ANAFRANIL Prolonged-release, film-coated tablet Ref.[2672] Active ingredients: Clomipramine

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 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.

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 (SNRIs). 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 medicinal 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, SNRIs 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.

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 hepatic and renal disease, periodic monitoring of the hepatic enzyme levels and renal function 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).

Specific treatment populations

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.

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.

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 tricyclic antidepressants may cause damage to the corneal epithelium in patients with contact lenses.

The excipient polyoxyl hydrogenated castor oil may cause stomach upset and diarrhoea.

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).

Treatment discontinuation

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 weeks wash-out period must be observed if the MAO-A inhibitor is used after Anafranil.

Selective serotonin reuptake inhibitors

Co-medication with SSRIs may lead to additive effects on the serotonin system (see serotonergic agents).

Serotonergic agents

Serotonin syndrome, a potentially life-threatening condition can possibly occur when clomipramine is administered with serotonergic co-medications such as selective serotonin re-uptake inhibitors (SSRIs), serotonin and noradrenergic re-uptake inhibitors (SNRIs), tricyclic antidepressants, buprenorphine/opioids, or lithium. Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, gastrointestinal symptoms, hyperpyrexia, myoclonus, agitation, seizures, delirium, and coma.

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

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 (clomipramine) 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 is catalysed 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 concentrations 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 co-administration with clomipramine.
• Antiarrhythmics (such as quinidine and propafenone), which are potent inhibitors of CYP2D6, should not be used in combination with tricyclic antidepressants.
• SSRIs, 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 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.
• Oral antifungal, terbinafine. Co-administration 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 co-administered with terbinafine.
• Co-administration with the histamine 2 (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.
• No interaction between chronic oral contraceptive use (15 or 30 mg ethinyl estradiol daily) and Anafranil (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 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 oestrogen regimens. Monitoring therapeutic response of tricyclic antidepressants at high dose oestrogen regimens (50 mg daily) is recommended and dose adjustments may be necessary.
• Methylphenidate (e.g. Ritalin) may also increase concentrations of tricyclic antidepressants by potentially inhibiting their metabolism, and a dose reduction of tricyclic antidepressant may be necessary.
• Concomitant administration of valproate with clomipramine may cause inhibition of CYP2C and/or UGT enzymes resulting in increased serum levels of clomipramine and desmethylclomipramine.
• Concomitant administration of Anafranil with grapefruit, grapefruit juice or cranberry juice may increase the plasma concentrations of clomipramine.
• 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), 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).
• 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.
• Concomitant administration of Anafranil with St. John’s wort during the treatment may decrease the plasma concentrations of clomipramine.

Clomipramine is also an in vitro (Ki = 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.

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/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.

Breast-feeding

Since the active substance passes into 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.

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).

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, have been observed. In the presence of such effects, patients 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.

Frequency estimates: Very common ≥10%, common ≥1% to <10%, uncommon ≥0.1% to <1%, rare ≥0.01% to <0.1%, very rare <0.01%. The ADRs listed below are based on clinical trials as well as post marketing reports.

Table 1. Tabulated summary of adverse drug reactions:

Additional adverse drug reaction from port-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 known: Serotonin syndrome, extrapyramidal symptoms (including akathisia and tardive dyskinesia)

Musculoskeletal and connective tissue disorders

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

Reproductive system and breast disorders

Frequency not known: Ejaculation failure, Ejaculation delayed

Investigations

Frequency not known: Blood prolactin increased

Bone fractures

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.

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.

Geriatric 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 HPRA Pharmacovigilance, Website: www.hpra.ie.

Not applicable.