Novartis Ireland Limited

Anafranil 50mg Capsules

Each capsule contains 50mg clomipramine hydrochloride.

Also contains lactose monohydrate, 98.0mg per capsule.

For a full list of excipients see section 6.1.

Hard Capsules

Size No. 4, opaque hard gelatin capsules, with a caramel cap and a light grey body, imprinted on both cap and body with the 'Geigy' logo, and containing a white powder.

In the management of endogenous depression including manic depression, periodic and involutional depression, reactive and neurotic depression, obsessional and phobic states and as an adjunctive treatment of cataplexy associated with narcolepsy.

Before initiating treatment with Anafranil, hypokalemia should be treated (see 4.4 Special warnings and precautions for use).

As a precaution against possible serotonergic toxicity, adherence to the recommended doses of Anafranil is advised and any increase in dose should be made with caution if other serotonergic agents are co-administered (see 4.4 Special warnings and precautions for use and 4.5 Interactions with other medicaments and other forms of interaction).

Adults:

Depression:

The usual daily dosage is in the range of 30 to 75mg in single or divided doses. Initial dosage should be 10mg/day with gradual increments to 30-150mg/day in divided doses or as a single dose at bedtime. Dosage may exceed the stated range if necessary up to a maximum of 250mg.

Obsessional/phobic states:

Doses in the higher range are generally required.

Adjunctive treatment of cataplexy associated with narcolepsy:

Initially 10mg, increasing to 50mg daily. Control of cataplexy should be achieved within 24 hours of reaching optimal dose.

Elderly:

Daily dose should generally be low, initiated at the lowest level (10mg) with very slow cautious increments to 30-75mg daily.

Paediatric Patients

Anafranil is not recommended for use in children due to insufficient data on safety and/or efficacy (See Section 4.4 Special Warnings and Precautions for use)

Use in patients who are currently receiving, or have received within 3 weeks, monoamine oxidase inhibitors.

Use in patients in acute recovery phase of myocardial infarction.

Use in patients hypersensitive to dibenzazepines.

Use in patients with cardiac arrhythmias, particularly heartblock.

Use during lactation in women breast-feeding infants.

Use in mania, severe liver disease, narrow-angle glaucoma, and retention of urine.

Use in patients with congenital QT syndrome.

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 Anafranil 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.

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.

Prescriptions for Anafranil should be written for the smallest quantity of tablets or capsules consistent with good patient management, in order to reduce the risk of overdose.

Other Psychiatric effects

Many patients with panic disorder experience more marked anxiety at the start of treatment with Anafranil. 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 Anafranil or to withdraw it and administer an antipsychotic agent. After such episodes have subsided, low dose therapy with Anafranil may be resumed if required.

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

Cardiac and vascular disorders

Anafranil should be administered with particular caution in patients with cardiovascular disorders, especially those with cardiovascular insufficiency, conduction disorders, (e.g. atrioventricular block grades I to III), or arrhythmias. Monitoring of cardiac function and the ECG is indicated in such patients, as well as in elderly patients. There may be a risk of QTc prolongation and Torsades de Pointes, particularly at supratherapeutic doses or supra-therapeutic plasma concentrations of clomipramine, as occur in the case of co-medication with selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenergic reuptake inhibitors (SNaRIs). 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 sections 4.2 Posology and method of administration and 4.5. Interactions with other medicinalaments products and other forms of interaction). 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 Anafranil and Anafranil should be used with caution when combined with SSRIs, SNaRIs or diuretics (see section 4.5)

Tricyclic antidepressants are known to lower the convulsion threshold and Anafranil 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 Anafranil should not be exceeded.

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.

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

Elderly patients are particularly liable to experience adverse effects, especially agitation, confusion, and postural hypotension.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency of glucose-galactose malabsorption should not use this medication.

Precautions:

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.

White Blood Cell Count

Although changes in the white blood cell count have been reported with Anafranil 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.

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

Anticholinergic effects

Because of its anticholinergic properties, Anafranil should be used with caution in patients with a history of increased intra-ocular pressure, narrow angle glaucoma or urinary retention (e.g. diseases of the prostate).

Special Treatment Population

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

Caution should be exercised when using Anafranil in patients with severe renal disease.

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.

Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are not available. Anafranil is not recommended for use in children due to insufficient data on safety and/or efficacy.

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

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

Risk of suicide is inherent to severe depression and may persist until significant remission occurs. Patients posing a high suicide risk require close initial supervision.

Anaesthesia

Before general or local anaesthesia, the anaesthetist should be aware that the patient has been receiving Anafranil and of the possible interactions (see 4.5 Interaction with other medicaments and other forms of interaction).

