Cipramil 20 Mg Tablets

Treatment of depression and prevention of relapse.

Treatment of panic disorder with or without agoraphobia.

Treatment of obsessive compulsive disorder (OCD).

Posology

Adults

Treating depression

CIPRAMIL should be administered as a single oral dose of 20 mg daily. Dependent on individual patient response, this may be increased to a maximum of 40 mg daily.

Duration of treatment

• The antidepressant effect usually sets in after 2 to 4 weeks.
• Treatment with CIPRAMIL is symptomatic and must therefore be continued for an appropriate length of time, usually up to 6 months after recovery in order to prevent relapse.

Treating panic disorder

A single dose of 10 mg is recommended for the first week before increasing the dose to 20 mg daily. The dose may be further increased, up to a maximum of 40 mg daily, dependent on individual patient response.

Treating obsessive compulsive disorder (OCD)

An initial dose of 20 mg is recommended. Dependent on individual patient response, the dose may be increased to a maximum of 40 mg daily.

Duration of treatment

• The onset of action in treating OCD is 2 u2013 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 - 20 mg daily. The recommended maximum dose for the elderly is 20 mg daily.

Children and adolescents (< 18 years)

CIPRAMIL should not be used in the treatment of children and adolescents under the age of 18 years (See sections 4.3 and 4.4).

Reduced renal function

Dosage adjustment is not necessary in cases of mild or moderate renal impairment. CIPRAMIL is contra-indicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min) (see sections 4.3 and 5.2).

Reduced hepatic function

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 CIPRAMIL 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 sections 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.

Method of administration

CIPRAMIL tablets are administered as a single daily dose. CIPRAMIL tablets can be taken any time of the day without regard to food intake.

Hypersensitivity to citalopram or to any of the excipients.

CIPRAMIL is contraindicated in children and adolescents under 18 years of age.

MAOIs (monoamine oxidase inhibitors): Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the selective MAO-B inhibitor selegiline and the reversible MAOI (RIMA), moclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI. Some cases presented with features resembling serotonin syndrome.

CIPRAMIL must not be used in combination with a MAOI, including selegiline in doses above 10 mg daily. Treatment with CIPRAMIL may be instituted 14 days after discontinuation of non-selective MAOIs and minimum one day after discontinuation of moclobemide. Treatment with MAOIs may be introduced 7 days after discontinuation of citalopram (See section 4.5).

Concomitant treatment with pimozide (See section 4.5).

CIPRAMIL is contraindicated in combination with linezolid.

Severely impaired renal function (creatinine clearance less than 30 ml/min) (see section 5.2).

CIPRAMIL is contraindicated in patients with known QT interval prolongation or congenital long QT syndrome (see sections 4.4, 4.8 and 5.1).

Use in children and adolescents under 18 years of age - CIPRAMIL should not be used in the treatment of children and adolescents under the age of 18 years. Suicide related behaviours (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. (See section 4.3).

In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Suicide / suicidal thoughts or clinical worsening - 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. A causal role, however, for CIPRAMIL in inducing such behaviour has not been established. Patients being treated with CIPRAMIL 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 disorders should be observed when treating patients with other psychiatric and non-psychiatric disorders.

The following symptoms have been reported in patients being treated with CIPRAMIL 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 suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing CIPRAMIL, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patientu2019s presenting symptoms.

If the decision is made to discontinue treatment, CIPRAMIL should be tapered (see sections 4.4 and 4.8 WITHDRAWAL SYMPTOMS).

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

A meta-analysis of placebo-controlled clinical trials of antidepressant medicines in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants such as CIPRAMIL compared to placebo in patients less than 25 years old.

Paradoxical anxiety - 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 of CIPRAMIL is advised to reduce the likelihood of a paradoxical anxiogenic effect (see section 4.2).

Hyponatraemia - Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported as an adverse reaction with the use of SSRIs and generally reverses on discontinuation of therapy. Elderly female patients seem to be at higher risk.

Akathisia/psychomotor restlessness - 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 of CIPRAMIL may be detrimental.

Mania - In patients with manic-depressive illness a change towards the manic phase may occur. CIPRAMIL should be discontinued if the patient enters a manic phase.

Seizures - Seizures are a potential risk with antidepressant medicines. CIPRAMIL should be discontinued in any patient who develops seizures. CIPRAMIL should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. CIPRAMIL should be discontinued if there is an increase in seizure frequency.

Diabetes - In patients with diabetes, treatment with an SSRI including CIPRAMIL may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

Serotonin syndrome - Serotonin syndrome has been reported in patients using SSRIs. A combination of symptoms such as agitation, tremor, myoclonus, and hyperthermia may indicate the development of this condition. Treatment with CIPRAMIL should be discontinued immediately and symptomatic treatment initiated.

Serotonergic medicines - CIPRAMIL should not be used concomitantly with medicinal products with serotonergic effects such as triptans (including sumatriptan and oxitriptan), opioids (including tramadol) and tryptophan (see section 4.5).

