ANAFRANIL 25 mg/2 mL solution for injection 5Ampoule/2mL

VIDAL
Medicines
Update of 03/12/2025

ANAFRANIL^®
clomipramine

Forms and presentations

Injectable solution at 25 mg/2 ml:  Ampoules of 2 ml, box of 5.

Composition

	per ampoule
Clomipramine hydrochloride	25 mg

Excipients: glycerol at 99%, water for injectable preparations.

Indications

• Major depressive episodes (i.e., characterised).
  
• Obsessive compulsive disorders.
  
• Neuropathic pain in adults.
  

Dosage and administration

Use the pharmaceutical form and dosage adapted to the patient's clinical condition and the prescribed daily dose.

In all cases, treatment will be started at the lowest effective dose, and the maximum dose will not be exceeded. The dosage may be increased with caution, depending on the individual clinical response. The need to continue treatment should be reassessed periodically.

An abrupt discontinuation of treatment with ANAFRANIL should be avoided due to the possible occurrence of withdrawal symptoms (see Warnings and Precautions for UseAdverse effects). Consequently, the dosage should be reduced gradually after regular use over a long period, and the patient should be closely monitored when treatment with ANAFRANIL is stopped.

DEPRESSION AND OBSESSIVE-COMPULSIVE DISORDERS IN ADULTS

Dosage

The initial treatment is started in a hospital setting (for the IV route) until improvement.

Intramuscular injection

Start treatment with 25 to 50 mg by intramuscular route, then increase the doses by 25 mg per day until the patient receives 100 to 150 mg per day.

Intravenous infusion

Start with 50-75 mg by intravenous route once a day.

Method of administration

Intramuscular injection

Once the patient's condition has improved, gradually switch from the intramuscular route to the oral route.

Intravenous infusion

The ampoules must be diluted and thoroughly mixed with 250 to 500 ml of isotonic saline or glucose solution and administered by slow intravenous infusion over a period of 1,5 to 3 hours.

During the infusion, adverse effects must be closely monitored. Particular attention must be paid to blood pressure, as orthostatic hypotension may occur. Ensure that the patient remains lying down for one hour after the end of the infusion. When a marked improvement is observed, the infusion treatment must be administered for an additional 3 to 5 days. To maintain the response, treatment must then be continued orally.

Duration of treatment

Antidepressant treatment is symptomatic.

Patients with a history of recurrent depression require long-term maintenance treatment. Treatment of an episode lasts several months (usually of the order of 6 months) in order to prevent the risk of relapse of the depressive episode. The duration of maintenance treatment and the need to continue treatment should be reassessed periodically.

NEUROPATHIC PAIN IN ADULTS

Dosage

Treatment must be initiated in a hospital setting for the I.V. route.

Intravenous infusion

Start treatment with 10 mg by slow intravenous infusion 1 week. The dose is then gradually increased in steps of 10 to 25 mg every week, depending on individual clinical response and tolerability. Dosage is individual (from 10 to 75 mg of solution per day), and must take into account any analgesic treatments that may be combined.

Method of administration

Intravenous infusion

The ampoules must be diluted and mixed thoroughly with 100 mL of isotonic saline or glucose solution and administered by slow intravenous infusion.

Ensure the patient remains lying down for one hour after the end of the infusion.

Once improvement is obtained, switch from the intravenous route to the oral route.

Maintenance treatment should be given at the lowest effective dose, and the benefit of treatment should be reassessed periodically.

OBSESSIVE COMPULSIVE DISORDERS

Dosage

Child and adolescent:

Limited data exist, from short-term clinical trials in children over 10 years and adolescents. The initial dose of 25 mg per day will be gradually increased if needed depending on tolerability. The maximum daily dosage is 3 mg/kg/day. The dosage must not exceed 100 mg/day during the first 2 weeks and 200 mg/day thereafter.

The benefit of treatment should be reassessed periodically.

Special populations

Elderly patients (65 years or older)

The capacity to metabolise and eliminate medicines may be reduced, which entails a risk of increased plasma levels at therapeutic doses. Treatment will be initiated cautiously and at a low dosage, that is, in practice at half the minimum recommended dosage (see Pharmacokinetics). Dose increases, if necessary, will be gradual, with clinical monitoring: the adverse effects of imipramine-like drugs (in particular anticholinergic, neurological and psychiatric effects) may indeed have serious consequences in elderly subjects (falls, confusion).

