in a minor increase in plasma concentration of citalopram (approximately 50%). Therefore, caution is required when using citalopram concomitantly with CYP2C19 inhibitors (e.g., omeprazole, esomeprazole, fluconazole, fluvoxamine, lansoprazole, ticlopidine) or cimetidine. Based on monitoring of adverse reactions during concomitant therapy, dose reduction of citalopram may be necessary if required.

Effect of citalopram on other medicinal products

Metoprolol

Escitalopram (the active enantiomer of citalopram) inhibits the CYP2D6 enzyme. Caution is recommended when citalopram is used with medicinal products primarily metabolized by this enzyme and having a narrow therapeutic index. This includes, for example, flecainide, propafenone, and metoprolol (for treatment of heart failure), as well as various central nervous system-acting agents primarily metabolized by CYP2D6 (e.g., antidepressants such as desipramine, clomipramine, and nortriptyline, or antipsychotics such as risperidone, thioridazine, and haloperidol). Dose adjustment may also be required. Concomitant use with metoprolol doubled plasma levels of metoprolol, but did not result in a statistically significant increase in the effect of metoprolol on blood pressure and heart rate.

Levomepromazine, digoxin, carbamazepine

Citalopram and didemethylcitalopram are negligible inhibitors of CYP2C9, CYP3A4, and CYP2E1 and only weak inhibitors of CYP1A2, CYP2C19, and CYP2D6 compared to other SSRIs known to be significant inhibitors.

No changes or only very minor changes of clinical significance were observed with the use of citalopram together with substrates of CYP1A2 (clozapine and theophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine, amitriptyline, risperidone), and CYP3A4 (warfarin, carbamazepine and its epoxide metabolites, carbamazepine, and triazolam).

No pharmacokinetic interaction between citalopram and levomepromazine or digoxin was observed (indicating that citalopram does not activate or inhibit P-glycoprotein).

Desipramine, imipramine

In pharmacokinetic studies, no effect on plasma levels of citalopram or imipramine was observed, although the level of desipramine, the main metabolite of imipramine, was increased. When desipramine was combined with citalopram, an increase in desipramine plasma concentration was observed. Dose reduction of desipramine may be necessary.

Special precautions for use.

Use with caution in elderly patients and in patients with impaired renal or hepatic function (see section "Dosage and method of administration").

Antidepressant drugs should not be used to treat children and adolescents (under 18 years of age). Behavioural disorders related to suicide (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behaviour, and anger) have been observed more frequently in clinical trials among children and adolescents receiving antidepressants compared to those receiving placebo. If, due to clinical necessity, a decision is made to initiate treatment, careful monitoring for the emergence of suicidal symptoms in the patient is required. In addition, long-term safety data regarding growth, maturation, cognitive, and behavioural development in children and adolescents are lacking.

Paradoxical anxiety

In some patients with panic disorders, symptoms of anxiety may worsen at the beginning of treatment. This paradoxical reaction usually resolves within the first two weeks of treatment initiation. To reduce the likelihood of a paradoxical anxiogenic effect, a low initial dose is recommended.

Hyponatremia

Hyponatremia has been reported during SSRI use — a rare adverse effect, possibly associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which typically resolves after discontinuation of therapy. The risk group primarily includes elderly women.

Suicide risk / suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicidal acts and manifestations). This risk persists until significant remission is achieved. Since improvement may not occur during the first weeks of treatment, patients should be closely monitored until substantial improvement is established. Clinical experience indicates that suicide risk may increase during the early stages of recovery.

Other psychiatric disorders for which citalopram is prescribed may also be associated with an increased risk of suicidal events. Moreover, such conditions may accompany major depressive disorder. Therefore, the special considerations for citalopram use also apply to other psychiatric disorders.

Patients with a history of suicide attempts or with pronounced suicidal ideation prior to treatment initiation are at high risk of suicide attempts or suicidal thoughts and should be carefully monitored throughout therapy. Additionally, there is a likelihood of increased risk of suicidal behaviour in younger patients.

A meta-analysis of placebo-controlled clinical trials involving adult patients with psychiatric disorders showed an increased risk of suicidal behaviour in patients under 25 years of age taking antidepressants compared to those receiving placebo.

Treatment of patients, especially those at high risk of suicidal behaviour, should be accompanied by close supervision, particularly at the beginning of therapy and after dose adjustments.

Patients and their caregivers should be warned to monitor carefully for any signs of clinical worsening, suicidal behaviour or thoughts, or unusual changes in behaviour, and to seek immediate medical attention if such symptoms develop.

