CLOMIPRAMINE

4). After a response has been obtained, maintenance therapy should be continued at the optimum dose to avoid relapse. Patients with a history of recurrence require maintenance treatment for a longer duration. Duration of maintenance treatment and need for further treatment should be reviewed periodically.

5). Abrupt discontinuation of clomipramine therapy should be avoided because of possible withdrawal symptoms. Therefore, dosage should be stopped gradually after regular use for long duration and the patient should be monitored carefully when clomipramine therapy is discontinued.

Adults Oral – 10 mg/day initially, increasing gradually to 30-150 mg/day, if required, in divided doses throughout the day or as a single dose at bedtime. Many patients will be adequately maintained on 30- 50 mg/day. Higher doses may be needed in some patients, particularly those suffering from obsessional or phobic disorders.

In severe cases this dosage can be increased up to a maximum of 250 mg per day. Once a distinct improvement has set in, the daily dosage may be adjusted to a maintenance level of about 50-100 mg. Elderly Elderly patients generally show a stronger response to clomipramine than patients of intermediate age groups, clomipramine should be used with caution in elderly patients and doses should be increased cautiously.

The initial dose should be 10 mg/day, which may be increased with caution under close supervision to an optimum level of 30-75 mg daily which should be reached after about 10 days and then maintained until the end of treatment. 4). Obsessional/phobic states The maintenance dosage of clomipramine is generally higher than that used in depression.

It is recommended that the dose be built up to 100-150 mg clomipramine daily, according to the severity of the condition. This should be attained gradually over a period of 2 weeks starting with 1 x 25 mg clomipramine daily. In elderly patients and those sensitive to tricyclic antidepressants a starting dose of 1 x 10 mg clomipramine daily is recommended.

Again where a higher dosage is required the sustained-release 75 mg formulation may be preferable. Adjunctive treatment of cataplexy associated with narcolepsy (Oral treatment): 10-75 mg daily. It is suggested that treatment is commenced with 10 mg clomipramine daily and gradually increased until a satisfactory response occurs.

Control of cataplexy should be achieved within 24 hours of reaching the optimal dose. Where necessary, therapy may be combined with capsules up to the maximum dose of 75 mg per day. Treatment discontinuation Abrupt withdrawal should be avoided because of possible adverse reactions.

8 for a description of the risks of discontinuation of clomipramine). 4 and 5). 4 and 5). Method of administration For oral use

Unwanted effects are usually mild and transient, disappearing under continued treatment or with a reduction in the dosage. They do not always correlate with plasma drug levels or dose. It is often difficult to distinguish certain undesirable effects from symptoms of depression such as fatigue, sleep disturbances, agitation, anxiety, constipation, and dry mouth.

If severe neurological or psychiatric reactions occur, clomipramine should be withdrawn. Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to < 1/100); rare (≥1/10,000 to < 1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

g. g. widening of QRS complex, prolonged QT interval, PQ changes, bundle-branch block, torsades de pointes, particularly in patients with hypokalaemia) Not Known Cardiomyopathy, cardiac failure Vascular disorders Common Hot flush Respiratory, thoracic, and mediastinal disorders Common Yawning Very rare Alveolitis allergic (pneumonitis) with or without eosinophilia Gastrointestinal disorders Very common Nausea, dry mouth, constipation Common Vomiting, gastrointestinal disorders, diarrhoea Hepatobiliary disorders Very rare Hepatitis with or without jaundice Skin and subcutaneous tissue disorders Very common Hyperhidrosis Common Dermatitis allergic (skin rash, urticaria), photosensitivity reaction, pruritus Very rare Ecchymosis, purpura, alopecia Musculoskeletal and connective tissue disorders Common Muscular weakness Not known Rhabdomyolysis (as a complication of neuroleptic malignant syndrome)3 Renal and urinary disorders Very common Micturition disorder Common Urinary retention Reproductive system and breast disorders Very common Libido disorder, erectile dysfunction Common Galactorrhoea, breast enlargement, women occasionally experience orgasmic impotence Rare Vaginal bleeding Not known Ejaculation failure, ejaculation delayed General disorders and administration site conditions Very common Fatigue Very rare Oedema (local or generalised), hyperpyrexia Investigations Very common Weight increased, blood sugar changes Common Transaminases increased Very rare Electroencephalogram abnormal Not known Blood prolactin increased3 1 In post-marketing experience very rarely malignant neuroleptic syndrome has been reported although a causal relationship has not been confirmed.

4). 3 These adverse events were reported in patients treated with clomipramine based on post marketing reports. 4). Class effects Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs.

The mechanism leading to this risk is unknown. Elderly population Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric, or cardiovascular effects. Their ability to metabolise and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at therapeutic doses.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard

Suicide/suicidal thoughts or clinical worsening Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs.

It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions for which clomipramine is prescribed can also be associated with an increased risk of suicide-related events.

In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

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 drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Patients with depressive disorders, both adult and paediatric, may experience worsening of depression and/or suicidality or other psychiatric symptoms, whether or not they are taking antidepressant medication. 1). Antidepressants increase the risk of suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominately 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.

If based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long term safety data in children and adolescents concerning growth, maturation and cognitive behavioural development are lacking.

8), as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Prescriptions for clomipramine should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

4). Other psychiatric effects Many patients with panic disorders experience intensified anxiety symptoms at the start of the treatment with antidepressants. This paradoxical initial increase in anxiety is most pronounced during the first few days of treatment and generally subsides within two weeks.

Activation of psychosis has occasionally been observed in patients with schizophrenia receiving tricyclic antidepressants. Hypomanic or manic episodes have also been reported during a depressive phase in patients with cyclic affective disorders receiving treatment with a tricyclic antidepressant.

In such cases it may be necessary to reduce the dosage of clomipramine or to withdraw it and administer an antipsychotic agent. After such episodes have subsided, low dose therapy with clomipramine may be resumed if required. In predisposed patients, tricyclic antidepressants may provoke pharmacogenic (delirious) psychoses, particularly at night.

These disappear within a few days of withdrawing the drug. As improvement in depression may not occur for the first two to four weeks treatment, patients should be closely monitored during this period. Elderly patients are particularly liable to experience adverse effects, especially agitation, confusion, and postural hypotension.

g. atrioventricular block grades I to III), arrhythmias. Monitoring of cardiac function and the ECG is indicated in such patients. There may be a risk of QTc prolongation and torsades de pointes, particularly at supra-therapeutic doses or supra-therapeutic plasma concentrations of clomipramine, as occur in the case of co- medication with selective serotonin reuptake inhibitors (SSRIs).

Therefore, concomitant administration of drugs that can cause accumulation of clomipramine should be avoided. 5). It is established that hypokalaemia is a risk-factor of QTc prolongation and torsades de pointes. 5). Before initiating […]

5) - concomitant treatment with selective, reversible MAO-A inhibitors, such as moclobemide - narrow-angle glaucoma - retention of urine - mania.