Deprecitel 10 Mg/20 Mg/40 Mg Tablets

DEPRECITEL is indicated for the treatment of:

• Depression and prevention of relapse.
• Panic disorders with or without agoraphobia.
• Obsessive-compulsive disorder (OCD).

Posology

Treating Depression

20 mg a day as a single dose. Dosage may be increased by 20 mg a day at intervals of at least one week to a maximum of 40 mg depending on the patientu2019s response. Duration of treatment The antidepressant effect usually sets in after 2 to 4 weeks. Treatment with DEPRECITEL is symptomatic and must therefore be continued for an appropriate length of times, usually up to 6 months after recovery in order to prevent relapse.

Treating Panic Disorder

10 mg a day as a single dose for the first week then increased to 20 mg a day. The dose may be increased thereafter as required to a maximum of 40 mg a day depending on the patientu2019s response.

Treating Obsessive Compulsive Disorder (OCD)

20 mg a day as a single dose. This dose can be increased by 20 mg increments to a maximum of 40 mg a day depending on the patientu2019s response. Duration of treatment The onset of action in treating OCD is 2 - 4 weeks with further improvement over time.

Special populations

Elderly patients (> 65 years of age) For elderly patients the dose should be decreased to half of the recommended dose, e.g., 10 u2013 20 mg daily. The recommended maximum dose for the elderly is 20 mg daily.

Renal impairment Dose adjustment is not necessary in cases of mild or moderate renal impairment. DEPRECITEL is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min) (see section 4.3 and 5.2)

Hepatic impairment An initial dose of 10 mg daily for the first two weeks of treatment is recommended in patients with mild or moderate hepatic impairment. Depending on individual patient response, the dose may be increased to a maximum of 20 mg daily. Caution and extra careful dose titration is advised in patients with severely reduced hepatic function.

Poor metabolisers of CYP2C19 An initial dose of 10 mg daily during the first two weeks of treatment is recommended for patients who are known to be poor metabolisers with respect to CYP2C19. The dose may be increased to a maximum of 20 mg daily depending on individual patient response.

Withdrawal symptoms seen on discontinuation Abrupt discontinuation should be avoided. When stopping treatment with DEPRECITEL the dose should be gradually reduced over a period of at least one or two weeks in order to reduce the risk of withdrawal symptoms (see section 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the medical practitioner may continue decreasing the dose, but at a more gradual rate.

Paediatric population DEPRECITEL should not be used in the treatment of children and adolescents under the age of 18 years (see section 4.3 and 4.4).

Method of administration DEPRECITEL tablets are administered as a single daily (oral) dose. DEPRECITEL should be gradually withdrawn during a couple of weeks when stopping therapy (see section 4.4). DEPRECITEL may be taken with or without food in the morning or evening.

• Hypersensitivity to citalopram or any of the excipients listed in section 6.1.
• DEPRECITEL is contraindicated in children and adolescents under the age of 18 years (see section 4.4).
• MAOIs (monoamine oxidase inhibitor): Cases of serious and sometimes fatal reactions have been reported in patients receiving and SSRI in combination with a MAOI, including selective MAO - B inhibitor selegiline and the reversible MAOI (RIMA) moclobemide and in patients who have discontinued an SSRI and have been started on a MAOI. Some cases presented with features resembling serotonin syndrome.
• DEPRECITEL must not be used in combination with a MAOI, including selegiline in doses above 10 mg daily.
• At least 14 days should elapse between discontinuing the non-selective MAOI and minimum one day after discontinuation of moclobemide before initiating therapy with DEPRECITEL. MAOIs should not be introduced for 7 days after discontinuation of DEPRECITEL (see section 4.5).
• DEPRECITEL is contraindicated in combination with linezolid.
• DEPRECITEL should not be used concomitantly with pimozide (see section 4.5).
• Severe renal impairment (creatinine clearance less than 30 mL/min).
• DEPRECITEL is contraindicated in patients with known QT-interval prolongation or congenital long QT syndrome.
• DEPRECITEL is contraindicated together with medicines that are known to prolong the QT-interval (see section 4.5).

