Adults

Treatment of depressive states of varying aetiology and symptomatology, e.g.:

·           depressive syndromes - mild, moderate and severe, with and without psychotic symptoms, with recurrent depression or bipolar affective disorder;

·           depression associated with schizophrenia and personality disorders.

Obsessive-compulsive syndromes, phobias and panic attacks. Cataplexy accompanying narcolepsy.

 

Children and adolescents

In children and adolescents, there is not sufficient evidence of safety and efficacy of Anafranil in the treatment of depressive states of varying aetiology and symptomatology, phobias and panic attacks, cataplexy accompanying narcolepsy and chronic painful conditions. The use of Anafranil in children and adolescents (0-17 years of age) in these indications is therefore not recommended (see section 4.4.).

Before initiating treatment with Anafranil, hypokalaemia should be treated (see section 4.4).The dosage should be adapted to the individual patient's condition. The aim is to achieve an optimum effect while keeping the doses as low as possible.

 

After a response has been obtained, maintenance therapy should be continued at the optimum dose to avoid relapse. Patients with a history of recurrent depression 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 Anafranil 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 Anafranil 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 Anafranil therapy is discontinued.

 

Depression, obsessive-compulsive syndromes, and phobias

Start treatment with 1 coated tablet of 25 mg 2-3 times daily. Raise the daily dosage stepwise, e.g. 25 mg every few days, (depending on how the medication is tolerated) to 100-150 mg in the end of the first week of treatment. In severe cases this dosage can be increased up to a maximum of 250 mg daily. Once there is a distinct improvement, adjust the daily dosage to a maintenance level of about 50-100 mg..

 

Panic attacks and agoraphobia

Start with 10 mg daily. Depending on how the medication is tolerated, raise the dosage until the desired response is obtained. The daily dosage required varies greatly from patient to patient and lies between 25 and 100 mg. If necessary it can be increased up to 150 mg. It is advisable for treatment not to be discontinued for at least 6 months and for the maintenance dose to be reduced slowly during this time.

 

Cataplexy accompanying narcolepsy

Daily dose of 25-75 mg.

 

Dosage and administration in special populations

 

Elderly patients (65 years or older)

Elderly patients generally show a stronger response to Anafranil than patients of intermediate age groups, Anafranil should be used with caution in elderly patients and doses should be increased cautiously. Start treatment with 10 mg daily. Gradually raise the dosage to an optimum level of 30-50 mg daily, which should be reached after about 10 days and then maintained until the end of treatment.

 

Children and adolescents

 

Adolescents generally show a stronger response to Anafranil than patients of intermediate age groups, Anafranil should be used with caution in adolescents and doses should be increased cautiously.

 

Obsessive-compulsive syndromes

The starting dose is 25 mg daily and should be gradually increased (given in divided doses) during the first 2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller. Thereafter, the dosage may be increased gradually over the next several weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller

 

 

Renal impairment

Anafranil should be given with caution in patients with renal impairment (see section 4.4 Special warnings and precautions for use.)

 

Hepatic impairment

Anafranil should be given with caution in patients with hepatic impairment (see section 4.4 Special warnings and precautions for use.)

 

Method of administration

The dose should be adapted to the individual patient's condition.

Anafranil can be administered with or without food.

Known hypersensitivity to clomipramine or any of the excipients, or cross-sensitivity to tricyclic antidepressants of the dibenzazepine group. Anafranil should not be given in combination, or within 14 days before or after treatment, with a MAO inhibitor (see section 4.5). The concomitant treatment with selective, reversible MAO-A inhibitors, such as moclobemide, is also contraindicated. Recent myocardial infarction. Congenital long QT syndrome.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with increased risk of suicidal thoughts, self-harm and suicide (events relating to suicide). This risk persists until significant remission occurs. 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. Antidepressants increased the risk of suicidal thinking and behaviour (suicidality) in short-term studies in children, adolescents and young adults less than 25 years old with depressive disorders and other psychiatric disorders.

All patients being treated with Anafranil for any indication should be observed closely for clinical worsening, suicidality and other psychiatric symptoms (see section 4.8 Adverse drug reactions), especially during the initial phase of therapy or at times of dose changes.

 

 

It must be taken into account the possibility of changing the dosage including the possibility of discontinuing therapy in patients with severe, abrupt changes at treatment beginning or changes which are not part of current symptoms (see also Treatment discontinuing in section 4.4. Special warnings and precautions for use).

 

The patients being treated with antidepressants for both psychiatric and non-psychiatric indications as well as the families and caregivers of those patients, should be alerted about the need to monitor patients for the emergence of other psychiatric symptoms (see section 4.8 Adverse drug reactions), as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.

