Active ingredients: Clomipramine
NAFRANIL 10 mg coated tablets
NAFRANIL 25 mg coated tablets
NAFRANIL 75 mg coated tablets
NAFRANIL 25mg / 2ml solution for injection
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01.0 NAME OF THE MEDICINAL PRODUCT
ANAFRANIL
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
ANAFRANIL 10 mg coated tablets
One tablet contains:
Active principle: clomipramine hydrochloride 10 mg
Excipients: lactose, sucrose
ANAFRANIL 25 mg coated tablets
One tablet contains:
Active principle: clomipramine hydrochloride 25 mg
Excipients: lactose, sucrose
ANAFRANIL 75 mg prolonged release tablets
One tablet contains:
Active principle: clomipramine hydrochloride 75 mg
ANAFRANIL 25 mg / 2 ml solution for injection
One vial contains:
Active principle: clomipramine hydrochloride 25 mg.
For the full list of excipients see section 6.1
03.0 PHARMACEUTICAL FORM
Coated tablets.
Prolonged-release tablets.
Injectable solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Depressive states of various etiology and symptomatology: endogenous, reactive, neurotic, organic, masked, and involutional forms of depression; depression associated with schizophrenia and personality disorders; depressive syndromes from presenility or senility, from chronic painful states and chronic somatic disorders.
Other indications: obsessive-compulsive syndromes, phobias, panic attacks and chronic painful states.
04.2 Posology and method of administration
Before initiating therapy with Anafranil, any hypokalaemia present should be adequately treated (see section 4.4).
Before starting treatment, it is also advisable to check the patient's blood pressure, as hypotensive subjects with postural hypotension or circulatory problems can react to the drug with a drop in blood pressure.
The posology and methods of administration should be determined individually and adapted to the patient's condition. As a rule, the optimal effect should be sought with minimal effective doses and gradually increased with caution, especially in elderly patients as this category of patients generally exhibits a more marked response to Anafranil.
Compliance with the indicated dosages and caution in increasing doses are recommended when administered concomitantly with drugs that prolong the QT interval or with other serotonergic drugs, in order to avoid any episodes of long QT or serotonergic toxicity (see section 4.4 and 4.5).
The coated tablets should be swallowed whole.
The 75 mg prolonged-release tablets can be divided into exactly equal halves and allow the dosage to be tailored to the needs of the individual patient.
Depressions, obsessive-compulsive syndromes, phobias
to) Oral: Start treatment with 1 25 mg coated tablet 2-3 times a day or 1 75 mg prolonged-release tablet once a day (preferably in the evening). During the first week of treatment, increase the daily dosage gradually, according to the tolerability of the treatment, eg. 25 mg every few days up to 4-6 25 mg coated tablets or 2 75 mg prolonged release tablets.
In severe cases, the dosage can be increased up to a maximum of 250 mg per day. Once marked improvement is achieved, adjust the daily dosage to a maintenance level of 2-4 25 mg coated tablets or 1 75 mg prolonged release tablet.
b) Intramuscular: start with 1-2 ampoules of 25 mg; then increase the dosage by 1 ampoule per day until the patient receives 4-6 ampoules per day. After improvement has been established, gradually reduce the number of injections while giving the patient oral treatment with maintenance doses.
c) Intravenous infusion: initially 2-3 ampoules (50-75 mg), diluted and mixed with 250-500 ml of isotonic saline or glucose solution and perfused once a day over a period of 1.5-3 hours. During the infusion it is necessary to closely monitor the occurrence of undesirable reactions; in particular, blood pressure should be checked as postural hypotension may occur.
Once marked improvement has been achieved, the infusion should be administered for a further 3-5 days. Oral therapy should be continued to maintain response; 2 25 mg coated tablets are generally equivalent to 1 ampoule. 25 mg.
A gradual change from infusion therapy to oral maintenance therapy can also be made by resorting to an intermediate stage of intramuscular injections.
Elderly patients
In the treatment of elderly patients, the posology must be carefully established by the physician who will have to evaluate a possible reduction of the dosages indicated above.
It is therefore advisable to start treatment with 1 coated tablet of 10 mg per day and gradually increase the dosage to an optimal level of 30-50 mg per day, to be reached after about 10 days and to be followed until the end of the treatment.