Paediatric population

The use of ANAFRANIL is not recommended in children and adolescents under 18 years for the treatment of major (i.e., characterized) depressive episodes, certain depressive states occurring during schizophrenia, prevention of panic attacks and neuropathic pain, as the safety and efficacy of clomipramine have not been established in this age group (see Warnings and Precautions for Use).

Renal impairment

ANAFRANIL must be administered with caution in patients with renal impairment (see Warnings and Precautions for Use). The dosage should be reduced (see Pharmacokinetics).

Hepatic impairment

ANAFRANIL must be administered with caution in patients with hepatic impairment (see Warnings and Precautions for Use). The dosage should be reduced (see Pharmacokinetics).

Contraindications

This medicine MUST NEVER BE prescribed in the following cases:

• Hypersensitivity to the active substance or to any of the excipients listed in section Composition, or cross-sensitivity to all tricyclic antidepressants;
  
• known risk of angle-closure glaucoma;
  
• risk of urinary retention related to urethro-prostatic disorders;
  
• recent myocardial infarction;
  
• concomitant associations, or within 14 days before or after treatment, with irreversible MAOIs (iproniazid, phenelzine) (see Interactions).
  
• concomitant treatment with dapoxetine (see Interactions) or within 14 days following discontinuation of treatment with clomipramine. Likewise, clomipramine must not be administered within 7 days following discontinuation of treatment with dapoxetine.
  

Warnings and precautions

Insomnia or nervousness at the start of treatment may warrant a dose reduction or short-term symptomatic treatment.

Anaphylactic shock

Isolated cases of anaphylactic shock have been reported. Caution should be exercised when administering ANAFRANIL intravenously.

Suicides/suicidal ideation or clinical worsening

Depression is associated with an increased risk of suicidal ideation, self-harm and suicide (suicide-related behaviour). This risk persists until significant remission occurs. As clinical improvement may not occur for several weeks of treatment, patients must be closely monitored until such improvement is achieved. Clinical experience shows that suicide risk may increase at the very beginning of recovery.

Other psychiatric disorders for which ANAFRANIL is prescribed may also be associated with an increased risk of suicidal behaviour. In addition, these disorders may be associated with a major depressive episode. The same precautions for use as those mentioned for patients suffering from major depressive episodes should therefore be applied to patients with other psychiatric disorders.

Patients with a history of suicide-related behaviour or those expressing significant suicidal ideation before starting treatment are at higher risk of suicidal thoughts or suicide-related behaviour and must be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials on the use of antidepressants in adults with psychiatric disorders showed an increased risk of suicide-related behaviour in patients under 25 years of age treated with antidepressants compared with those receiving placebo. Close monitoring of patients, particularly those at high risk, must accompany drug treatment, especially at the start of treatment and when doses are changed. Patients (and their carers) must be advised to watch for the occurrence of clinical worsening, emergence of suicidal thoughts/behaviours and any unusual changes in behaviour, and to seek medical advice immediately if such symptoms occur.

Other psychiatric effects

Some patients with panic disorder experience increased anxiety at the start of treatment with ANAFRANIL. This initial paradoxical increase in anxiety is more pronounced during the first days of treatment and generally resolves within two weeks.

Reactivation of psychosis has sometimes been observed in patients with schizophrenia receiving tricyclic antidepressants.

Hypomanic or manic episodes have been observed during treatment with tricyclic antidepressants. In case of frank manic switch, treatment with clomipramine will be discontinued and, most often, a sedative neuroleptic will be prescribed. After these episodes have resolved, low-dose ANAFRANIL treatment may be resumed if necessary.

Cardiac and vascular disorders

ANAFRANIL must be administered with particular caution in patients with cardiovascular disorders, in particular those with cardiovascular insufficiency, conduction disorders (for example, atrioventricular blocks of grades I to III) or arrhythmias.

Monitoring of cardiac function and ECG is indicated in these patients.

Like other tricyclic antidepressants, clomipramine can prolong the QTc interval and be associated with a risk of torsades de pointes. This risk is low at therapeutic doses but increases with concomitant administration of substances that can increase clomipramine plasma concentrations, such as during co-medication with selective serotonin reuptake inhibitors (SSRIs). Therefore, concomitant administration of medicinal products that may cause clomipramine accumulation must be avoided. Likewise, concomitant administration of medicinal products that may prolong the QTc interval must be avoided (see Posology and Method of administrationInteractions).

Hypokalaemia and hypomagnesaemia are known risk factors for QTc prolongation and torsades de pointes and must be corrected before starting treatment with ANAFRANIL (see Posology and Method of administrationInteractions). Caution is also recommended in patients with bradycardia.