 

Anafranil should be prescribed in the lowest available dose of tablets in order to avoid overdose and abuse. There is evidence that the application of Anafranil is associated with fewer deaths due to overdose, compared with other tricyclic antidepressants

 

Children and adolescents (0-17 years of age)

Anafranil should not be used to treat depression, phobias and cataplexy associated with narcolepsy in children under 18 years of age (see section 4.1).

Antidepressants increase the risk of suicidal behavior (attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior and anger) are more frequently observed in clinical trials in children, adolescents and young people under 25 years treated with antidepressants compared to those treated with placebo. However if based on clinical need, a decision to carry out treatment, the patient should be carefully monitored for the appearance of suicidal symptoms. Moreover, long-term safety data in children and adolescents concerning growth, maturation and cognitive-behavioral development are insufficient.

Families and caregivers of paediatric and adult patients treated with antidepressants because of both psychiatric and due to non-psychiatric testimony, should be alert about the need to monitor patients for the emergence of psychiatric symptoms (see section 4.8) and suicidality and to report immediately the occurrence of such symptoms to health professionals

 

Other psychiatric effects

Many patients with panic disorder experience more marked anxiety at the start of the treatment with Anafranil (section 4.2).

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 supra-therapeutic 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 and 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 Anafranil (see sections 4.2 and 4.5).

 

Before starting treatment with Anafranil, it is advisable to check blood pressure because patients with postural hypotension or a labile circulation may experience 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 (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 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.

Like related tricyclic antidepressants, Anafranil should be given with electroconvulsive therapy only under careful supervision.

 

Anticholinergic effects

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

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 indicated in patients with hyperthyroidism or patients receiving thyroid preparations, owing to the possibility of cardiac toxicity.

In patients with hepatic and renal disease, periodic monitoring of the hepatic enzyme levels and renal function is recommended.

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

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.

 

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 and during prolonged treatment  

 

Anesthesia

Before general or local anesthesia, the anesthesist should be told that the patient has been receiving ANAFRANIL (see section 4.5).

 

Treatment discontinuation

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

 

Lactose and sucrose

Anafranil coated tablets contain lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, severe lactase deficiency, sucrase-isomaltase insufficiency or glucose-galactose malabsorption should not take Anafranil coated tablets.

Interactions resulting in a contraindication

MAO inhibitors

Do not give Anafranil for at least 2 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). MAO inhibitors, which are also potent CYP2D6 inhibitors in vivo, such as moclobemide, are contraindicated for coadministration with clomipramine (see section 4.3). The same applies when giving a MAO inhibitor after previous treatment with Anafranil. In both instances Anafranil or the MAO inhibitor should initially be given in small, gradually increasing doses and its effects monitored (see section  4.3).

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 two-week washout period must be observed if the MAO-A inhibitor is given after Anafranil has been used.

 

Interactions resulting in a concomitant use not recommended

 

Antiarrhythmics

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

 

Diuretics

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

 

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, comedication with SSRIs may lead to additive effects on the serotonergic system (see serotonergic agents). (See sections 4.2 Posology and method of administration and 4.4 Special warnings and precautions for use).

 

Serotonergic agents

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

 

Interactions to be considered

 

Interactions resulting in increased effect of Anafranil

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

 

Terbinafine

Coadministration of Anafranil with oral antifungal 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.

 

Cimetidine

Coadministration 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 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 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 estrogen regimens. Monitoring therapeutic response of tricyclic antidepressants at high dose estrogen regimens (50 micrograms daily) is recommended and dose adjustments may be necessary.

 

Antipsychotics

Comedication of antipsychotics (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

Methylphenidate may also increase concentrations of tricyclic antidepressants by potentially inhibiting their metabolism and a dose reduction of the tricyclic antidepressant may be necessary.

 

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 Anafranil with grapefruit, grapefruit juice, or cranberry juice may increase the plasma concentrations of clomipramine.

 

Interactions resulting in decreased effect of Anafranil

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 Anafranil.

 

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 Anafranil.

 

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 Anafranil 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. phenothiazine, antiparkinsonian agents, antihistamines, atropine, biperiden) on the eye, central nervous system, bowel and bladder.

 

Antiadrenergic agents

Anafranil may diminish or abolish the antihypertensive effects of adrenergic neuron blockers such as 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).

 

CNS depressants

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

 

Sympathomimetic drugs

Anafranil may potentiate the cardiovascular effects of sympathomimetics such as adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine (e.g. local anaesthetics).

 

Anticoagulants

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.

 

Clomipramine is also an in vitro (K_i = 2.2 microM) 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

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 Anafranil in pregnant women that indicates a potential to harm the foetus or cause congenital malformation. Anafranil should be used during pregnancy only if the potential benefit outweighs 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/spasms/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.