Chronic painful states
Dosage should be individualized (10-150 mg per day), taking into account any concomitant treatment with analgesic drugs (and the possibility of reducing analgesic doses).
Panic attacks
Initially 1 10 mg coated tablet, possibly in combination with a benzodiazepine. On the basis of the tolerability of the drug, increase the dosage until the desired response is obtained, and at the same time gradually discontinue the benzodiazepine.
The daily dosage required varies greatly from patient to patient, with values ranging from 25 to 100 mg. If necessary, it can be raised to 150 mg.
It is recommended not to stop treatment earlier than 6 months and during this time the maintenance dose should be slowly reduced.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Cross-hypersensitivity to other tricyclic antidepressants belonging to the dibenzazepine group.
Concurrent or within two weeks of treatment with a monoamine oxidase inhibitor (MAOI) (see section 4.5).
Concomitant treatment with selective and reversible MAO-A inhibitors, such as moclobemide.
Glaucoma.
Prostatic hypertrophy, pyloric stenosis and other stenosing affections of the gastro-enteric and genito-urinary system.
Liver disease.
Heart failure. Myocardial rhythm and conduction disturbances. Post-infarct recovery period.
Mania.
Congenital long QT syndrome.
Known or suspected pregnancy.
Feeding time.
Individuals under the age of 18.
04.4 Special warnings and appropriate precautions for use
Use in children and adolescents under 18 years
Tricyclic antidepressants should not be used to treat children and adolescents under the age of 18. Studies conducted in depression in children of this age group have not demonstrated efficacy for this class of drugs. Studies with other antidepressants have highlighted the risk of suicide, self-harm and hostility related to these drugs. This risk may also occur with these drugs. tricyclic antidepressants.
Furthermore, tricyclic antidepressants are associated with a risk of adverse cardiovascular events in all age groups. It should be borne in mind that there are no long-term safety data available in children and adolescents regarding growth, maturation and cognitive and behavioral development.
Suicide / Suicidal ideation
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 or immediate weeks of treatment, patients should be monitored closely until improvement occurs. It is generally clinical experience that the risk of suicide may increase in the early stages of improvement.
Other psychiatric conditions for which Anafranil is prescribed may also be associated with an increased risk of suicidal behavior. Furthermore, these conditions can be associated with major depressive disorder. Therefore, the same precautions followed when treating patients with other psychiatric disorders should be observed when treating patients with major depressive disorders.
Patients with a history of suicidal behavior or thoughts, or who exhibit a significant degree of suicidal ideation prior to initiation of treatment, are at increased risk of suicidal thoughts or suicidal thoughts, and should be closely monitored during treatment. of clinical trials conducted with antidepressant drugs in comparison with placebo in the therapy of psychiatric disorders, showed an increased risk of suicidal behavior in the age group below 25 years of patients treated with antidepressants compared to placebo.
Drug therapy with antidepressants should always be associated with close surveillance of patients, particularly those at high risk, especially in the initial stages of treatment and after dose changes. Patients (or caregivers) should be advised of the need to monitor and report immediately to their physician any clinical worsening, the onset of suicidal behavior or thoughts, or changes in behavior.
In these patients, the possibility of modifying the treatment regimen, including discontinuation of treatment, should be considered, especially if these symptoms are severe, abrupt onset or are not part of the symptoms presented by the patient prior to treatment (see also " Treatment interruption "in section 4.4).
In order to reduce the risk of overdose, Anafranil prescriptions should be for the minimum quantities of tablets useful for good patient management.
Other psychiatric effects
Many patients with panic attacks reported heightened anxiety at the start of treatment with Anafranil (see section 4.2); this paradoxical effect is very evident in the first days of treatment, and then generally disappears within 2 weeks.
Exacerbation of psychotic states has occasionally been observed in patients with schizophrenia taking tricyclic antidepressants.
In patients with bipolar affective disorder, on treatment with tricyclic antidepressants, episodes of mania or hypomania during the depressive phase have been reported. In these cases it is necessary to reduce the dosage or discontinue Anafranil and administer antipsychotic drugs. control these episodes, if necessary, a low dose treatment with Anafranil can be resumed.