Akathisia / psychomotor restlessness

SSRIs/SSNRIs are associated with the development of akathisia, characterised by an unpleasant, distressing sensation of restlessness and inability to remain still or seated. This condition may occur during the first few weeks of treatment. Increasing the dose in patients experiencing such symptoms may be harmful.

Mania

Citalopram should be used with caution in patients with mania/hypomania.

In patients with bipolar disorder, a shift to manic phase may occur. Citalopram use should be discontinued in patients experiencing a manic episode.

Seizures

There is a potential risk of seizures with the use of antidepressants. Citalopram should be discontinued in any patient who develops seizures or an increase in seizure frequency. Citalopram should be avoided in patients with unstable epilepsy, and patients with controlled epilepsy should be closely monitored. Citalopram should be discontinued if an increase in seizure frequency is observed.

Diabetes mellitus

In patients with diabetes mellitus, SSRI use may alter glycaemic control.

In such cases, dose adjustments of insulin and/or oral antidiabetic agents may be required.

Serotonin syndrome

Serotonin syndrome has been reported rarely with SSRI use. A combination of symptoms such as anxiety, tremor, myoclonus, and hyperthermia may indicate the development of this condition. Citalopram treatment should be immediately discontinued and symptomatic therapy initiated.

Serotonergic drugs

Citalopram should not be used concomitantly with medicinal products that induce serotonergic effects, such as triptans (including sumatriptan and oxitriptan), opioids (including tramadol), and tryptophan (see section "Interaction with other medicinal products and other forms of interaction").

Bleeding

During SSRI use, development and/or prolongation of bleeding events such as ecchymoses, gynaecological, gastrointestinal, and other skin or mucosal bleeding may occur. SSRIs/SSNRIs may increase the risk of postpartum haemorrhage (see sections "Use in pregnancy or breastfeeding" and "Adverse reactions").

SSRIs should be prescribed with caution, especially in patients who are concurrently taking agents affecting blood coagulation or other agents increasing bleeding risk, as well as in patients with a history of bleeding.

Electroconvulsive therapy (ECT)

Clinical experience with concomitant use of SSRIs and ECT is limited; therefore, caution is recommended.

Psychosis

Treatment of depressive episodes in patients with psychosis may exacerbate psychotic symptoms.

QT interval prolongation

Citalopram causes dose-dependent QT interval prolongation. Cases of QT interval prolongation and ventricular arrhythmias, including torsade de pointes, have been reported during the post-marketing period, primarily in women, patients with hypokalaemia or pre-existing QT prolongation, and those with other cardiac conditions.

Caution is recommended in patients with marked bradycardia, recent acute myocardial infarction, or uncompensated heart failure.

Electrolyte disturbances, such as hypokalaemia and hypomagnesaemia, increase the risk of malignant arrhythmias and should be corrected before initiating citalopram therapy.

Before initiating citalopram treatment, ECG parameters should be reviewed in patients with stable cardiac disease.

An ECG should be performed and citalopram discontinued if signs of cardiac arrhythmia develop during treatment.

Closed-angle glaucoma

SSRIs, including citalopram, may affect pupil size, leading to mydriasis. This mydriatic effect may potentially narrow the anterior chamber angle, resulting in increased intraocular pressure and closed-angle glaucoma, particularly in predisposed individuals. Therefore, citalopram should be used with caution in patients with closed-angle glaucoma or a history of glaucoma.

St. John’s wort

Concomitant use of citalopram and herbal preparations containing St. John’s wort may lead to an increased frequency of adverse reactions. Citalopram and St. John’s wort-containing products should not be used simultaneously.

Withdrawal symptoms observed upon discontinuation of SSRIs

Withdrawal symptoms usually occur after abrupt discontinuation of citalopram treatment.

In clinical studies, adverse events following discontinuation were observed subsequently in 40% of patients who had received placebo, compared to 20% of patients who had received citalopram.

The risk of withdrawal symptoms may depend on several factors, including duration of therapy, dosage, and rate of dose reduction.

The most common symptoms include dizziness, sensory disturbances (including paraesthesia), sleep disturbances, anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances. These symptoms are usually mild and transient, but may be severe and/or prolonged in some patients.

Symptoms may appear within the first few days after stopping treatment, although very rare cases have been reported even when a dose was missed.

These symptoms generally resolve within 2 weeks, but may persist longer in some patients (2–3 months or more). Therefore, gradual dose reduction over several weeks or months is recommended when discontinuing the drug, according to patient needs.