 

Lactation

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

 

 

 

Fertility

No adverse effects on reproductive performance, including male and female fertility, were observed in rats at oral doses up to 24 mg/kg. (see section 5.3. Preclinical safety data)

Patients receiving ANAFRANIL should be warned that blurred vision 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) may occur, in which case they should not drive, operate machinery, or do anything else requiring alertness.

Patients should also be warned that alcohol or other drugs may potentiate these effects (see section 4.5 ).

Summary of the safety profile

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.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1 000, < 1/100); rare (≥ 1/10 000, < 1/1 000) very rare (< 1/10 000), including isolated reports.

Table1 Summary of adverse drug reactions

Blood and lymphatic system disorders
	Very rare	Leukopenia, agranulocytosis, thrombocytopenia, eosinophilia,
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, torsade de pointes, particularly in patients with hypokalaemia)
Ear and labyrinth disorders
	Common	Tinnitus
Endocrine disorders
	Very rare	Inappropriate antidiuretic hormone secretion (SIADH)
Eye disorders
	Very common	Accommodation disorder, vision blurred
	Common	Mydriasis
	Very rare	Glaucoma
Gastrointestinal disorders
	Very common	Nausea dry mouth, constipation
	Common	Vomiting, gastrointestinal disorder, diarrhoea
General disorders and administration site conditions
	Very common	Fatigue
	Very rare	Oedema (local or generalised), alopecia hyperpyrexia
Hepatobiliary disorders
	Very rare	Hepatitis with or without jaundice
Immune system disorders
	Very rare	Anaphylactic and anaphylactoid reactions including hypotension
Investigations
	Very common	Weight increase
	Common	Transaminases increased
	Very rare	Electroencephalogram abnormal
Metabolism and nutrition disorders
	Very common	Increased appetite
	Common	Decreased appetite
Musculoskeletal and connective tissue disorders
	Common	Muscular weakness
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 syndrome
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
Renal and urinary disorders
	Very common	Micturition disorder
	Very rare	Urinary retention
Reproductive system and breast disorders
	Very common	Libido disorder, erectile dysfunction
	Common	Galactorrhoea, breast enlargement
Respiratory, thoracic, and mediastinal disorders
	Common	Yawning
	Very rare	Alveolitis allergic (pneumonitis) with or without eosinophilia
Skin and subcutaneous tissue disorders
	Very common	Hyperhidrosis
	Common	Dermatitis allergic (skin rash, urticaria), photosensitivity reaction, pruritus
	Very rare	Purpura
Vascular disorders
	Common	Hot flush

 

Additional adverse drug reactions from post-marketing spontaneous reports

The following additional adverse drug reactions have been identified with Anafranil oral or im/iv dosage forms based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency

 

Nervous system disorders

Frequency not unknown: Serotonin syndrome, extrapyramidal disordersymptoms (including akathisia and tardive dyskinesia).

 

Musculoskeletal and connective tissue disorders

Frequency not unknown: Rhabdomyolysis (as a complication of neuroleptic malignant syndrome) .

 

Reproductive system and breast disorders

Frequency not known: Ejaculation failure, Ejaculation delayed

 

Investigations

Frequency not unknown: Blood prolactin increased  

 

Withdrawal symptoms

The following symptoms commonly occur after abrupt withdrawal or reduction of the dose: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, and anxiety (see section 4.4)

 

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 and tricyclic antidepressants. The mechanism leading to this risk is unknown.

 

Geriatric population

Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric, or cardiovascular effects. Their ability to metabolisze 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 to:: Bulgarian Drug Agency, 8 Damyan Gruev str., 1303 Sofia; tel: +359 2 8903417; website: www.bda.bg.

 

--To reports any side effect(s):

·    Saudi Arabia:

·         Saudi Food and Drug Authority National Pharmacovigilance Center (NPC):

o Fax: +966112057662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.

o Toll free phone: 8002490000

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

 

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

O Toll Free Number: 8001240078

O Phone: +966112658100
O Fax: +966112658107
O Email: adverse.events@novartis.com

·    Other GCC States:

-- Please contact the relevant competent authority.

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-life, 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 choreoathetosis, convulsions. In addition, symptoms consistent with Serotonin Syndrome (e.g. hyperpyrexia, myoclonus, delirium and coma) may be observed.

 

Cardiovascular system

Hypotension, tachycardia, arrhythmias, QTc prolongation and arrhythmias including torsades de pointes, condition 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 even longer after the overdose, since the anticholinergic effect of the drug may delay gastric emptying. Administration of activated charcoal may help to reduce drug absorption.

Since it has been reported that physostigmine may cause severe bradycardia, asystole, and seizures, its use is not recommended in cases of overdosage with Anafranil. Haemodialyses or peritoneal dialyses are ineffective because of the low plasma concentrations of clomipramine.

 

Pharmacotherapeutic group

Pharmacotherapeutic group: Tricyclic antidepressant. Noradrenaline and preferential serotonin-reuptake inhibitor (non selective monoamine reuptake inhibitors), ATC code: N06A A04.

