Document: spc-doc_PL 04569-0231 change

• spc-doc_PL 00289-0219
• spc-doc_PL 04569-0231

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Clomipramine 50 mg Capsules, Hard

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Clomipramine capsules contains 50 mg of clomipramine hydrochloride

Excipient with known effect:

Each capsule contains 67 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Capsule, hard

Clomipramine 50 mg capsules are red and blue capsules, marked “G CI50” and contain a white powder.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Adults

Clomipramine capsules are indicated for the treatment of:

-    the symptoms of depressive illness especially where sedation is required

-    obsessional and phobic states

-    adjunctive treatment of cataplexy associated with narcolepsy.

Children and adolescents

In children and adolescents, there is not sufficient evidence of safety and efficacy of clomipramine in the treatment of depressive states, phobias and cataplexy associated with narcolepsy. The use of clomipramine in children and adolescents (0-17 years of age) in these indications is therefore not recommended (see section 4.4).

4.2 Posology and method of administration

Posology

Before initiating treatment with clomipramine, hypokalaemia should be treated (see section 4.4).

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.

As a precaution against possible QTc prolongation and serotonergic toxicity, adherence to the recommended doses of clomipramine is advised and any increase in dose should be made with caution if drugs that prolong QT interval or other serotonergic agents are co-administered (see sections 4.4 and

4.5).

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 3050 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.

Paediatric population

Not recommended (see section 4.4).

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. If the decision is made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see sections 4.4 and 4.8 for a description of the risks of discontinuation of clomipramine).

Renal impairment Clomipramine should be given with

Hepatic impairment Clomipramine should be given with 5).

Method of administration For oral use

4.3 Contraindications

- hypersensitivity to the active substance, or to any of the excipients listed in section 6.1 or cross-sensitivity to tricyclic antidepressants of the dibenzazepine group

-    recent myocardial infarction, any degree of heart block or other cardiac arrhythmias

-    severe liver disease

-    concurrent administration with monoamine oxidase inhibitors or within 3 weeks of start or cessation of therapy (see section 4.5)

-    concomitant treatment with selective, reversible MAO-A inhibitors, such as moclobemide

-    narrow-angle glaucoma

-    retention of urine

-    mania.

4.4 Special warnings and precautions for use

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.

Paediatric population

Clomipramine should not be used in the treatment of depressive states, phobias and cataplexy associated with narcolepsy in children and adolescents under the age of 18 years (see section 4.1).

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.

Families and care givers of both paediatric and adult patients being treated with antidepressants for both psychiatric and non psychiatric indications, should be alerted about the need to monitor patients for the emergence of other psychiatric symptoms (see section 4.8), 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.

Modifying the therapeutic regimen, including possibly discontinuing the medication, should be considered in these patients, especially if these changes are severe, abrupt in onset, or were not part of the patient's presenting symptoms (see also treatment discontinuation in section 4.4).

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.

Cardiac and vascular disorders

Clomipramine should be administered with particular precaution in patients with cardiovascular disorders, especially those with cardiovascular insufficiency, conduction disorders, (e.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 comedication with selective serotonin reuptake inhibitors (SSRIs). Therefore, concomitant administration of drugs that can cause accumulation of clomipramine should be avoided. Equally, concomitant administration of drugs that can prolong the QTc interval should be avoided (see section

4.5) . It is established that hypokalaemia is a risk-factor of QTc prolongation and torsades de pointes. Therefore, hypokalaemia should be treated before initiating treatment with clomipramine (see section

4.5) .

Before initiating treatment it is advisable to check the patient's blood pressure, because individuals with hypotension or a labile circulation may react to the drug with a fall in blood pressure.

Serotonin syndrome

Due to the risk of serotonergic toxicity, it is advisable to adhere to recommended doses. Serotonin syndrome, with symptoms such as hyperpyrexia, myoclonus, agitation, seizures, delirium and coma, can possibly occur when clomipramine is administered with serotonergic co-medications such as SSRIs, SNaRIs, tricyclic antidepressants or lithium. Therefore, concomitant administration of drugs that can cause accumulation of clomipramine should be avoided (see sections 4.2 and 4.5). For fluoxetine a washout period of two to three weeks is advised before and after treatment with fluoxetine.