In predisposed patients and elderly patients, tricyclic antidepressants can cause drug-induced psychosis (delusions), especially at night, which disappear within a few days as soon as the drug is discontinued.
Cardiac and vascular disorders
Treatment with Anafranil should be administered with caution in patients with cardiovascular dysfunction, especially those with cardiovascular insufficiency, conduction disturbances (e.g. Grade I to III atrioventricular block), or arrhythmias.In these patients, as well as in elderly patients, monitoring of cardiac function and performing an electrocardiogram is recommended.
QTc interval prolongation and "torsade de pointes" arrhythmias may occur, particularly with doses above the therapeutic range or with plasma concentrations of clomipramine above therapeutic levels, as occurs with concomitant administration of selective serotonin reuptake inhibitors or serotonin and norepinephrine re-uptake inhibitors. Therefore, concomitant administration of drugs that cause clomipramine accumulation should be avoided. Concomitant administration of drugs that can prolong the QTc interval should also be avoided (see section 4.5). Hypokalaemia is known to be a risk factor for prolongation of the QTc interval and for the onset of torsade de pointes arrhythmias. Therefore, hypokalaemia should be adequately treated before starting treatment with Anafranil. Anafranil should be administered with caution in case of concomitant treatment with selective serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors or diuretics (see section 4.5).
Convulsions
Tricyclic antidepressants can lower the seizure threshold. Their use, therefore, in epileptics and in patients with other predisposing factors, such as brain damage of various etiology, concomitant use of neuroleptics, abstinence from alcohol or drugs with anticonvulsant properties (e.g. benzodiazepines), is allowed only under close supervision of the doctor. The onset of seizures appears to be dose-dependent, therefore the recommended daily doses should not be exceeded.
As with other tricyclic antidepressants, concomitant electroconvulsive therapy should only be conducted by particularly experienced personnel.
Anticholinergic effects
Due to 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. prostate disease).
The decrease in lacrimation and the accumulation of mucoid secretions, due to the anticholinergic properties of tricyclic antidepressants, can damage the corneal epithelium in patients with contact lenses.
Particular categories of patients
Particular caution is recommended when administering tricyclic antidepressants to patients with severe hepatic or renal dysfunction and adrenal gland tumors (pheochromocytoma, neuroblastoma) as hypertensive crises can be caused.
Caution is also required in hyperthyroid patients or in patients taking thyroid preparations, due to the possibility of an aggravation of cardiac side effects.
In the case of patients with liver dysfunction, liver enzyme levels should be checked periodically.
Caution is advised when administering Anafranil to patients with chronic constipation. Tricyclic antidepressants can cause paralytic ileus, particularly in elderly or bedridden patients for long periods.
Long treatments with tricyclic antidepressants can lead to an increase in the incidence of dental caries. It is therefore advisable to carry out regular checks during prolonged treatments.
Many patients with panic attacks reported heightened anxiety at the start of treatment with Anafranil (see section 4.2); this paradoxical effect is very evident in the first days of treatment, and then generally disappears within 2 weeks.
Exacerbation of psychotic states has occasionally been observed in patients with schizophrenia taking tricyclic antidepressants.
Episodes of mania or hypomania during the depressive phase have been reported in patients with bipolar affective disorder receiving tricyclic antidepressants. In these cases it is necessary to reduce the dosage or discontinue Anafranil and administer antipsychotic drugs. After these have been monitored. episodes, if necessary, low dose Anafranil treatment can be resumed.
In predisposed patients and the elderly, tricyclic antidepressants can cause drug-induced delusions and psychosis, especially at night, which disappear within a few days as soon as the drug is discontinued.
White blood cell count
Although there have been only isolated cases of alteration in the number of white blood cells following treatment with Anafranil, it is advisable to periodically check the blood count and monitor the onset of symptoms such as fever and sore throat, particularly during the first months of therapy. and during prolonged treatments.
Anesthesia
Before a local or general anesthesia, it is advisable to inform the anesthetist that the patient is being treated with Anafranil (see section 4.5).
Discontinuation of treatment
Abrupt discontinuation of treatment due to the possible occurrence of adverse reactions should be avoided. If it is decided to discontinue treatment, the dosage of the drug should be reduced as quickly as possible, however, taking into account that abrupt cessation may be associated with certain symptoms (see section 4.8 for the description of the risks of discontinuing therapy with Anafranil).