 

Mechanism of action

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

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

 

Pharmacodynamic effects

ANAFRANIL acts on the depressive syndrome as a whole, including in particular typical features such as psychomotor retardation, depressed mood, and anxiety. The clinical response usually sets in after 2-3 weeks of treatment.

ANAFRANIL also exerts a specific effect on obsessive-compulsive disorder distinct from its antidepressant effects. In chronic pain with or without somatic causes, ANAFRANIL acts presumably by facilitating serotonin and noradrenaline neurotransmission.

Absorption

Clomipramine is completely absorbed from the gastrointestinal tract. The systemic bioavailability of unchanged clomipramine is reduced to about 50% by hepatic first-pass metabolism to the active metabolite, N-desmethylclomipramine.  Following administration of 25 mg coated tablet, the mean maximum plasma concentration (Cmax) of clomipramine were 63.37 ± 12.71 ng/mL (Tmax 4.83 ± 0.39 hr). The dose of 75 mg daily, administered either as coated tablets of 25 mg t.i.d., produces steady-state plasma concentrations ranging from about 20 to 175 ng/mL

 

The steady-state plasma concentrations of the active metabolite N-desmethylclomipramine follow a similar pattern. However, at a dose of 75 mg Anafranil per day, they are 40-85% higher than those of clomipramine.

 

Distribution

Clomipramine is 97.6% bound to plasma proteins. The apparent distribution volume is about 12 to 17 l/kg bodyweight. Concentrations in cerebrospinal fluid are about 2% of the plasma concentration. Clomipramine passes into maternal milk in concentrations similar to those in plasma.

 

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

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

About two thirds of a single dose of clomipramine are 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 is about 2% and 0.5% of the dose administered, respectively.

 

Food effect

Food has no significant impact on the pharmacokinetics of clomipramine. A slight delay in the onset of absorption may be observed with the administration of Anafranil with food Dose proportionality

The drug follows dose-proportionate pharmacokinetics over a dose range of 25 to 150 mg  

 

Effect of age

In elderly patients, clomipramine has relatively low clearance in comparison to younger adult patients. It is reported to reach a therapeutic steady state at doses lower than that reported for middle-age patients. Clomipramine should be used with caution in elderly patients.

 

Renal impairment

There are no specific reports describing the pharmacokinetic of the drug in patients with renal impairment. Although the drug is excreted as inactive metabolites in the urine and feces, the accumulation of inactive metabolites may subsequently result in the accumulation of the parent drug and its active metabolite. In moderate and severe renal impairment, it is recommended to monitor the patient during the treatment.

 

Hepatic impairment

Clomipramine is extensively metabolized in the liver by CYP2D6, CYP3A4, CYP2C19 and CYP1A2, hepatic impairment may impact on its pharmacokinetics. In patients with liver impairment, clomipramine should be administered with caution.

 

Ethnic sensitivity

Although the impact of ethnic sensitivity and race on the pharmacokinetics of clomipramine has not been studied extensively, the metabolism of clomipramine and its active metabolite is governed by genetic factors leading to poor and extensive metabolism of the drug and its metabolite. The metabolism of clomipramine in Caucasians population may not be extrapolated to Asians, in particular, Japanese and Chinese because of the pronounced differences of metabolism of clomipramine between these two ethnic groups.

Repeat-dose toxicity

Phospholipidosis and testicular changes, commonly associated with tricyclic compounds, have been observed with clomipramine hydrochloride at doses >10 fold greater than the maximum recommended human daily dose.

 

Reproductive toxicity

No adverse effects on reproductive performance, including male and female fertility, were observed in rats at oral doses up to 24 mg/kg.

No teratogenic effects were detected in mice, rats, and rabbits at doses up to 100, 50, and 60 mg/kg, respectively (See section 5.3. Preclinical safety data)

 

Mutagenicity

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

 

Carcinogenicity

There was no evidence of carcinogenicity in mice and rats after 104 weeks of treatment with clomipramine hydrochloride.

Lactose monohydrate, Magnesium stearate, Maize starch, Silica colloidal anhydrous, Hypromellose (hydroxypropyl methylcellulose), Copovidone (vinylpyrrolidone-vinylacetate copolymer), Cellulose microcrystalline, Titanium dioxide (Е171), Iron oxide, yellow (Е172), Macrogol 8 000 (polyethylene glycol 8 000), Povidone (polyvinylpyrrolidone), Sucrose, Talc.

 

The 25 mg Coated tablets also contain Stearic acid and Glycerol (85%).

Not applicable.

 

2 years

Store below 30ºC

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

To be kept out of the reach and sight of children

PVC/PE/PVDC blisters

25 mg x 30 coated tablets

There is no special precautions for use and handling.