Haemorrhage - There have been reports of cutaneous bleeding time and/or bleeding abnormalities such as ecchymoses, gynaecological haemorrhages, gastrointestinal bleedings, 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, 4.8).

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

ECT (electroconvulsive therapy) - There is limited clinical experience of concurrent administration of CIPRAMIL and ECT; therefore caution is advisable.

St. Johnu00b4s Wort - Undesirable effects may be more common during concomitant use of CIPRAMIL and herbal preparations containing St Johnu2019s wort (Hypericum perforatum). Therefore CIPRAMIL and St Johnu2019s wort preparations should not be taken concomitantly (see section 4.5).

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

QT interval prolongation - CIPRAMIL has been found to 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 sections 4.3, 4.5, 4.8, 4.9 and 5.1). 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 CIPRAMIL is started. If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started. If signs of cardiac dysrhythmia occur during treatment with CIPRAMIL, the treatment should be withdrawn, and an ECG should be performed.

Withdrawal symptoms - After prolonged administration, abrupt cessation of CIPRAMIL may produce withdrawal symptoms such as 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 in some patients. These symptoms are not indicative of addiction. It is recommended that withdrawal of treatment should proceed by gradually tapering off the dosage over a period of several weeks or months, according to the patientu2019s needs to avoid occurrence of discontinuation symptoms.

Special precaution - Treatment of elderly patients and patients with reduced kidney and liver function (see section 4.2).

Angle-Closure Glaucoma - SSRIs including citalopram 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. Citalopram should therefore be used with caution in patients with angle-closure glaucoma or history of glaucoma.

Excipients - CIPRAMIL tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not receive this medicine.

Pharmacodynamic interactions

At the pharmacodynamic level, cases of serotonin syndrome with CIPRAMIL and moclobemide and buspirone have been reported.

Contraindicated combinations:

Monoamine Oxidase Inhibitors (MAOIs) - Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the irreversible MAOI selegiline, the reversible MAOIs linezolid and moclobemide and in patients who have recently discontinued SSRI and have been started on a MAOI. Some cases presented with features resembling serotonin syndrome. Symptoms of citalopram interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma (see section 4.3).

Pimozide - Co-administration of a single dose of pimozide 2 mg to subjects treated with CIPRAMIL 40 mg/day for 11 days caused an increase in AUC and C max of pimozide. The co-administration of pimozide and CIPRAMIL 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 CIPRAMIL and pimozide is contraindicated (see section 4.3).

Combinations requiring precaution for use:

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

Serotonergic medicinal products

Lithium and tryptophan: No pharmacodynamic interactions have been found in clinical studies in which CIPRAMIL 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 the concomitant use of CIPRAMIL with these medicinal products should be undertaken with caution. Routine monitoring of lithium levels should be continued as usual.

Co-administration with serotonergic medicinal products e.g. opioids (including tramadol, and triptans (including sumatriptan and oxitriptan) may lead to enhancement of 5-HT associated effects. The simultaneous use of CIPRAMIL and 5-HT agonists, such as sumatriptan and other triptans, is not recommended (see section 4.4).

St. Johnu2019s Wort - Pharmacodynamic interactions between SSRIs such as CIPRAMIL and herbal remedy St Johnu2019s wort (Hypericum perforatum) can occur, resulting in an increase in undesirable effects (see section 4.4).

Pharmacokinetic interactions have not been investigated.

Haemorrhage - Simultaneous treatment with anticoagulants, medicinal products that affect the platelet function, such as non-steroidal anti-inflammatory medicines (NSAIDs), acetylsalicylic acid, dipyridamol, and ticlopidine or other medicines (e.g. atypical antipsychotics, phenothiazines, tricyclic antidepressants) can increase the risk of haemorrhage (see section 4.4).

Safety in pregnancy and lactation has not been established.

Pregnancy

The following symptoms may occur in neonates after maternal SSRI 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. In a majority of instances the complications begin immediately or soon (< 24 hours) after delivery.

Epidemiological data have suggested that the use of SSRIs such as CIPRAMIL in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). 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, 4.8). Neonates should be observed if maternal use of CIPRAMIL continues into the later stages of pregnancy, particularly in the third trimester. Abrupt discontinuation should be avoided during pregnancy.

Breastfeeding

Citalopram is excreted into 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.

CIPRAMIL does not impair intellectual function or psychomotor performance. Nevertheless, patients who are depressed and require treatment may have an impaired ability to drive or operate machinery. They should be warned of the possibility and advised to avoid such tasks if so affected.