Suicidality Patients with major depressive disorder, both adults and children, may experience worsening of their depression and or the emergence of suicidal ideation and behaviour, whether or not they are taking antidepressant medicines. This risk may persist until significant remission occurs. Patients should be monitored during early therapy until improvement in depression is observed because suicide is an inherent risk in depressed patients. A causal role, however, for antidepressant medicines in inducing such behaviour has not been established. Patients being treated with DEPRECITEL should, nevertheless, be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy, or at any time of dose changes, either increases or decreases. Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and non-psychiatric disorders.

The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness, impulsivity, akathisia, hypomania and mania). Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing DEPRECITEL, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patientu2019s presenting symptoms.

Withdrawal symptoms seen on discontinuation of SSRI treatment If the decision is made to discontinue treatment, DEPRECITEL should be tapered (see section 4.2). Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense 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. Generally, these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2 - 3 months or more). It is therefore advised that citalopram should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see u201cWithdrawal symptoms seen on discontinuation of citalopramu201d, section 4.2)

DEPRECITEL should be used with caution in: Elderly patients u2022 Elderly patients because of a longer half-life and decreased clearance due to a reduced rate of metabolism. A lower dose is recommended in the elderly (see section 4.2).

Reduced liver function u2022 Hepatic impairment - Clearance of DEPRECITEL is reduced. Cautious dosage titration and a lower maximum dose are recommended.

Reduced kidney function u2022 Renal impairment - Elimination is decreased. If creatine clearance is less than 30 mL/min DEPRECITEL should not be used (see section 4.3).

Seizures or history thereof u2022 There is an increased risk of seizures. DEPRECITEL should be used with caution in patients with controlled epilepsy and avoided in patients who are poorly controlled epileptics. Care is advised in patients receiving electroconvulsive therapy.

Mania or history of mania u2022 In patients with manic-depressive illness a change towards the manic phase may occur. Condition may be re-activated. DEPRECITEL should be discontinued if the patient enters the manic phase.

Paradoxical anxiety u2022 Some patients with panic disorder may experience intensified anxiety symptoms at the start of treatment with antidepressants. This paradoxical reaction usually subsides within the first two weeks of starting treatment. A low starting dose is advised to reduce the likelihood of a paradoxical anxiogenic effect (see section 4.2).

Psychosis u2022 Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.

Bradycardia u2022 DEPRECITEL may cause a reduction in heart rate. Caution is advised in patients with a pre-existing slow heartrate.

Diabetes mellitus u2022 Occurrences of hypoglycaemia have been reported. In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

Other medicines u2022 DEPRECITEL should not be used with monoamine oxidase inhibitors; imipramine; moclobemide; alcohol; warfarin; and cimetidine (see section 4.3 and 4.5).

Citalopram, as in DEPRECITEL, should not be used concomitantly with medicines with serotonergic effects such as sumatriptan or other triptans, tramadol, oxitriptan and tryptophan (see section 4.3 and 4.5).

Undesirable effects may be more common during concomitant use of, as in DEPRECITEL, and herbal preparations containing St John's wort (Hypericum perforatum). Therefore, DEPRECITEL and St John's wort preparations should not be taken concomitantly (see section 4.3 and 4.5).

Haemorrhage u2022 There have been reports of prolonged bleeding time and/or bleeding abnormalities such as ecchymoses, gynaecological haemorrhages, gastrointestinal bleeding and other cutaneous or mucous bleedings with SSRIs (see section 4.8).

SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6 and 4.8).

Caution is advised in patients taking SSRIs, particularly with concomitant use of active ingredients known to affect platelet function or other active ingredients that can increase the risk of haemorrhage, as well as in patients with a history of bleeding disorders (see section 4.5).

QT-interval prolongation u2022 DEPRECITEL may cause a dose-dependent prolongation of the QT-interval. Cases of QT interval prolongation and ventricular dysrhythmia including torsade de pointes have been reported during the post-marketing period, predominantly in patients of female gender, with hypokalaemia, or with pre-existing QT prolongation or other cardiac diseases (see section 4.3, 4.5, 4.8 and 4.9).

Caution is advised in patients with significant bradycardia; or in patients with recent acute myocardial infarction or uncompensated heart failure.

Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for malignant dysrhythmias and should be corrected before treatment with DEPRECITEL is started.