Convulsions

Tricyclic antidepressants are known to lower the convulsion threshold and clomipramine should therefore, be used with extreme caution in patients with epilepsy and other predisposing factors, e.g. brain damage of varying aetiology, concomitant use of neuroleptics, withdrawal from alcohol or drugs with anticonvulsive properties (e.g. benzodiazepines). It appears that the occurrence of seizures is dose dependent. Therefore, the recommended total daily dose of clomipramine should not be exceeded.

Concomitant treatment of clomipramine and electroconvulsive therapy should only be resorted to under careful supervision.

Anticholinergic effects

Because of its anticholinergic properties, clomipramine should be used with caution in patients with a history of increased intra-ocular pressure, narrow-angle glaucoma, urinary retention or with symptoms of bladder neck obstruction, e.g. diseases of the prostate, such as prostatic hypertrophy.

Decreased lacrimation and accumulation of mucoid secretions due to the anticholinergic properties of tricyclic antidepressants may cause damage to the corneal epithelium in patients with contact lenses.

Specific treatment populations

Caution is called for when giving tricyclic antidepressants to patients with severe hepatic disease and tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom they may provoke hypertensive crises.

Caution is advised in patients with hyperthyroidism or during concomitant treatment with thyroid preparations since aggravation of unwanted cardiac effects may occur.

It is advisable to monitor cardiac and hepatic function during long-term therapy with clomipramine. In patients with hepatic and renal disease, periodic monitoring of hepatic enzyme levels and renal function is recommended.

An increase in dental caries has been reported during long-term treatment with tricyclic antidepressants. Regular dental check-ups are therefore advisable during long-term treatment.

Caution is called for in patients with chronic constipation. Tricyclic antidepressants may cause paralytic ileus, particularly in the elderly and in bed-ridden patients.

In elderly patients, tricyclic antidepressants may provoke pharmacogenic (delirious) psychoses, particularly at night. These disappear within a few days of withdrawing the drug.

Monitoring of cardiac function and the ECG is indicated in elderly patients.

White blood cell count

Although changes in the white blood cell count have been reported with clomipramine only in isolated cases, periodic blood cell counts and monitoring for symptoms such as fever and sore throat are called for, particularly during the first few months of therapy. They are also recommended during prolonged therapy.

Anticoagulants / Non-steroidal anti-inflammatory drugs

Skin and mucous membrane bleeding has been reported with clomipramine. The product should be used with caution among patients that simultaneously use medicines that increase the risk of bleeding, for example anticoagulants, salicylic acid derivatives and non-steroidal anti-inflammatory drugs (NSAIDs). Care should be taken in patients with an increased tendency to bleed.

Anaesthesia

Anaesthetics given during tri/tetracyclic antidepressant therapy may increase the risk of arrhythmias and hypotension.

Before general or local anaesthesia, the anaesthetist should be aware that the patient has been receiving clomipramine and of the possible interactions (see section 4.5).

Treatment discontinuation

Abrupt withdrawal should be avoided because of possible adverse reactions. If the decision is made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see section 4.8 for a description of the risks of abrupt discontinuation of clomipramine).

Clomipramine capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions resulting in a contraindication

MAO inhibitors

Do not give clomipramine for at least 3 weeks after discontinuation of treatment with MAO inhibitors (there is a risk of severe symptoms consistent with Serotonin Syndrome such as hypertensive crisis, hyperpyrexia, myoclonus, agitation, seizures, delirium and coma). The same applies when giving a MAO inhibitor after previous treatment with clomipramine. In both instances the treatment should initially be given in small gradually increasing doses and its effects monitored. There is evidence to suggest that clomipramine may be given as little as 24 hours after a reversible MAO-A inhibitor such as moclobemide, but the 3-week wash-out period must be observed if the MAO-A inhibitor is used after clomipramine.