It is advised to check blood pressure before starting treatment with ANAFRANIL, as patients with orthostatic hypotension or blood circulation disorders are at risk of a drop in blood pressure.

ANAFRANIL must not be used in patients with a congenital long QT interval syndrome (see Contraindications).

Serotonin syndrome

A serotonergic syndrome is caused by an excess of serotonin and may occur when tricyclic antidepressants such as clomipramine are taken simultaneously with other serotonergic active substances (see Interactions). It may be fatal and includes motor symptoms (hyperreflexia, myoclonus, tremor, rigidity, hyperactivity), autonomic symptoms (hyperthermia, tachycardia, changes in blood pressure, chills, diarrhoea, sweating, possibly coma) and psychiatric symptoms (agitation, confusion, hypomania). Strict adherence to recommended doses is an essential factor in preventing the occurrence of this syndrome. Should serotonin syndrome occur, clomipramine treatment must be stopped immediately.

Convulsions

Tricyclic antidepressants are known to lower the epileptogenic threshold; therefore, ANAFRANIL must be used with caution (enhanced clinical and electrical monitoring) in patients with epilepsy or a history of epilepsy, or presenting risk factors for convulsions, such as brain damage of various aetiologies, concomitant use of medicinal products that lower the epileptogenic threshold (see Interactions), alcohol or drug withdrawal (medicines with anticonvulsant properties such as benzodiazepines). As the risk of convulsive seizures is dose-dependent, the recommended maximum dose of ANAFRANIL must not be exceeded. The occurrence of convulsive seizures requires discontinuation of treatment.

Anticholinergic effects

Due to its anticholinergic properties, ANAFRANIL should be used with caution in patients with a history of increased intraocular pressure, closed-angle glaucoma, urinary retention (for example, prostate diseases) or chronic constipation.

The decrease in tear production and accumulation of mucous secretions due to the anticholinergic properties of tricyclic antidepressants may damage the corneal epithelium in patients wearing contact lenses.

This medicine should be used with caution in elderly subjects (see the subsection on elderly people).

Elderly people (65 years and over)

Clomipramine should be used with caution in elderly subjects presenting with:

• increased sensitivity to orthostatic hypotension and sedation,
  
• chronic constipation (risk of paralytic ileus),
  
• possible prostatic hypertrophy.
  

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

Clomipramine should be used with caution in elderly patients.

Special populations

• Particular caution should be exercised when using tricyclic antidepressants such as clomipramine in patients with adrenal medullary tumours (for example pheochromocytoma, neuroblastoma), in whom they may cause hypertensive crises.
  
• Caution is recommended in subjects with certain cardiovascular conditions, due to the quinidine-like, tachycardic and hypotensive effects of this class of products. A complete initial cardiovascular assessment, including an ECG, is recommended.
  
• Caution should be exercised in patients suffering from hyperthyroidism or receiving thyroid hormones, due to the possibility of increased cardiac adverse effects.
  
• Particular attention should be paid to patients with hepatic and renal impairment, due to the risk of overdose (see Pharmacokinetics). Periodic monitoring of liver enzyme levels and renal function is recommended.
  

Paediatric population

The use of ANAFRANIL is not recommended in children and adolescents under 18 years in the treatment of depression and the treatment of neuropathic pain because the safety and efficacy of clomipramine have not been demonstrated in this age group (see Posology and Method of administration).

In addition, clinical studies conducted in children and adolescents treated with antidepressants have shown a higher frequency of suicidal-type behaviours (suicide attempts and suicidal ideation) and hostile-type behaviours (mainly aggressiveness, oppositional behaviour and anger) compared with those treated with placebo. This risk cannot be excluded for clomipramine. Furthermore, long-term safety data in children and adolescents regarding growth, sexual maturation and cognitive, emotional and behavioural development are not available.

White blood cell count

Isolated cases of changes in white blood cell count, including agranulocytosis, have been reported with ANAFRANIL. Regular blood counts and monitoring of symptoms such as fever and sore throat are necessary, particularly during the first months of treatment and in cases of prolonged treatment.

Anaesthesia

Before general or local anesthesia, the anesthesiologist must be informed that the patient has received ANAFRANIL (see Interactions) because concomitant use of anesthetics and tricyclic antidepressants may increase the risk of arrhythmias and hypotension, and tricyclic antidepressants may potentiate the effects of general anesthetics (see Interactions).

Discontinuation of treatment

Rare cases of withdrawal syndrome (with the occurrence of adverse effects such as headache, nausea, anxiety, sleep disturbances, etc. See section Adverse effects) have been observed upon discontinuation of treatment; it is recommended to gradually reduce doses and to monitor the patient particularly closely during this period.