If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.

ECG monitoring may be advisable in case of overdose or conditions of altered metabolism with increased peak levels, e.g. liver impairment.

If signs of cardiac dysrhythmia occur during treatment with DEPRECITEL, the treatment should be withdrawn, and an ECG should be performed.

Serotonin syndrome u2022 Serotonin syndrome is more likely to occur after an increase in dose.

A combination of symptoms such as agitation, tremor, myoclonus and hyperthermia may indicate the development of this condition (see section 4.5).

Treatment with DEPRECITEL should be discontinued immediately and symptomatic treatment initiated.

Hyponatraemia u2022 Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported with the use of SSRIs and generally reverses on discontinuation of therapy. Elderly female patients seem to be at particularly high risk.

Akathisia / psychomotor restlessness u2022 The use of SSRIs/SNRIs has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Angle-closure Glaucoma u2022 SSRIs including DEPRECITEL may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, especially in patients pre-disposed. DEPRECITEL should therefore be used with caution in patients with angle-closure glaucoma or history of glaucoma.

Sexual dysfunction u2022 Selective serotonin reuptake inhibitors (SSRIs/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI.

Excipient lactose: DEPRECITEL contains lactose monohydrate: patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Paediatric population DEPRECITEL should not be used in the treatment of children and adolescents under the age of 18 years. In clinical trials in Major Depressive Disorder, there were increased reports of hostility (predominantly aggression, oppositional behaviour, and anger) and suicide-related adverse events such as suicidal ideation and self-harm (see section 4.3). In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Pharmacodynamic interactions At the pharmacodynamic level cases of serotonin syndrome with citalopram and moclobemide and buspirone have been reported.

Contraindicated combinations

Monoamine oxidase inhibitors (MAOI) Concurrent use is contra-indicated. Serious and potentially fatal reactions have occurred such as: hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation of vital signs and mental status changes including extreme agitation progressing to delirium and coma (see section 4.3).

QT interval prolongation Pharmacokinetic and pharmacodynamic studies between citalopram and other medicines that prolong the QT interval have not been performed. An additive effect of citalopram and these medicines cannot be excluded. Therefore, co-administration of citalopram with medicines that prolong the QT interval, such as Class IA and III antidysrhythmics, antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial medicines (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, anti-malarial treatment particularly halofantrine), certain antihistamines (astemizole, mizolastine) etc., is contraindicated.

Pimozide Co-administration of a single dose of pimozide 2 mg to subjects treated with racemic citalopram 40 mg/day for 11 days caused an increase in AUC and C max of pimozide, although not consistently throughout the study. The co-administration of pimozide and citalopram resulted in a mean increase in the QTc interval of approximately 10 msec. Due to the interaction noted at a low dose of pimozide, concomitant administration of citalopram, as in DEPRECITEL, and pimozide is contraindicated.

Combinations requiring precautions for use

Selegiline (selective MAO-B inhibitor) A reported pharmacokinetic / pharmacodynamic interaction study with concomitantly administered citalopram (20 mg daily) and selegiline (10 mg daily) (a selective MAO B inhibitor) demonstrated no clinically relevant interactions. The concomitant use of citalopram, as in DEPRECITAL and selegiline (in doses above 10 mg daily) is not recommended (see section 4.3)

Serotonergic medicines or medicines with serotonergic activity Lithium and tryptophan No pharmacodynamic interactions have been found in reported clinical studies in which citalopram has been given concomitantly with lithium. However there have been reports of enhanced effects when SSRIs have been given with lithium or tryptophan and therefore concomitant use of citalopram with these medicines should be undertaken with caution. Routine monitoring of lithium levels should be continued as usual. Co-administration with serotonergic medicines (e.g. tramadol, sumatriptan) may lead to enhancement of 5-HT associated effects. Increased risk of developing the serotonin syndrome, a rare but potentially fatal hyperserotonergic state. The simultaneous use of DEPRECITEL and 5-HT agonists, such as sumatriptan and other triptans, is not recommended (see section 4.4)

St. John's wort Pharmacodynamic interactions between SSRIs and the herbal remedy St John's wort (Hypericum perforatum) can occur, resulting in an increase in undesirable effects (see section 4.4). Pharmacokinetic interactions have not been investigated.