Abrupt withdrawal should be avoided because of possible adverse reactions (see 4.8 Undesirable Effects). If the decision has been 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 Undesirable effects, for a description of the risks of discontinuation of Anafranil).

Adrenergic neurone blockers: Anafranil may diminish or abolish the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine and alpha-methyldopa.

Patients requiring comedication for hypertension should therefore be given antihypertensives of a different type (e.g. vasodilators, or beta-blockers).

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

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

Diuretics: Comedication of Anafranil with diuretics may lead to hypokalemia, which in turn increases the risk of QTc prolongation and Torsades de Pointes. Hypokalaemia should therefore be treated prior to administration of Anafranil (see 4.2 Posology and 4.4 Special warnings and precautions).

MAO inhibitors: Do not give Anafranil for at least 3 weeks after discontinuation of treatment with MAO inhibitors (there is a risk of severe symptoms such as hypertensive crisis, hyperpyrexia and those consistent with Serotonin Syndrome e.g. myoclonus, agitation, seizures, delirium and coma). The same applies when giving a MAO inhibitor after previous treatment with Anafranil. In both instances the treatment should initially be given in small gradually increasing doses and its effects monitored. There is evidence to suggest that Anafranil 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 Anafranil.

Selective serotonin reuptake inhibitors: Co-medication with SSRI's may lead to additive effects on the serotonin system (see serotonergic agents).

Serotenergic Agents: Seretonin Syndrome can possible occur when clomipramine is administered with serotonergic co-medications such as slective serotonin re-uptake inhibitors (SSRIs), serotonin and nonadrenergic reuptake inhibitors SNaRI's), tricyclic antidepressants –or lithium. For fluoxetine, a washout period of two to three weeks is advised before and after treatment with fluoxetine.

Sympathomimetic drugs: Anafranil 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).

Pharmacokinetic-related interactions:

Anafranil (clomapramine) is predominantly eliminated through metabolism. The primary route of metabolism is demethylation to form the active metabolite, N-desmethylclomipramine, followed by hydroxylation and further conjugation of both N-desmethylclomipramine and the parent drug. Several cytochrome P450's are involved in the desmethylation, mainly CYP3A4, CYP2C19 and CYP1A2. Elimination of both active components is by hydroxylation and its catalyzed by CYP2D6.

Concomitant administration of CYP2D6 inhibitors may lead to an increase in concentration of both active components, up to 3 fold in patients with desbrinoquine/sparteine extensive metabolizer phenotype, converting them to poor-metabolizer phenotype. Concomitant administration of CYP1A2, CYP2C19 and CYP3A4 inhibitors are expected to increase clomipramine concerntrations and decrease N-desmethylclomipramine, thus not necessarily affecting the overall pharmacology.

• MAO inhibitors which are also potent CYP2D6 inhibitors in vivo, such as moclobemide, are contraindicated for coadministration with clomipramine.

• Antiarrhythmics (such as quinidine and propafenone), which are potent inhibitors of CYP2D6, should not be used in combination with tricyclic antidepressants.

• SSRI's which are inhibitors of CYP2D6, such as fluoxetine, paroxetine or sertraline and of others including CYP1A 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)

• Comedication of neuroleptics (e.g.phenothiazines) may result in increased plasma levelsof tricyclic antidepressants, a lowered convulsion threshold and seizures. Combination with thioridazine may produce severe cardiac arrhytmias.

• Oral antifungal, terbinafine. Coadministration of Anafranil 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 Anafranil may be necessary when coadministered with terbinafine.

• Coadministration with the histamine ₂ (H₂) receptor antagonist, cimetine (an inhibitor of several P450 enzymes, including CYP2D6 and CYP3A4), may increase plasma concentrations of tricyclic antidepressants, whose dosage should therefore be reduced.

• No interaction between chronic oral contraceptive use (15 or 30 mg ethinyl estradiol daily) and Anafranil (25 mg daily) has been documented. Estrogens 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 estrogen (50 mg 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 estrogen regimens. Monitoring therapeutic response of tricyclic antidepressants at high dose estrogen regimems (50mg daily) is recommended and dose adjustments may be necessary.

• Methylphenidate (e.g. Ritalin) may also increase concentrations of tricyc lic antidepressants by potentially inhibiting their metabolism, and a dose reduction of tricyclic antidepressant may be necessary.

• Some tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs, such as warfarin, and this may be through inhibition of their metabolism (CYP2C9). There is no evidence for the ability of clomipramine to inhibit the metabolism of anticoagulants, such as warfarin, however, careful monitoring of plasma prothrombin has been advised for this class of drug.

• Concomitant administration of drugs known to induce cytochrome P450 enzymes, particularly CYP3A4, CYP2C19, and/or CYP1A2 may accelerate the metabolism and decrease the efficacy of Anafranil.