ANAFRANIL is associated with blurred vision and other nervous and psychiatric disorders such as drowsiness, attention disorder, confusion, disorientation, worsening of depression, delirium, etc. (see Undesirable effects). ANAFRANIL has a major influence on the ability to drive vehicles and use machines. Patients receiving ANAFRANIL must be informed that this may cause drowsiness, attention disorder, confusion, disorientation, worsening of depression and delirium. If these symptoms occur, patients must not drive, use machines or perform other tasks that require alertness. A dose reduction or discontinuation of treatment may be considered. Patients must be informed that alcohol and other sedative medicines may potentiate these effects (see InteractionsDriving and using machinesAdverse effects).

Dental caries

An increase in dental caries has been reported during long-term treatment with tricyclic antidepressants. Regular dental examinations are therefore recommended in cases of long-term treatment.

Interactions

Serotonin syndrome

Certain overdoses or certain medicines may give rise to a serotonergic syndrome requiring immediate discontinuation of treatment.

These medicines are mainly represented by:

• linezolid,
  
• methylene blue,
  
• St John's wort,
  
• pethidine and tramadol,
  
• most antidepressants:
  
  • the class of serotonin reuptake inhibitors,
    
  • certain tricyclics (clomipramine, amitriptyline, imipramine),
    
  • mixed agents (venlafaxine, milnacipran, sibutramine),
    
  • with indications other than depression: atomoxetine, duloxetine, oxitriptan),
    
  • MAOIs, essentially irreversible, or even reversible MAO-A inhibitors,
    
  • buprenorphine, naloxone, opioids.
    

The serotonergic syndrome manifests as the simultaneous or sequential onset (possibly abrupt) of a set of symptoms that may require hospitalisation and, exceptionally, may result in death.

These symptoms may be of the following types:

• digestive (diarrhea),
  
• neuropsychiatric (agitation, confusion, hypomania),
  
• motor (myoclonus, tremors, hyperreflexia, rigidity, hyperactivity),
  
• autonomic (blood pressure variations, tachycardia, chills, hyperthermia, sweating, possibly coma).
  

Strict adherence to the recommended doses is an essential factor in preventing the onset of this syndrome.

Medicines lowering the epileptogenic threshold

The concomitant use of proconvulsant medicines, or medicines lowering the epileptogenic threshold, should be carefully weighed, given the severity of the risk incurred. These medicines are notably represented by most antidepressants (imipramine-like, selective serotonin reuptake inhibitors), neuroleptics (phenothiazines and butyrophenones), mefloquine, chloroquine, bupropion, tramadol.

Medicines causing orthostatic hypotension

Besides antihypertensives, many medicines may cause orthostatic hypotension. This is notably the case for nitrates, phosphodiesterase type 5 inhibitors, alpha-blockers used in urology, imipramine-like antidepressants and phenothiazine neuroleptics, dopamine agonists and levodopa. Their concomitant use therefore risks increasing the frequency and intensity of this undesirable effect. Refer to the interactions specific to each class, with the corresponding levels of constraint.

Atropinic medicinal products

It must be taken into account that atropine-like substances can add up their undesirable effects and more easily cause urinary retention, an acute attack of glaucoma, constipation, dry mouth, etc.

The various anticholinergic medicines are represented by imipramine-like antidepressants, most anticholinergic H1 antihistamines, anticholinergic antiparkinsonian agents, anticholinergic antispasmodics, disopyramide, phenothiazine neuroleptics as well as clozapine.

Contraindicated combinations

(See Contraindications)

+ irreversible MAOIs (iproniazid, phenelzine):

Risk of developing serotonin syndrome: myoclonus, agitation, convulsive seizures, diarrhoea, tachycardia, sweating, tremors, delirium, confusion or even coma.

Observe a two-week interval between stopping the MAOI and starting treatment with the antidepressant, and at least one week between stopping the antidepressant and starting treatment with the MAOI.

+ Dapoxetine

As with other SSRIs, co-administration of dapoxetine with clomipramine may give rise to serotonin-related effects. Dapoxetine must not be used in combination with clomipramine or within 14 days following discontinuation of clomipramine treatment. Likewise, clomipramine must not be administered within 7 days following discontinuation of dapoxetine treatment (see Contraindications).

Combinations not recommended

(See Warnings and Precautions for use)

+ Reversible MAO-A inhibitors (moclobemide, toloxatone), including linezolid and methylene blue:

Risk of serotonin syndrome: myoclonus, agitation, convulsive seizures, diarrhoea, tachycardia, sweating, delirium, confusion or even coma.