Interactions resulting in a concomitant use not recommended

Diuretics

Diuretics may lead to hypokalaemia, which increases the risk of QTc prolongation and torsades de pointes. Hypokalaemia should therefore be treated prior to administration of clomipramine (see sections 4.2 and 4.4).

Quinidine

Tricyclic antidepressants should not be employed in combination with antiarrhythmic agents of the quinidine type.

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs which are inhibitors of CYP2D6, such as fluoxetine, paroxetine, or sertraline, and of others including CYP1A2 and CYP2C19 (e.g. fluvoxamine), may also increase plasma concentrations of clomipramine, with corresponding adverse effects. Steady-state serum levels of clomipramine increased ~4-fold by co-administration of fluvoxamine (N-desmethylclomipramine decreased ~2-fold). In addition, co-medication with SSRIs may lead to additive effects on the serotonergic system (see serotonergic agents) (see sections 4.2 and 4.4).

Serotonergic agents

Serotonin Syndrome can possibly occur when clomipramine is administered with other serotonergic co-medications such as selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenergic reuptake inhibitors (SNaRIs), tricyclic antidepressants and lithium (see sections 4.2 and 4.4). For fluoxetine, a wash-out period of two to three weeks is advised before and after treatment with fluoxetine.

Interactions to be considered

Interactions resulting in increased effect of clomipramine

Oral antifungal, terbinafine

Co-administration of clomipramine with terbinafine, a strong inhibitor of CYP2D6, may result in increased exposure and accumulation of clomipramine and its N-demethylated metabolite. Therefore, dose adjustments of clomipramine may be necessary when co-administered with terbinafine.

Cimetidine

Co-administration with the histamine₂ (H₂)-receptor antagonist, cimetidine (an inhibitor of several P450 enzymes, including CYP2D6 and CYP3A4), may increase plasma concentrations of tricyclic antidepressants, whose dosage should therefore be reduced.

Oral contraceptives

No interaction between chronic oral contraceptive use (15 or 30 micrograms ethinylestradiol daily) and clomipramine (25 mg daily) has been documented. Oestrogens are not known to be inhibitors of CYP2D6, the major enzyme involved in clomipramine clearance and, therefore, no interaction is expected. Although, in a few cases with high dose oestrogen (50 micrograms daily) and the tricyclic antidepressant imipramine, increased side effects and therapeutic response were noted, it is unclear as to the relevance of these cases to clomipramine and lower dose oestrogen regimens. Monitoring therapeutic response of tricyclic antidepressants at high dose oestrogen regimens (50 micrograms daily) is recommended and dose adjustments may be necessary.

Antipsychotics

Co-medication of antipsychotic (e.g. phenothiazines) may result in increased plasma levels of tricyclic antidepressants, a lowered convulsion threshold, and seizures. Combination with thioridazine may produce severe cardiac arrhythmias.

Methylphenidate

This drug may also increase plasma concentrations of tricyclic antidepressants, whose dosage should therefore be reduced.

Valproate

Concomitant administration of valproate with clomipramine may cause inhibition of CYP2C and/or UGT enzymes resulting in increased serum levels of clomipramine and desmethylclomipramine.

Grapefruit, grapefruit juice, or cranberry juice

Concomitant administration of Clomipramine with grapefruit, grapefruit juice, or cranberry juice may increase the plasma concentrations of clomipramine.

Interactions resulting in decreased effect of clomipramine

Rifampicin

Rifampicin (CYP3A and CYP2C inducer), may decrease clomipramine concentrations as concomitant administration of drugs known to induce cytochrome P450 enzymes, particularly CYP3A4, CYP2C19 may accelerate the metabolism and decrease the efficacy of clomipramine.

Anticonvulsants

Anticonvulsants (CYP3A and CYP2C inducer) e.g. barbiturates, carbamazepine, phenobarbital and phenytoin, may decrease clomipramine concentrations as concomitant administration of drugs known to induce cytochrome P450 enzymes, particularly CYP3A4, CYP2C19 may accelerate the metabolism and decrease the efficacy of clomipramine.