Haemorrhage Caution is warranted for patients who are being treated simultaneously with anticoagulants, medicines that affect the platelet function, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, dipyridamole, and ticlopidine or other medicines (e.g. atypical antipsychotics) that can increase the risk of haemorrhage (see section 4.4). Warfarin u2013 the anticoagulant activity of warfarin may be increased.

ECT (electroconvulsive therapy) There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and citalopram (see section 4.4).

Alcohol No pharmacodynamic or pharmacokinetic interactions have been demonstrated between citalopram and alcohol. However, the combination of DEPRECITAL and alcohol is not advisable. The effects of alcohol may be increased.

Medicines inducing hypokalaemia/hypomagnesaemia Caution is warranted for concomitant use of hypokalaemia-/hypomagnesaemia-inducing medicines as these conditions increase the risk of malignant dysrhythmias.

Medicines lowering the seizure threshold SSRIs can lower the seizure threshold. Caution is advised when concomitantly using other medicines capable of lowering the seizure threshold (e.g. antidepressants [SSRIs], neuroleptics [thioxanthenes and butyrophenones]), mefloquine, bupropion and tramadol).

Pharmacokinetic interactions Biotransformation of citalopram to demethylcitalopram is mediated by CYP2C19 (approx. 38 %), CYP3A4 (approx. 31 %) and CYP2D6 (approx. 31 %) isozymes of the cytochrome P450 system. Therefore, co-administration of citalopram, as in DEPRECITAL with other medicines in clinical practice has very low likelihood of producing pharmacokinetic medicine interactions.

Food The absorption and other pharmacokinetic properties of citalopram have not been reported to be affected by food.

Effect of other medicines on the pharmacokinetics of citalopram Co-administration with ketoconazole (potent CYP3A4 inhibitor) did not change the pharmacokinetics of citalopram. A reported pharmacokinetic interaction study of lithium and citalopram did not reveal any pharmacokinetic interactions (see also above). Cimetidine Cimetidine (potent CYP2D6, 3A4 and 1A2 inhibitor) caused a moderate increase in the average steady state levels of citalopram. Caution is advised when administering DEPRECITAL in combination with cimetidine. Dose adjustment may be warranted.

Co-administration of escitalopram (the active enantiomer of citalopram) with omeprazole 30 mg once daily (a CYP2C19 inhibitor) resulted in moderate (approximately 50 %) increase in the plasma concentrations of escitalopram. Thus, caution should be exercised when used concomitantly with CYP2C19 inhibitors (e.g., omeprazole, esomeprazole, fluconazole, fluvoxamine, lansoprazole, ticlopidine) or cimetidine. A reduction in the dose of citalopram may be necessary based on monitoring of side-effects during concomitant treatment (see section 4.4).

Metoprolol Escitalopram (the active enantiomer of citalopram) is an inhibitor of the enzyme CYP2D6. Caution is recommended when DEPRECITAL is co-administered with medicines that are mainly metabolised by this enzyme, and that have a narrow therapeutic index, e.g. flecainide, propafenone and metoprolol (when used in cardiac failure), or some CNS acting medicines that are mainly metabolised by CYP2D6, e.g. antidepressants such as desipramine, clomipramine and nortriptyline or antipsychotics like risperidone, thioridazine and haloperidol. Dosage adjustment may be warranted. Co-administration with metoprolol resulted in a twofold increase in the plasma levels of metoprolol but did not statistically significantly increase the effect of metoprolol on the blood pressure and cardiac rhythm.

Effects of citalopram on other medicines A reported pharmacokinetic / pharmacodynamic interaction study with concomitant administration of citalopram and metoprolol (a CYP2D6 substrate) showed a twofold increase in metoprolol concentrations, but no statistically significant increase in the effect of metoprolol on blood pressure and heart rate in healthy volunteers. Citalopram and demethylcitalopram are negligible inhibitors of CYP2C9, CYP2E1 and CYP3A4, and only weak inhibitors of CYP1A2, CYP2C19 and CYP2D6 as compared to other SSRIs established as significant inhibitors.