If the combination cannot be avoided, very close clinical monitoring. Start the combination at the recommended minimum doses.

There is evidence suggesting that ANAFRANIL may be administered within 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 administered after use of ANAFRANIL.

+ Diuretics:

Diuretics may cause hypokalaemia, which in turn increases the risk of QTc interval prolongation and torsades de pointes. Hypokalaemia must therefore be corrected before administration of ANAFRANIL (see Warnings and Precautions for Use).

+ Alpha and beta sympathomimetics (IM and IV routes):

Paroxysmal hypertension with possible rhythm disorders (inhibition of sympathomimetic uptake into the sympathetic nerve fibre).

Associations requiring precautions for use

+ Adrenaline (buccal or subcutaneous route):

Serious ventricular rhythm disorders due to increased cardiac excitability. Limit the intake, for example: no more than 0,1 mg of adrenaline in 10 minutes or 0,3 mg in 1 hour in adults.

+ Selective serotonin reuptake inhibitors: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline.

Increased plasma concentrations of clomipramine with risk of convulsions and increased undesirable effects.

Increased clinical monitoring and, if necessary, dose adjustment.

Associations to be taken into account

+ Other medicinal products causing serotonin syndrome :

Serotonin syndrome may occur when clomipramine is co-administered with serotonergic medicinal products such as selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants, lithium or buprenorphine, naloxone, opioids (see Posology and Method of administrationWarnings and precautions).

+ Dapoxetine:

Risk of increased adverse effects, in particular dizziness or syncope after treatment with dapoxetine.

+ Anticoagulants:

Tricyclic antidepressants may potentiate the anticoagulant effect of coumarin medicinal products by inhibiting their hepatic metabolism. Careful monitoring of plasma prothrombin is therefore recommended.

+ Antipsychotics: Co-medication with antipsychotics (for example, phenothiazines) may lead to increased plasma levels of tricyclic antidepressants, lowering of the seizure threshold and convulsive seizures. Association with thioridazine may cause severe cardiac arrhythmias.

+ Baclofen:

Risk of increased muscle hypotonia.

Fertility, pregnancy and breastfeeding

Pregnancy

Maintaining good maternal psychological balance is desirable throughout pregnancy. If drug treatment is necessary to ensure this balance, it should be instituted or continued at an effective dose throughout pregnancy and, if possible, as monotherapy.

Animal toxicity studies have shown an embryolethal effect and decreased foetal weight in mice and rats (see Preclinical safety).

The data available on the use of ANAFRANIL in pregnant women are insufficient to assess the risk of malformation.

In newborns whose mothers were treated at the end of pregnancy with an imipramine-type antidepressant, signs of exposure (notably anticholinergic) and/or withdrawal have sometimes been described:

• neurological disorders (lethargy, hypotonia, irritability, hyperexcitability, tremors, myoclonus, and exceptionally convulsions);
  
• respiratory disorders (polypnoea, cyanosis, dyspnoea, and exceptionally respiratory distress);
  
• vascular disorders (hypotension or hypertension);
  
• digestive disorders (difficulty initiating feeding, colic, delayed passage of meconium and abdominal distension).
  

All these signs appear within the first days of life and are most often of short duration and not severe.

In view of these data, the use of clomipramine is possible regardless of the stage of pregnancy. Nevertheless, monitoring of the newborn is recommended and will take into account the effects described above.

Breast-feeding

Passage into breast milk is poorly known but probably low (corresponding to a value below 5 % of the maternal dose); nevertheless, as a precautionary measure, breastfeeding should be avoided during treatment.

Fertility

Clomipramine does not appear to have a significant effect on fertility (see Preclinical safety).

Driving and using machines

ANAFRANIL has a major influence on the ability to drive vehicles and use machines.
Patients treated with ANAFRANIL must be warned of the risk of adverse effects such as drowsiness, blurred vision, dizziness and other central nervous system and psychiatric symptoms (see Undesirable effects). In the presence of such effects, patients must not drive, operate machinery or perform hazardous tasks requiring vigilance. Patients should also be warned that alcohol or other drugs may potentiate these adverse effects (see Interactions).

Adverse effects

Summary of the safety profile

Suicidal ideas or behaviours have been reported during treatment with ANAFRANIL or shortly after its discontinuation (see Warnings and Precautions for Use).

In case of severe neurological or psychiatric reactions, treatment with ANAFRANIL must be stopped.