Sexual dysfunction

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Persistent sexual dysfunction with symptoms continuing after discontinuation of SSRIs/SNRIs has been reported.

Excipients

The tablets contain lactose monohydrate. Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Based on reproductive toxicity study data (phases I, II, and III), there are no specific concerns regarding the use of citalopram in women of reproductive age.

Pregnancy

Extensive published data from pregnant women (over 2500 documented outcomes) indicate no evidence of teratogenic, foetal, or neonatal toxicity.

Citalopram should not be prescribed to pregnant women unless, after careful evaluation of risks and benefits, a clear need for the drug has been established.

Close monitoring of newborns whose mothers received citalopram during pregnancy, particularly in the third trimester, is recommended.

Abrupt discontinuation of treatment should be avoided.

Newborns whose mothers took SSRIs/SNRIs in late pregnancy may develop symptoms such as respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycaemia, hypertension, hypotension, hyperreflexia, tremor, agitation, irritability, lethargy, persistent crying, somnolence, and sleep disturbances.

These symptoms may result from excessive serotonergic activity or may represent withdrawal symptoms. In most cases, complications manifest immediately or shortly (within 24 hours) after delivery.

Epidemiological data indicate that SSRI use during pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (up to 5 cases per 1000 pregnancies according to observational data), compared to 1–2 cases per 1000 pregnancies in the general population.

Observational data suggest an increased risk (by < 2-fold) of postpartum haemorrhage following SSRI or SNRI use within one month before delivery (see sections "Adverse reactions" and "Special precautions for use").

Lactation

Citalopram passes into breast milk. The dose received by the infant via milk is approximately 5% of the maternal daily dose of citalopram adjusted for body weight (mg/kg). No or minimal effects have been observed in infants. However, available data are insufficient to assess the risk to the infant. Caution is advised.

Fertility

Animal studies have shown that citalopram may affect sperm quality. Clinical experience with some SSRIs in men suggests that effects on sperm quality are reversible. No effect on human fertility has been observed to date.

Ability to affect reaction speed when driving or operating machinery.

Citalopram has a weak or moderate effect on the ability to drive or operate machinery. Patients prescribed psychotropic drugs should be warned of a potential reduction in overall attention and concentration, and of the drug's effects on the ability to drive or operate machinery.

Dosage and Administration

Citalopram should be taken once daily in the morning or evening by adults. Film-coated tablets may be taken independently of food intake, but with sufficient fluid.

If a dosage of 10 mg is recommended, the 20 mg tablet should be divided in half along the score line.

Depression treatment

Initially, adults should take 20 mg of the drug orally once daily. Depending on individual patient sensitivity, the dose may be increased up to a maximum of 40 mg per day.

The antidepressant effect usually occurs within 2–4 weeks. Treatment of depression is symptomatic and therefore long-term, and should generally continue for at least 6 months after remission to prevent relapse. In patients with recurrent (unipolar) depression, maintenance therapy may continue for several years to prevent new episodes.

Panic disorder

To avoid paradoxical reactions (see section "Special precautions"), an initial dose of 10 mg is recommended before increasing the dose to 20 mg per day.

Depending on individual patient sensitivity, the dose may be increased up to a maximum of 40 mg per day.

Maximum efficacy of citalopram in treating panic disorders is achieved after approximately 3 months of continuous treatment and maintained with prolonged therapy.

Depending on the individual patient response, treatment may be continued for months.

Clinical data on efficacy beyond 6 months are insufficient.

Obsessive-compulsive disorder (OCD) treatment

Therapeutic effect in OCD treatment occurs within 2–4 weeks and increases over time. Since OCD is a chronic condition, patients should be treated for a sufficiently long period to ensure absence of symptoms. The recommended initial dose is 20 mg. Depending on individual patient sensitivity, the dose may be increased up to a maximum of 40 mg per day.

Elderly patients (> 65 years)

The dose should be half the recommended daily dose, i.e., 10–20 mg per day; the initial dose should be 10 mg per day. The maximum recommended dose for elderly patients is 20 mg per day.

Children and adolescents (under 18 years of age)

Citalopram should not be used for the treatment of children and adolescents (under 18 years of age), as safety and efficacy in these age groups have not been established.

Dosing in renal impairment

Dose adjustments are not necessary in cases of mild or moderate renal impairment. Caution is recommended in severe renal dysfunction (creatinine clearance less than 30 mL/min).