Adverse events observed with CIPRAMIL are most frequent during the first one or two weeks of treatment, and usually decrease in intensity and frequency as the depressive state improves. For the following reactions a dose-response was discovered: Sweating increased, dry mouth, insomnia, somnolence, diarrhoea, nausea and fatigue. The tables show the percentage of adverse reactions associated with SSRIs and/or CIPRAMIL seen in either u2265 1% of patients in double-blind placebo-controlled trials or in the post-marketing period. Frequencies are defined as: very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u2265 1/1 000, < 1/100); rare (u2265 1/10 000, < 1/1 000); very rare (< 1/10 000), not known (cannot be estimated from available data).

Adverse reactions from clinical trials

System organ class Frequency Undesirable Effect

Psychiatric disorders Common Female and male: libido decreased

Nervous system disorders Very common Insomnia, somnolence

Common Tremor

Gastrointestinal disorders Very common Dry mouth, nausea

Common Diarrhoea

Skin and subcutaneous tissue disorders Very common Sweating increased

Reproductive system and breast disorders Common Male: ejaculation disorder

General disorders and administration site conditions Common Fatigue

Number of patients: CIPRAMIL / placebo = 1346/ 545

Adverse reactions from post marketing data

System organ class Undesirable Effect

Blood and lymphatic disorders Thrombocytopenia

Immune system disorders Hypersensitivity, anaphylactic reaction

Endocrine disorders Inappropriate ADH secretion Hyperprolactinaemia

Metabolism and nutrition disorders Appetite decreased, weight decreased Increased appetite, weight increased Hyponatraemia Hypokalaemia

Psychiatric disorders Agitation, anxiety, nervousness, confusional state, abnormal orgasm (female), sleep disturbances including abnormal dreams

Aggression, depersonalization, hallucination, mania Panic attack, bruxism, restlessness, suicidal ideation, suicidal behaviour

Nervous system disorders Restlessness Paraesthesia, dizziness, disturbance in attention

Syncope Convulsion, dyskinesia, taste disturbance Serotonin syndrome, extrapyramidal disorder, akathisia, movement disorder

Eye disorders Mydriasis Visual disturbance

Ear and labyrinth disorders Tinnitus

Cardiac disorders Bradycardia, tachycardia, palpitations

Electrocardiogram QT prolonged, ventricular dysrhythmia including torsade de pointes

Vascular disorders Haemorrhage Orthostatic hypotension

Respiratory thoracic and mediastinal disorders Yawning Nose congestion Epistaxis

Gastrointestinal disorders Dyspepsia Vomiting, constipation Salivation Gastrointestinal haemorrhage (including rectal haemorrhage)

Hepatobiliary disorders Hepatitis Liver function test abnormal

Skin and subcutaneous tissue disorders Pruritus Urticaria, alopecia, rash, purpura, photosensitivity

Ecchymosis, angioedema

Musculoskeletal and connective tissue disorders Myalgia, arthralgia

Renal and urinary disorders Micturition disorder including urinary retention

Reproductive system and breast disorders Impotence, ejaculation failure

Female: Menorrhagia Galactorrhoea

Female: Metrorrhagia, postpartum haemorrhage

Male: Priapism

General disorders and administration site conditions Asthenia, headache, malaise, yawning

Oedema Pyrexia

Neuroleptic malignant syndrome

Cases of suicidal ideation and suicidal behaviours have been reported during CIPRAMIL therapy or early after treatment discontinuation (see section 4.4).

This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4, 4.6).

This event has been reported for the therapeutic class of SSRIs/SNRIs

Bone fractures - Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs. The mechanism leading to this risk is unknown.

QT interval prolongation - 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 interval prolongation of other cardiac diseases (see section 4.3, 4.4, 4.5, 4.9 and 5.1).

Withdrawal symptoms seen on discontinuation - Discontinuation of CIPRAMIL (particularly when abrupt) commonly leads to withdrawal symptoms. 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. In some patients they may be severe and/or prolonged. It is therefore advised that when CIPRAMIL treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

Children and adolescents under 18 years of age - In children reports of hostility and suicidal ideation (see sections 4.3 and 4.4).

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Toxicity

Fatal cases of CIPRAMIL overdose have been reported with CIPRAMIL alone; however, the majority of fatal cases have involved overdose with concomitant medications/alcohol.

Symptoms

The following symptoms have been seen in reported overdose of CIPRAMIL: tiredness, weakness, sedation, convulsion, tachycardia, somnolence, QT interval prolongation, coma, vomiting, tremor, hypotension, cardiac arrest, nausea, serotonin syndrome, agitation, bradycardia, dizziness, bundle branch block, QRS prolongation, hypertension, and mydriasis, torsade de pointes, stupor, sweating, cyanosis, hyperventilation, and atrial- and ventricular dysrhythmia.

Management

There is no known specific antidote to CIPRAMIL. Treatment should be symptomatic and supportive. Activated charcoal, osmotically working laxative (such as sodium sulphate) and stomach evacuation should be considered. If consciousness is impaired the patient should be intubated. ECG and vital signs should be monitored. Medical surveillance for about 24 hours is advisable. ECG monitoring should be considered in all cases of overdose especially in congestive heart failure.