• CYP3A and CYP2C inducers such as rifampicin or anticonvulsants (e.g. barbiturates, carbamazepine, Phenobarbital and phenytoin), may decrease clomipramine concentrations.

• Known inducers of CYP1A2 (e.g. nicotine/components in cigarette smoke), decreae 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).

Clomipramine is also an in vitro (K_i = 2.2µM) and in vivo inhibitor of CYP2D6 activity (sparteine oxidation) and therefore, may cause increased concentrations of co-administered compounds that are primarily cleared by CYP2D6 in extensive metabolizers.

Experience with Anafranil in pregnancy and lactation is limited. Since there have been isolated reports of a possible connection between the use of tricyclic antidepressants and adverse effects (developmental disorders) on the foetus, treatment of Anafranil should be avoided during pregnancy, unless the anticipated benefits justify the potential risk to the foetus.

Neonates whose mothers had taken tricyclic antidepressants until delivery showed drug withdrawal symptoms, such as dyspnoea, lethargy, colic, irritability, hypotension or hypertension, and tremor /convulsions, during the first few hours or days. To avoid such symptoms, Anafranil should if possible be gradually withdrawn at least 7 weeks before the calculated date of confinement.

Since the active substance passes into breast milk, Anafranil should be gradually withdrawn or the infant weaned if the patient is breast-feeding.

Patients receiving Anafranil should be warned that blurred vision, drowsiness and other CNS symptoms (see Undesirable Effects) may occur in which case they should not drive or operate machinery or do anything else which may require alertness or quick actions.

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, Anafranil should be withdrawn.

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.

Frequency estimates: Very common > 10%, common >1% to <10%, uncommon >0.1% to <1%, rare > 0.01% to <0.1%, very rare <0.01%.

Central nervous system

Psychic effects

Very common: drowsiness, fatigue, restlessness, increased appetite.

Common: confusion, disorientation, hallucinations (particularly in elderly patients and patients with Parkinson's disease), anxiety states, agitation, sleep disturbances, mania, hypomania, aggressiveness, impaired memory, depersonalisation, aggravated depression, impaired concentration, insomnia, nightmares, yawning.

Uncommon: activation of psychotic symptoms.

Unknown: suicidal ideation* and suicidal behaviour*

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

Neurological effects

Very common: dizziness, tremor, headache, myoclonus.

Common: delirium, speech disorders, paraesthesias, muscle weakness, muscle hypertonia.

Uncommon: convulsions, ataxia.

Very rare: EEG changes, hyperpyrexia, neuroleptic malignant syndrome.

Anticholinergic effects

Very common: dry mouth, sweating, constipation, disorders of visual accommodation, blurred vision, disturbances of micturition.

Common: hot flushes, mydriasis.

Very rare: glaucoma, urinary retention

Cardiovascular system

Common: sinus tachycardia, palpitations, postural hypotension, clinically irrelevant ECG changes (e.g. ST and T changes) in patients of normal cardiac status.

Uncommon: arrhythmias, increased blood pressure.

Very rare: conduction disorders (e.g. widening of QRS complex, prolonged QT interval. PQ changes, bundle-branch block Torsade de Pointes particularly in patients with hypokalemia.

Gastrointestinal tract

Very common: nausea.

Common: vomiting, abdominal disorders, diarrhoea, anorexia.

Liver

Common: elevated transaminases.

Very rare: hepatitis with or without jaundice.

Skin

Common: allergic skin reactions (skin rash, urticaria), photosensitivity, pruritus.

Very rare: oedema (local or generalised), hair loss.

Endocrine system and metabolism

Very common: weight gain, disturbances of libido and potency.

Common: galactorrhoea, breast enlargement.

Very rare: SIADH (inappropriate antidiuretic hormone secretion syndrome).

Hypersensitivity

Very rare: allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions including hypotension.

Blood

Very rare: leucopenia, agranulocytosis, thrombocytopenia, eosinophilia, purpura.

Sense organs

Common: taste disturbances, tinnitus.

Class effects

Epidemiological studies, mainly 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 the risk is unknown.

Others

The following symptoms commonly occur after abrupt withdrawal or reduction of the dose: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, and anxiety.

The signs and symptoms of overdose with Anafranil are similar to those reported with other tricyclic antidepressants. Cardiac abnormalities and neurological disturbances are the main complications. In children accidental ingestion of any amount should be regarded as serious and potentially fatal.

Signs and symptoms

Symptoms generally appear within 4 hours of ingestion and reach maximum severity after 24 hours. Owing to delayed absorption (anticholinergic effect), long half-fife, and enterohepatic recycling of the drug, the patient may be at risk for up to 4-6 days.