Dosing in hepatic impairment

For patients with mild or moderate liver impairment, the recommended initial dose for the first 2 weeks is 10 mg. Depending on individual patient sensitivity, the dose may be increased up to a maximum of 20 mg per day. Extreme caution and careful dose titration are recommended for patients with severe hepatic impairment. These patients should undergo clinical monitoring.

Reduced CYP2C19 function

For patients with reduced CYP2C19 function, the recommended initial dose for the first 2 weeks is 10 mg per day. Depending on treatment efficacy and individual patient tolerability, the dose may be increased up to a maximum of 20 mg per day.

SSRI discontinuation symptoms

Abrupt discontinuation should be avoided. If treatment with citalopram is to be discontinued, the dose should be gradually reduced over at least 1–2 weeks to minimize the risk of withdrawal reactions. If adverse reactions occur after dose reduction or discontinuation, consideration should be given to resuming the previous dose. Subsequently, the dose may be reduced more slowly.

Children

Antidepressants should not be used for the treatment of children and adolescents (under 18 years of age). Suicidal behavior (suicidal ideation and suicide attempts) and hostility (predominantly aggression, oppositional behavior, and anger) have been observed more frequently in children and adolescents taking antidepressants compared to those receiving placebo in clinical trials. If a decision to prescribe is made based on clinical judgment, careful monitoring for the emergence of suicidal symptoms is required. Furthermore, long-term safety data regarding growth, maturation, and cognitive and behavioral development in children and adolescents are lacking.

Overdose

Toxicity. Comprehensive clinical data on citalopram overdose are limited and, in many cases, involve concomitant overdose with other drugs or alcohol. Fatal cases have been reported following overdose with citalopram alone; however, most fatalities are associated with concomitant overdose of other medications.

Symptoms: seizures, tachycardia, somnolence, QT interval prolongation, coma, vomiting, tremor, hypotension, cardiac arrest, nausea, serotonin syndrome, anxiety, bradycardia, dizziness, cardiac block, QRS prolongation, hypertension, mydriasis, supraventricular tachycardia, stupor, increased sweating, cyanosis, hyperventilation, atrial and ventricular arrhythmias.

Treatment. There is no specific antidote. Treatment is symptomatic and supportive. Gastric lavage, activated charcoal, and an osmotic laxative (such as sodium sulfate) should be administered. Patients with impaired consciousness should be intubated. ECG and vital sign monitoring are recommended.

ECG monitoring is recommended in cases of overdose for patients with congestive heart failure/bradyarrhythmias, patients taking drugs that prolong the QT interval, or patients with metabolic disorders, such as hepatic disorders.

Adverse reactions.

The adverse effects of citalopram are transient and mild. They most commonly occur during the first 1 or 2 weeks of treatment and gradually diminish over time.

Dose-dependent symptoms include increased sweating, dry mouth, insomnia, somnolence, diarrhea, nausea, and fatigue.

The frequency of adverse reactions associated with SSRIs and/or citalopram observed in ≥ 1 % of patients during double-blind, placebo-controlled studies or in the post-marketing period is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), or frequency not known (cannot be estimated).

Number of patients: Citalopram / Placebo = 1346 / 545

1 Cases of suicidal thoughts and suicidal behavior were reported during treatment with citalopram or shortly after discontinuation.

2 Such cases have been reported for the therapeutic class of SSRIs or SNRIs (see sections "Use during pregnancy or breastfeeding", "Special precautions for use").

Bone fractures

Epidemiological studies, predominantly involving patients aged over 50 years, show an increased risk of bone fractures with the use of tricyclic antidepressants and SSRIs. The mechanism of this phenomenon is unknown.

QT interval prolongation

Cases of QT interval prolongation and ventricular arrhythmia, including torsades de pointes, have been reported during the post-marketing period, predominantly in women, patients with hypokalemia, or those with pre-existing QT interval prolongation and other cardiac diseases.

Withdrawal symptoms observed upon discontinuation of SSRIs

Discontinuation of citalopram treatment (particularly abrupt discontinuation) usually leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions.

These symptoms are generally mild to moderate in severity and transient; however, in some patients they may be severe and/or prolonged. Therefore, when citalopram treatment is no longer required, a gradual reduction of the dose is recommended.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Packaging.

Film-coated tablets, № 28 (14×2) in blisters, in a cardboard box.

Prescription status. By prescription only.

Manufacturer.

H. Lundbeck A/S.

Manufacturer's address and place of business.

Ottiliavej 9, 2500 Valby, Denmark.