Undesirable effects are presented by order of frequency, the most frequent first, according to 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); frequency not known (cannot be estimated from the available data). The undesirable effects listed below are based on the results of clinical trials as well as post-marketing reports.

System Organ Class	Frequency	Adverse effects
Blood and lymphatic system disorders	Very rare	Leukopenia, agranulocytosis, thrombocytopenia, thrombocytopenic purpura, eosinophilia
Immune system disorders	Very rare	Anaphylactic reaction, anaphylactoid reaction
Endocrine disorders	Very rare	Syndrome of inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders	Very common	Increased appetite
	Common	Decreased appetite
Psychiatric disorders	Very common	Inability to remain still
	Common	Confusional state, disorientation, anxiety, agitation (sometimes in the context of serotonin syndrome or neuroleptic malignant syndrome), sleep disorders, mania, hypomania, insomnia, delirium, delusion
	Frequency not known	Suicidal ideation, suicidal behaviour, hallucinations (in particular in elderly patients and patients with Parkinson's disease), depersonalisation, nervousness
Nervous system disorders	Very common	Vertigo, tremor, myoclonic seizure NOS, drowsiness
	Common	Paraesthesia, dysgeusia, memory impairment, attention disorders, headache
	Uncommon	Convulsions, ataxia
	Frequency not known	Serotonin syndrome, extrapyramidal disorders (including akathisia and tardive dyskinesia), syncope, hypotonia, dysarthria, hypertonia, neuroleptic malignant syndrome
Eye disorders	Very common	Accommodation disorder, blurred vision, malignant syndrome
	Common	Mydriasis
	Very rare	Glaucoma
	Frequency not known	Dry eye
Ear and labyrinth disorders	Common	Tinnitus
Cardiac disorders	Common	Sinus tachycardia, palpitations
	Uncommon	Arrhythmia
	Very rare	Conduction disorder (for example QRS complex widening, QT interval prolongation, PQ changes, bundle branch block, torsade de pointes, in particular in patients with hypokalaemia), cardiomyopathy
Vascular disorders	Very common	Orthostatic hypotension
	Common	Hot flushes, vasculitis
Respiratory, thoracic and mediastinal disorders	Very rare	Hypersensitivity pneumonitis
Gastrointestinal disorders	Very common	Nausea, dry mouth, constipation
	Common	Vomiting
	Frequency not known	Abdominal pain, paralytic ileus
Hepatobiliary disorders	Very rare	Hepatitis with or without jaundice
Skin and subcutaneous tissue disorders	Very common	Hyperhidrosis
	Common	Allergic dermatitis (skin rash, urticaria), pruritus
	Rare	Photosensitivity reaction
	Very rare	Purpura, alopecia
	Frequency not known	Hyperpigmentation
Renal and urinary disorders	Very common	Micturition disorder
	Very rare	Urinary retention
Disorders of the reproductive system and breast	Very common	Libido disorder, erectile dysfunction
	Rare	Galactorrhoea, breast hypertrophy
	Frequency not known	Anejaculation, delayed ejaculation
General disorders and administration site conditions	Very common	Fatigue
	Very rare	Peripheral oedema, hyperpyrexia
Investigations	Very common	Weight gain
	Common	Elevation of transaminases
	Frequency not known	Abnormal electrocardiogram, prolongation of the QT interval on electrocardiogram, abnormal electroencephalogram
Injury, poisoning and procedural complications	Frequency not known	Fracture

Other

• Withdrawal reaction with the following adverse effects: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, anxiety, occur frequently on abrupt discontinuation of treatment or during dose reduction (see Warnings and Precautions for Use).
  
• Serotonin syndrome, exceptionally in monotherapy, most often described in cases of drug interaction or overdose (see InteractionsOverdose).
  
• Bone fractures:
  Epidemiological studies, carried out mainly in patients aged 50 years and over, show an increased risk of bone fractures in patients receiving selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants. The mechanism leading to this risk is unknown.
  

Some of these adverse effects can be prevented or counteracted by adjuvant or corrective therapies, or even by a dose reduction.

• Elderly population (65 years and over):
  Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric or cardiovascular effects (see Warnings and Precautions for Use).
  

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres. Website: https://signalement.social-sante.gouv.fr.

Overdose

The manifestations of an overdose of clomipramine are similar to those reported with other tricyclic antidepressants. Cardiac abnormalities and neurological disorders represent the main complications. In children, accidental ingestion must be considered serious and potentially fatal, regardless of the dose ingested.