Cigarette smoking

Known inducers of CYP1A2 (e.g. nicotine/components in cigarette smoke), decrease plasma concentrations of tricyclic drugs. In cigarette smokers, clomipramine steady-state plasma concentrations were decreased 2-fold compared to non-smokers (no change in N-desmethylclomipramine).

Colestipol and cholestyramine

Concomitant administration of ion exchange resins such as cholestyramine or colestipol may reduce the plasma levels of clomipramine. Staggering the dosage of clomipramine and resins, such that the drug is administered at least 2 h before or 4-6 h after the administration of resins, is recommended.

St. John's wort

Concomitant administration of clomipramine with St. John's wort during the treatment may decrease the plasma concentrations of clomipramine.

Interactions affecting other drugs

Anticholinergic agents

Tricyclic antidepressants may potentiate the effects of these drugs (e.g. phenothiazines, antiparkinsonian agents, antihistamines, atropine, biperiden) on the eye, central nervous system, bowel and bladder).

Antiadrenergic agents

Clomipramine may diminish or abolish the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine and alpha-methyldopa. Patients requiring co-medication for hypertension should therefore be given antihypertensives of a different type (e.g. vasodilators, or beta-blockers).

It would be advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.

CNS depressants

Tricyclic antidepressants may potentiate the effects of alcohol and other central depressant substances (e.g. barbiturates, benzodiazepines, or general anaesthetics).

Sympathomimetic drugs

Clomipramine may potentiate the cardiovascular effects of adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine (e.g. as contained in local and general anaesthetic preparations and nasal decongestants).

Anticoagulants

Tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs by inhibiting their metabolism by the liver. Careful monitoring of plasma prothrombin is therefore advised.

Drugs that can cause increase plasma clomipramine levels or which in themselves prolong the QTc interval

The risk of QTc prolongation and torsades de pointes is likely to be increased if clomipramine is coadministered with other drugs that can cause QTc prolongation. Therefore concomitant use of such agents with clomipramine is not recommended (see section 4.4). Examples include certain antiarrhythmics, such as those of Class 1A (such as quinidine, disopyramide and procainamide) and Class III (such as amiodarone and sotalol), tricyclic antidepressants (such as amitriptyline), certain tetracyclic antidepressants (such as maprotiline), certain antipsychotic medications (such as phenothiazines and pimozide), certain antihistamines (such as terfenadine); lithium, quinine and pentamidine. This list is not exhaustive. The risk of QTc prolongation and torsades de pointes is likely to be increased if clomipramine is co-administered with drugs that can cause increased plasma clomipramine levels. Clomipramine is metabolised by cytochrome P450 2D6 and the plasma concentration of clomipramine may therefore be increased by drugs that are either substrates and/or inhibitors of this P450 isoform. Therefore, concurrent use of these drugs with clomipramine is not recommended (see section 4.4). Examples of drugs which are substrates or inhibitors of cytochrome P450 2D6 include antiarrhythmics, certain antidepressants including SSRIs, tricyclic antidepressants and moclobemide; certain antipsychotics; P-blockers; protease inhibitors, opiates, ecstasy (MDMA), cimetidine and terbinafine. This list is not exhaustive.

Calcium channel blockers

Diltiazem and verapamil may increase the plasma concentration of imipramine, and possibly other tricyclics.

Non-steroidal anti-inflammatory drugs

The potential pharmacodynamic interactions with drugs that increase the risk of bleeding, for example, salicylic acid derivatives, non-steroidal anti-inflammatory / antirheumatic drugs (NSAIDs) should be considered because of the increased risk of bleeding with concomitant clomipramine.

Cytotoxic

Altretamine: risk of severe postural hypotension.

Analgesics

Possible increased side effects with nefopam; possible increased risk of convulsions with tramadol; possible increased sedation with opioid analgesics; increased risk of ventricular arrhythmias with levacetylmethadol.