The following signs and symptoms may be seen:

Central nervous system

Drowsiness, stupor, coma, ataxia, restlessness, agitation, enhanced reflexes, muscular rigidity and choreoathetoid movements, convulsions. In addition, symptoms consistent with Seotonin Syndrome (e.g. hyperpyrexia, myoclonus, delirium and coma) may be observed.

Cardiovascular system

Hypotension, tachycardia, arrhythmias, QTc prolongation and arrhythmias including Torsades de Pointes, conduction disorders, shock, heart failure; in very rare cases cardiac arrest.

Respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, and oliguria or anuria may also occur.

Treatment

There is no specific antidote, and treatment is essentially symptomatic and supportive.

Anyone suspected of receiving an overdose of Anafranil, particularly children, should be hospitalised and kept under close surveillance for at least 72 hours.

Perform gastric lavage or induce vomiting as soon as possible if the patient is alert. If the patient is not alert, secure the airway with a cuffed endotracheal tube before beginning lavage, and do not induce vomiting. These measures are recommended for up to 12 hours or ever longer after the overdose, since the anticholinergic effect of the drug may help to reduce drug absorption.

Treatment of symptoms is based on modern methods of intensive care, with continuous monitoring of cardiac function, blood gases, and electrolytes, and if necessary emergency measures such as anticonvulsive therapy, artificial respiration, and resuscitation. Since it has been reported that phyotigmine may cause severe bradycardia, asystole, and seizures, it's use is not recommended in cases of overdosage with Anafranil. Haemodialysis or peritoneal dialysis are ineffective because of the low plasma concentrations of clomipramine.

Pharmacotherapeutic group

Tricyclic antidepressant.

Mechanism of action

The pharmacological action includes alpha-adrenolytic, anticholinergic, anti-histaminic and 5-HT receptor blocking properties. The main property displayed by the compound is its ability to inhibit the neuronal re-uptake of noradrenaline and 5-HT. Inhibition of the latter is the dominant component.

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 Anafranil 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. 75mg Anafranil daily produces steady state concentrations of clomipramine ranging from about 20 to 175ng/ml. Levels of desmethylclomipramine follow a similar pattern but are 40-85% higher.

Following repeated intravenous or intramuscular administration of 50-150mg Anafranil daily, steady-state plasma concentrations are attained in the second week of treatment. These range from <15 to 447 ng/ml for clomipramine and from <15 to 669 ng/ml for desmethylclomipramine.

Distribution:

Clomipramine is 97.6% bound to plasma proteins. The apparent volume of distribution is about 12-17 L/kg bodyweight. Concentrations in cerebrospinal fluid are about 2% of the plasma concentration.

Biotransformation:

The primary route of clomipramine metabolism is demethylation to form the active metabolite, N-desmethylclomipramine. N-desmethylclomipramine can be formed by several P450 enzymes, primary CYP3A4, CYP2C19, and CYP1A2. Clomipramine and N-desmethylclomipramine are hydroxylated to form 8-hydroxyclomipramine or 8-hydroxy-N-desmethylclomipramine. The activity of the 8-hydroxy metabolites are not defined in vivo. Clomipramine is also hydroxylated at the 2-position and N-desmethylclomipramine can be further demethylated to form didesmethylclomipramine. The 2- and 8-hydroxy metabolites are excreted primarily as glucuronides in the urine. Elimination of the active components, clomipramine and N-desmethylclomipramine, by formation of 2-and 8-hydroxy clomipramine is catalysed by CYP2D6.

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.

After intramuscular and intravenous administration, clomipramine is eliminated from plasma with a mean terminal half-life of 25 hours (range 20-40h) and 18 hours respectively.

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.

Characteristics in patients:

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

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

Use of high doses in animals has resulted in embryo-fetotoxicity; however, there was no indication of teratogenicity.

Lactose monohydrate

Gelatin

Magnesium stearate

Capsules

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide black (E172)

Iron oxide red (E172)

Gelatin

Printing Ink:

Opacode brown S-1- 26593:

Shellac

Industrial methylated spirits

Iron oxide red (E172)

Iron oxide black (E172)

Titanium dioxide (E171)

Propylene glycol

Isopropyl alcohol

N-butyl alcohol

Not applicable.

5 years.

Do not store above 30°C.

Store in the original package in order to protect from moisture.

PVC/PVDC/Aluminium blister strips in outer cartons of 100 and 56.

Not all pack sizes may be marketed

No special requirements.

Novartis Pharmaceuticals UK Ltd

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

England

PA 13/84/1

Date of first authorisation: April 25^th 1975

Date of last renewal: 1^st April 2008

15^th June 2011