Signs and Symptoms

They generally appear within 4 hours of ingestion, reaching maximum severity after 24 hours. Due to delayed absorption of the medicine (due to an anticholinergic effect), its long half-life and an enterohepatic cycle, the patient may be at risk for 4 to 6 days.

The following symptoms are possible:

• Central nervous system : drowsiness, stupor, coma, ataxia, inability to remain still, agitation, hyperreflexia, muscle rigidity and choreoathetosis, convulsions. Symptoms related to serotonin syndrome (hyperpyrexia, myoclonus, delirium and coma) may also be observed.
  
• Cardiovascular system : hypotension, tachycardia, QT prolongation and rhythm disorders including torsades de pointes, conduction disorders, shock, heart failure and, in very rare cases, cardiac arrest.
  
• Respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating and oliguria or anuria may occur.
  

Treatment

There is no specific antidote, and treatment is essentially symptomatic. Any person suspected of an overdose of clomipramine (particularly a child) must be hospitalised and kept under strict medical supervision for at least 72 hours.

If the patient is conscious, perform gastric lavage or induce vomiting as soon as possible. If the patient is unconscious, ensure airway patency using a cuffed endotracheal tube before starting lavage, and do not induce vomiting. These measures are recommended within 12 hours or more following the overdose, as the anticholinergic effect may delay gastric emptying. Administration of activated charcoal may help reduce absorption.

Symptomatic treatment requires intensive medical care, including continuous monitoring of cardiac function, blood gases and electrolytes, and, if necessary, emergency measures such as anticonvulsant treatment, respiratory or cardiac resuscitation. Administration of physostigmine is not recommended, as it may cause severe bradycardia, asystole and convulsions. Haemodialysis or peritoneal dialysis are ineffective due to the low plasma concentrations of clomipramine.

Pharmacodynamics

Pharmacotherapeutic class: Non-selective monoamine reuptake inhibitors, ATC code: N06AA04

Mechanism of action

Clomipramine is an antidepressant. It has significant anticholinergic and sedative properties. It prevents reuptake, and therefore leads to the inactivation of noradrenaline and serotonin in nerve terminals. Preventing the reuptake of these monoaminergic neurotransmitters potentiates their action in the brain. This appears to be associated with antidepressant activity.

Clomipramine appears to preferentially inhibit serotonin reuptake compared with noradrenaline reuptake.

Tricyclic antidepressants have affinity for adrenergic, muscarinic and histamine H1 receptors to varying degrees.

Pharmacodynamic effects

The efficacy and safety of clomipramine have been demonstrated in the treatment of the following indications in adults:

• Major depressive episodes.
  
• Obsessive compulsive disorders.
  
• Prevention of panic attacks.
  
• Certain depressive states occurring during schizophrenia, in association with neuroleptic treatment.
  
• Neuropathic pain.
  

The efficacy and safety of clomipramine have been demonstrated in the treatment of obsessive compulsive disorder in children aged 10 years and older (see Indications).

The recommended doses are given in section Dosage and administration.

ANAFRANIL also exerts a specific effect on obsessive-compulsive disorder that could be at least partially distinct from its antidepressant effects.

Pharmacokinetics

By avoiding the significant first-pass hepatic effect, the bioavailability of clomipramine by the parenteral route is approximately doubled compared with administration by the oral route.

Absorption

After repeated intramuscular or intravenous administration of 50 to 150 mg of ANAFRANIL per day, steady-state plasma concentrations are reached during the second week of treatment. These vary from < 15 to 447 ng/mL for clomipramine and from < 15 to 669 ng/mL for N-desmethylclomipramine, which is also pharmacologically active.

Distribution

Clomipramine is widely distributed throughout the body with an average volume of distribution of 12 l/kg to 17 l/kg of body weight.

Clomipramine crosses the blood-brain barrier.

Clomipramine diffuses into breast milk, at a concentration similar to that in plasma, and crosses the placenta.

Binding to plasma proteins:

Protein binding is high: 98 %.

Metabolism

The liver plays a major role in the metabolism of imipramine-type antidepressants: uptake (first-pass effect) followed by intense biotransformation, which explains:

• the high value of plasma clearance, relative to hepatic blood flow (1,5 l/min),
  
• the near absence of active compounds found in urine.
  

The main metabolite of clomipramine is desmethylclomipramine, an active compound whose half-life is longer than that of the parent molecule. This active metabolite can be formed by several P450 enzymes, mainly CYP3A4, CYP2C19 and CYP1A2. Clomipramine and N-desmethylclomipramine are hydroxylated by CYP2D6 into polar metabolites which are excreted in urine either unchanged or after glucuronidation or sulfation.