Pregnancy Safety and efficacy in pregnancy and lactation has not been established. DEPRECITEL should not be used during pregnancy. The following symptoms may occur in the neonates following maternal use of SSRI/SNRI use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either serotonergic effects or discontinuation symptoms and in the majority of instances complications begin immediately or shortly (< 24 hours) following delivery. Use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Should maternal use of citalopram continue into the later stages of pregnancy, particularly into the third trimester, neonates should be observed following birth. Abrupt discontinuation of citalopram should be avoided during pregnancy. Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within the month prior to birth (see sections 4.4 and 4.8).

Breastfeeding DEPRECITEL is excreted into the breast milk.

Fertility Animal data have shown that citalopram may affect sperm quality. Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed so far.

DEPRECITEL may impair performance of skilled tasks. If affected, these patients should not operate machinery or drive.

a) Tabulated list of adverse reactions The table below shows all adverse drug reactions (ADRs) observed during clinical trials and post-market spontaneous reports with citalopram.

System Organ Class Frequency Frequent Less Frequent Not known Blood and lymphatic system disorders Thrombocytopenia Immune system disorders Hypersensitivity, anaphylactic reactions, angioedema Endocrine disorders Inappropriate ADH secretion Metabolism and nutrition disorders Appetite decreased; weight decreased Increased appetite, weight increased and hyponatraemia Hypokalaemia Psychiatric disorders Agitation, libido decreased, anxiety, nervousness, confusional state, abnormal orgasm (female), abnormal dreams, aggression, depersonalisation, hallucination and mania Panic attack, bruxism, restlessness, suicidal ideation and suicidal behaviour. Nervous system disorders Somnolence, insomnia, tremor, paraesthesia, dizziness, Syncope, grand mal convulsion, dyskinesia, taste disturbance. Convulsions, serotonin syndrome, extrapyramidal disorders: akathisia and movement disorder disturbance in attention Eye disorders Mydriasis (which may lead to acute narrow angle glaucoma) Visual disturbance Ear and labyrinth disorders Tinnitus Cardiac disorders Bradycardia, tachycardia QT-prolongation, ventricular dysrhythmia including torsade de pointes. Palpitations Vascular disorders Haemorrhage Oedema and pyrexia, orthostatic hypotension Respiratory, thoracic and mediastinal disorders Yawning Epistaxis, nose congestion Gastrointestinal disorders Nausea, constipation, diarrhoea, vomiting, dry mouth. Gastrointestinal haemorrhage (including rectal haemorrhage), salivation, dyspepsia Hepatobiliary disorders Hepatitis Abnormal liver function tests Skin and subcutaneous tissue disorders Sweating increased, pruritus Urticaria, alopecia, purpura and photosensitivity reaction Ecchymosis and angioedema Musculoskeletal and connective tissue disorders Myalgia and arthralgia Renal and urinary disorders Urinary retention Reproductive system and breast disorders Impotence, ejaculation disorder and ejaculation failure Female: Menorrhagia Postpartum haemorrhage* Female: Metrorrhagia; Male: Priapism and galactorrhoea General disorders and administration site conditions Asthenia, headache, malaise, neuroleptic malignant syndrome * This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4 and 4.6). Cases of QT-prolongation and ventricular dysrhythmia including torsade de pointes have been reported during the post-marketing period, predominantly in patients of female gender, with hypokalaemia, or with pre-existing QT prolongation or other cardiac diseases (see section 4.3).

b. Paediatric population Hostility, suicidal ideation and self-harm have been reported in children (see section 4.3).

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms of overdose Tiredness, weakness, sedation, dizziness, tremor, nausea, somnolence and sinus tachycardia (see section 4.8).

Treatment of overdose There is no specific antidote to DEPRECITEL. Treatment is symptomatic and supportive and includes the maintenance of a clear airway and monitoring of ECG and vital signs until stable. ECG monitoring is advisable in case of overdose in patients with congestive heart failure/bradydysrhythmias, in patients using concomitant medications that prolong the QT interval, or in patients with altered metabolism, e.g. liver impairment. The stomach should be emptied as soon as possible by emesis. Monitoring of cardiac and vital signs necessary and medical surveillance is advisable for about 24 hours.