Antipsychotics

Increased risk of ventricular arrhythmias - avoid concomitant use with pimozide. Antipsychotic agents may increase the plasma concentration of tricyclic agents. No such effects are known to occur in combination with diazepam, but it might be necessary to reduce the dosage of clomipramine if administered concomitantly with alprazolam or disulfiram. There may be increased antimuscarinic side-effects with phenothiazines, and possibly clozapine.

Dopaminergics

Concomitant use of tricyclic antidepressants and entacapone should be avoided; central nervous system toxicity has been reported with selegiline.

Muscle relaxants

Tricyclic antidepressants may enhance the muscle relaxant effect of baclofen.

4.6 Fertility, pregnancy and lactation

Women of child-bearing potential

There are no data supporting any special recommendations in women of child-bearing potential. Pregnancy

There is limited amount of data from the use of clomipramine in pregnant women that indicates a potential to harm the foetus or cause congenital malformation.

Neonates whose mothers had taken tricyclic antidepressants up until delivery have developed dyspnoea, lethargy, colic, irritability, hypotension or hypertension, tremor or spasms, during the first few hours or days.

Studies in animals have shown reproductive toxicity (see section 5.3). Clomipramine is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

Clomipramine passes into the breast milk in small quantities. Therefore nursing mothers should be advised to withdraw the medication or cease breast-feeding.

Fertility

Clomipramine hydrochloride did not appear to have any significant effects on fertility and general reproductive performance.

4.7 Effects on ability to drive and use machines

Patients receiving clomipramine should be warned that blurred vision, drowsiness and other nervous system and psychiatric related disorders such as somnolence, disturbance in attention, confusion, disorientation, aggravation of depression, delirium etc (see section 4.8) have been observed. In the presence of such effects, patients should not drive, operate machinery or do anything else which may require alertness or quick actions. Patients should also be warned that alcohol or other drugs may potentiate these effects (see section 4.5).

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory defence’) if:

o    The medicine has been prescribed to treat a medical or dental problem and

o    You have taken it according to the instructions given by the prescriber and in the

information provided with the medicine and o It was not affecting your ability to drive safely

4.8 Undesirable effects

Very common	Restlessness
Common	Confusional state, disorientation, hallucinations (particularly in elderly patients and patients with Parkinson's disease), anxiety, agitation, sleep disorder, mania, hypomania, aggression, depersonalisation, aggravation of depression, insomnia, nightmares, delirium
Uncommon	Activation of psychotic symptoms
Not known	Suicidal ideation, suicidal behaviours2
Nervous system disorders
Very common	Dizziness, tremor, headache, myoclonus, somnolence
Common	Speech disorder, paraesthesia, hypertonia, dysgeusia, memory impairment, disturbance in attention
Uncommon	Convulsions, ataxia
Very rare	Neuroleptic malignant syndrome1
Not known	Serotonin syndrome, extrapyramidal disorder (including akathisia and tardive dyskinesia)3
Eye disorders
Very common	Accommodation disorder, vision blurred
Common	Mydriasis
Very rare	Glaucoma
Ear and labyrinth disorders
Common	Tinnitus
Cardiac disorders
Common	Sinus tachycardia, palpitation, orthostatic hypotension, clinically irrelevant ECG changes (e.g. ST and T changes) in patients of normal cardiac status
Uncommon	Arrhythmias, blood pressure increased
Very rare	Conduction disorder (e.g. widening of QRS complex, prolonged QT interval, PQ changes, bundle-branch block, torsades de pointes, particularly in patients with hypokalaemia)
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

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.8 Undesirable effects

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).