Serotonin syndrome
Considering the risk of serotonin toxicity, it is advisable to proceed with caution in administering the recommended dose and increasing it if another serotonergic drug is administered concomitantly. Serotonin syndrome, with symptoms such as hyperpyrexia, myoclonus, agitation, seizures, delirium and coma may occur when clomipramine is administered concomitantly with serotonergic drugs such as selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants and lithium (see sections 4.2 and 4.5). 2-3 week "washout" before and after fluoxetine treatment.
Anaphylactic shock
Isolated cases of anaphylactic shock have been reported. Caution is advised if Anafranil is administered intravenously.
04.5 Interactions with other medicinal products and other forms of interaction
Monoamine oxidase inhibitors
Monoamine oxidase inhibitors (MAOIs), such as moclobemide, are potent in vivo inhibitors of CYP2D6 (catalyst of hydroxylation of clomipramine and its active metabolite); therefore, tricyclic antidepressants should not be combined with MAOIs due to the possibility of severe side effects (hyperthermia, convulsions, hypertensive crisis, myoclonus, agitation, delirium, coma). The same caution should be observed when administering a MAOI after previous treatment with Anafranil. In both cases, Anafranil or the MAOI drug should be initially administered in low doses, which can then be gradually increased by monitoring the effects (see section 4.3).
Some data indicate that tricyclic antidepressants can only be administered 24 hours after administration of a reversible MAO type A inhibitor, such as moclobemide; however, the 2-week wash-out interval must in any case be observed if the MAO-A inhibitor is administered after treatment with a tricyclic antidepressant.
Selective Serotonin Reuptake Inhibitors (SSRIs)
Selective serotonin reuptake inhibitors, such as fluoxetine, paroxetine, or sertraline, are inhibitors of CYP2D6, and others (such as fluvoxamine) are also inhibitors of CYP1A2 and CYP2C19 (cytochromes P450 involved in the demethylation of clomipramine); therefore, concomitant administration of these drugs with clomipramine may cause additive effects on the serotonergic system due to a potential increase in the plasma concentrations of Anafranil, resulting in the onset of undesirable effects.
Steady-state serum clomipramine levels increase approximately 4-fold following concomitant administration of fluvoxamine (N-desmethylclomipramine decreases approximately 2-fold).
Serotonergic agents
Serotonin syndrome can occur when clomipramine is administered concomitantly with serotonergic drugs such as selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants and lithium. A washout period of 2-3 weeks is recommended before and after treatment with fluoxetine.
Diuretics
Administration of diuretics can induce hypokalaemia, which in turn increases the risk of QTc prolongation and "Torsade de Pointes" arrhythmias. Hypokaliema must therefore be adequately treated before starting treatment with Anafranil (see sections 4.2 and 4.4).
CNS depressant substances
Tricyclic antidepressants can accentuate the action of alcohol and other CNS depressant drugs such as hypnotics, sedatives, anxiolytics and anesthetics.
Neuroleptics
The concomitant administration of neuroleptics and tricyclic antidepressants can induce an increase in the plasma concentration of the latter, a lowering of the seizure threshold and the onset of seizures. Concomitant administration of thioridazine can induce severe cardiac arrhythmias.
Blockers of adrenergic neurons
Tricyclic antidepressants block the synaptic recovery of guanethidine and other hypotensive agents with a similar mechanism of action, reducing their therapeutic activity. Therefore it is advisable to administer drugs with different mechanisms of action to patients who require antihypertensive treatment (eg diuretics, vasodilators or β-blockers).
Anticoagulants :
Tricyclic antidepressants, by inhibiting the hepatic metabolism of coumarin drugs (eg warfarin), may increase the anticoagulant effect. Therefore, careful monitoring of plasma prothrombin levels is recommended.
Anticholinergic drugs
The use of parasympatholytic drugs (eg phenothiazines, drugs used in the therapy of Parkinson's disease, antihistamines, atropine, biperidene) requires attention as tricyclic antidepressants can enhance their effects on the eye, the central nervous system, intestines and bladder.