Elimination

The total plasma clearance of clomipramine, calculated after intravenous administration, is 0,73 l/min.

The plasma elimination half-life of clomipramine is about 21 hours (range: 12 to 36 h), and desmethylclomipramine has an average half-life of 36 h (between 25 and 50 hours). Two-thirds of the water-soluble conjugates are excreted in urine and about one-third in feces. Only about 2 % of the dose is excreted unchanged. Also 0,5 % of the dose is excreted as desmethylclomipramine.

Concentration-activity relationship

For clomipramine, the commonly accepted therapeutic range is between 40 and 80 ng/ml, and 250 to 500 ng/ml for the sum of clomipramine/desmethylclomipramine. In current practice, plasma measurement of clomipramine is not necessary to ensure therapeutic monitoring. However, 2 groups of patients are distinguished for whom monitoring of plasma concentrations may be desirable:

• patients at risk: elderly subjects, patients with cardiac, hepatic, or renal disease, children... (see Warnings and Precautions for Use) ;
  
• patients resistant to treatment or in whom adverse effects are marked, or who are on polypharmacy (see Interactions).
  

At-risk populations

Elderly subject

In elderly patients, clomipramine has a relatively low clearance compared with younger adult patients. It has been reported that a therapeutic steady state is reached at doses lower than those reported for middle-aged patients. Clomipramine should be used with caution in elderly patients.

Renal impairment

There are no specific data describing the pharmacokinetics of the drug in patients with renal impairment. Although the drug is excreted as inactive metabolites in urine and feces, accumulation of inactive metabolites may subsequently lead to accumulation of the parent drug and its active metabolite. In cases of moderate and severe renal impairment, it is recommended to monitor the patient during treatment. The dose of clomipramine should be reduced.

Hepatic impairment

Clomipramine is extensively metabolised in the liver by CYP2D6, CYP3A4, CYP2C19 and CYP1A2, and hepatic impairment may affect its pharmacokinetics. In patients with hepatic impairment, clomipramine should be administered with caution. The dose of clomipramine should be reduced.

Ethnic sensitivity

Although the impact of ethnic sensitivity and ethnic origin on the pharmacokinetics of clomipramine has not been extensively studied, the metabolism of clomipramine and its active metabolite is governed by genetic factors leading to slow and rapid metabolism of the drug and its metabolite. The metabolism of clomipramine in the Caucasian population cannot be extrapolated to people of Asian origin, in particular Japanese and Chinese, due to the marked differences in clomipramine metabolism between these two ethnic groups.

Preclinical safety

Preclinical safety data do not indicate any particular risk for humans. These data come from conventional research in safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenic potential.

Repeated dose toxicity

Phospholipidosis and testicular changes considered to be secondary to phospholipidosis, commonly associated with tricyclic compounds, have been observed in rats with clomipramine hydrochloride at doses exceeding ten times the maximum recommended daily dose for humans (MRDD) in mg/kg, and 1,5 times higher than the MRDD in mg/m². The clinical relevance of these observations is unknown.

Reproductive and developmental toxicity

  In reproduction studies, no effect on fertility was observed in rats given oral doses up to 24 mg/kg, namely 6 times the MRDD in mg/kg and approximately an equal dose to the MRDD in mg/m².

No teratogenic effect was observed during studies conducted in mice and rats at oral doses up to 100 mg/kg, namely 24 times the MRDD in mg/kg and 4 times (rats) and 2 times (mice) the MRDD in mg/m².

Embryotoxic effects (for example an increase in embryolethality and growth retardation) have been reported at 100 mg/kg in mice and from 25 mg/kg in rats.

Mutagenicity

Mutagenicity tests in vitro and in vivo were performed and revealed no mutagenic potential of clomipramine hydrochloride.

Carcinogenicity

Administration of clomipramine hydrochloride to mice and rats for 104 weeks showed no signs of carcinogenicity at doses corresponding to 16 to 20 times the estimated oral MRDD of 5 mg/kg.

INCOMPATIBILITIES

This medicine must not be mixed with other medicines, except those mentioned in the section Dosage and administration.

Storage conditions

Shelf life 4 years.

The product is sensitive to light; keep it in its outer packaging.

After opening: the product must be used immediately.

HANDLING/DISPOSAL INSTRUCTIONS

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Prescription, supply and reimbursement

LIST I

Marketing authorisation (AMM)

3400930043462 (1991, SmPC rev 06.07.2023).

Price:	2,07 euros (5 solution for injection ampoules 25 mg).
Reimbursed by Social Security at 65 %. Collective.

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