Table 1

Blood and lymphatic system disorders
Very rare	Leucopenia, agranulocytosis, thrombocytopenia, eosinophilia
Immune system disorders
Very rare	Anaphylactic and anaphylactoid reactions including hypotension
Endocrine disorders
Very rare	SIADH (inappropriate antidiuretic hormone secretion syndrome)
Metabolism and nutrition disorders
Very common	Increased appetite
Common	Decreased appetite
Psychiatric disorders
Very common	Restlessness
Common	Confusional state, disorientation, hallucinations (particularly in elderly patients and patients with Parkinson's disease), anxiety, agitation, sleep disorder, mania, hypomania, aggression, depersonalisation, aggravation of depression, insomnia, nightmares, delirium

Uncommon	Activation of psychotic symptoms
Not known	Suicidal ideation, suicidal behaviours2
Nervous system disorders
Very common	Dizziness, tremor, headache, myoclonus, somnolence
Common	Speech disorder, paraesthesia, muscle hypertonia, dysgeusia, memory impairment, disturbance in attention
Uncommon	Convulsions, ataxia
Very rare	Neuroleptic malignant syndrome1
Not known	Serotonin syndrome, extrapyramidal symptoms (including akathisia and tardive dyskinesia)3
Eye disorders
Very common	Accommodation disorder, vision blurred
Common	Mydriasis
Very rare	Glaucoma
Ear and labyrinth disorders
Common	Tinnitus
Cardiac disorders
Common	Sinus tachycardia, palpitation, orthostatic hypotension, clinically irrelevant ECG changes (e.g. ST and T changes) in patients of normal cardiac status
Uncommon	Arrhythmias, blood pressure increased
Very rare	Conduction disorder (e.g. widening of QRS complex, prolonged QT interval, PQ changes, bundle-branch block, torsades de pointes, particularly in patients with hypokalaemia)
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, abdominal 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

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antidepressants, Non-selective monoamine reuptake inhibitors, ATC code: N06AA04.

Mechanism of action

The therapeutic activity of clomipramine is believed to be based on its ability to inhibit the neuronal re-uptake of noradrenaline (NA) and serotonin (5-HT) released in the synaptic cleft, with inhibition of 5-HT reuptake being the more important of these activities.

Clomipramine also has a wide pharmacological spectrum of action, which includes alpha1-adrenolytic, anticholinergic, antihistaminic, and antiserotonergic (5-HT-receptor blocking) properties.

5.2 Pharmacokinetic properties

Absorption

The active substance is completely absorbed following oral administration and intramuscular injection.

The systemic bioavailability of unchanged clomipramine is reduced by 50% by "first-pass" metabolism to desmethylclomipramine (an active metabolite). The bioavailability of clomipramine is not markedly affected by the ingestion of food but the onset of absorption and therefore the time to peak may be delayed. Coated tablets and sustained release tablets are bioequivalent with respect to amount absorbed.

During oral administration of constant daily doses of clomipramine the steady state plasma concentrations of clomipramine and desmethylclomipramine (active metabolite) and the ratio between these concentrations show a high variability between patients, e.g. 75 mg clomipramine daily produces steady state concentrations of clomipramine ranging from about 20 to 175 ng/ml. Levels of desmethylclomipramine follow a similar pattern but are 40-85% higher.

Clomipramine slows gastro-intestinal transit time, absorption can, however, be delayed, particularly in overdosage.

Distribution

Clomipramine and desmethylclomipramine are widely distributed throughout the body and is 97.6% bound to plasma and tissue protein. The apparent volume of distribution is about 12-17 l/kg body weight. Concentrations in cerebrospinal fluid are about 2% of the plasma concentration.

It is reported to have a low and variable bioavailability following oral administration (48.2% of that after intravenous administration) and this has been related to extensive first-pass hepatic metabolism. Following single oral doses of 50 mg and 100 mg in healthy volunteers peak plasma concentrations of clomipramine of 28.8 ± 11.2 ng/ml range 16.5 to 53 ng/ml (at 3 to 5 hours post-dose) and 70-140 ng/ml (at 1 to 2.5 hours post-dose) respectively are reported). Peak plasma concentrations of desmethylclomipramine of 5.0 ± 1.4 ng/ml (range 2.9 to 7.8 ng/ml have been reported to occur between 5 to 12 hours after a single oral dose of 50 mg.

After chronic administration in depressed patients steady state plasma concentrations of clomipramine have been noted to vary 20 to 30 fold. Vandel et al reported that following repeated doses of 75 mg a

day for 1 month, steady state plasma concentrations of clomipramine and desmethylclomipramine were 124.5 ± 94 ng/ml and 144.8 ± 113 ng/ml respectively.

Biotransformation

The major route of transformation of clomipramine is demethylation to desmethylclomipramine. In addition, clomipramine and desmethylclomipramine are hydroxylated to 8-hydroxy-clomipramine and 8-hydroxy-desmethyl-clomipramine but little is known about their activity in vivo. The hydroxylation of clomipramine and desmethylclomipramine is under genetic control similar to that of debrisoquine. In poor metabolisers of debrisoquine this may lead to high concentrations of desmethylclomipramine; concentrations of clomipramine are less significantly influenced.

Elimination

Oral clomipramine is eliminated from the blood with a mean half-life of 21 hours (range 12-36 h), and desmethylclomipramine with a half-life of 36 hours.

About two-thirds of a single dose of clomipramine is excreted in the form of water-soluble conjugates in the urine, and approximately one-third in the faeces. The quantity of unchanged clomipramine and desmethylclomipramine excreted in the urine amounts to about 2% and 0.5% of the administered dose respectively.

Elderly

In the elderly, plasma clomipramine concentrations may be higher for a given dose than would be expected in younger patients because of reduced metabolic clearance.

Hepatic and renal impairment

The effects of hepatic and renal impairment on the pharmacokinetics of clomipramine have not been determined.

5.3 Preclinical safety data

Repeat-dose toxicity

Phospholipidosis and testicular changes considered to be secondary to the phospholipidosis, commonly associated with tricyclic compounds, have been observed with clomipramine hydrochloride at doses >4 fold greater than the maximum recommended human daily dose (MRHD). The clinical relevance of these findings is unknown.

Reproductive toxicity

Clomipramine hydrochloride demonstrated evidence of embryotoxicity e.g. increased embryolethality and growth retardation, in the rat and mouse studies (at doses which are 5 to 10 times the estimated oral MRHD of 5 mg/kg on a mg/kg basis), but not in the rabbit study. The safety margin for increased embryolethality based on the administered dose is 2.5 times the oral MHRD.

No teratogenic effects were detected in mice, rats, and rabbits at doses up to 100, 50, and 60 mg/kg, respectively.

Mutagenicity

Various in vitro and in vivo mutagenicity tests were performed and did not reveal any mutagenic activity of clomipramine hydrochloride.

Carcinogenicity

The administration of clomipramine hydrochloride to mice and rats for 104 weeks did not show any evidence of carcinogenicity at dose levels representing 16 - 20 times the estimated oral MRHD of 5 mg/kg on a mg/kg basis.

6.    PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate Maize starch Talc

Silica, colloidal anhydrous Magnesium stearate

Capsule Body

Indigo carmine    (E132)

Titanium dioxide (E171)

Gelatin

Capsule Cap

Iron oxide red    (E172)

Titanium dioxide (E171)

Gelatin

Capsule printing ink

Shellac

Titanium dioxide (E171)

Propylene glycol (E1520)

Ammonium hydroxide (E527)

Simeticone

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Store in a dry place below 25°C.

6.5    Nature and contents of container

Packs of 5, 7, 10, 14, 15, 20, 21, 25, 28, 30, 56, 60, 84, 90, 100, 112, 120, 168 and 180 capsules in either:

1)    Polypropylene containers with tamper evident polythylene caps and optional use of polyethylene ullage filler

2)    Aluminium foil/PVC blister packs

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Not applicable.

7. MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd t/a Mylan

Potters Bar, Herts,

EN6 1TL

8.    MARKETING AUTHORISATION NUMBER(S)

PL 04569/0231

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 November 1990 Date of latest renewal: 7 February 1996

10 DATE OF REVISION OF THE TEXT

16/06/2016