Sympathomimetic drugs
Sympathomimetic drugs (e.g. adrenaline, noradrenaline, isoprenaline, ephedrine, phenylephrine) should not be administered during treatment with clomipramine, the effects of which, especially those on the heart and circulation, can be significantly accentuated.
The association with L-DOPA facilitates the onset of hypotension and cardiac arrhythmias.
Furthermore, the use of nasal decongestants and products used in the treatment of asthma and pollinosis, containing sympathomimetic substances, must be avoided.
Antihypertensives
The combination of tricyclic antidepressants with antihypertensive agents can cause orthostatic hypotension (additive effect).
Antiarrhythmics
Tricyclic antidepressants should not be used in combination with antiarrhythmics (such as quinidine and propafenone), which are potent inhibitors of CYP2D6.
Inducers of liver enzymes
Concomitant administration of drugs known as inducers of cytochrome P450 enzymes, particularly CYP3A4, CYP2C19 and / or CYP1A2, may accelerate the metabolism and decrease the efficacy of Anafranil.
Inducers of CYP3A and CYP2C, such as rifampicin, oral contraceptives, antiepileptics (eg, barbiturates, carbamazepine, phenobarbital and phenytoin), may decrease clomipramine concentrations.
Known inducers of CYP1A2 (eg nicotine and other components of cigarette smoke), decrease the plasma concentrations of tricyclic drugs. In cigarette smokers, steady-state plasma concentrations were decreased in a 2: 1 ratio compared with non-smokers (no change for N-desmethylclomipramine).
Hepatic enzyme inhibitors
Concomitant use of the histamine 2 (H2) receptor antagonist cimetidine as an inhibitor of various P450 enzymes, including CYP2D6 and CYP3A4, may increase the plasma concentrations of tricyclic antidepressants, the dosage of which should therefore be reduced.
Methylphenidate may increase the concentrations of tricyclic antidepressants potentially by inhibiting their metabolism and a reduction in the dose of tricyclic antidepressants may be required.
Clomipramine is itself an inhibitor of CYP2D6 activity in vitro and in vivo and, therefore, may cause increased concentrations of concomitantly administered drugs that are primarily CYP2D6 deactivated in rapid metabolisers. Serum concentrations of phenytoin and carbamazepine may increase, resulting in side effects: the dosage of these drugs may need to be adjusted.
Various phenothiazines, haloperidol and cimetidine can delay the elimination of clomipramine by increasing its blood concentration.
Estrogen
It has been found that the simultaneous administration of estrogens can cause in some cases a paradoxical effect of reducing the efficacy and at the same time increasing the toxicity of Anafranil.
There are no documented interactions between the chronic use of oral contraceptives (15 or 30 mg / day of ethinylestradiol) and Anafranil (25 mg / day). Estrogens are not known to be inhibitors of CYP2D6, the enzyme involved most in the clearance of clomipramine and, therefore, no interactions are expected. Although, in a few cases, with therapies at high doses of estrogen (50 mg / day) and the tricyclic antidepressant clomipramine, increased undesirable effects and therapeutic response have been noted, the relevance between these cases and therapies with clomipramine is not clear. and low-dose estrogen Monitoring of therapeutic response to tricyclic antidepressants co-administered with high doses of estrogen (50 mg) is advisable and dose adjustment may be required.
Competition with plasma proteins
Plasma protein binding of clomipramine can be reduced by competition from phenytoin, phenylbutazone, acetylsalicylic acid, scopolamine and phenothiazines.
Important information about some of the ingredients of ANAFRANIL
ANAFRANIL 10 mg coated tablets and ANAFRANIL 25 mg coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
ANAFRANIL 10 mg coated tablets contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase isomaltase insufficiency should not take this medicine.
04.6 Pregnancy and lactation
Pregnancy
Not to be used in known or suspected pregnancy.
Feeding time
As clomipramine and its metabolite desmethylclomipramine pass into breast milk, treatment with Anafranil should be gradually discontinued in breastfeeding women, or patients should be advised to discontinue breastfeeding.
04.7 Effects on ability to drive and use machines
Patients taking Anafranil should be warned about the possible occurrence of blurred vision, somnolence and other Central Nervous System disorders (see section 4.8). In such cases, they must not drive, operate machinery or carry out work that requires perfect alertness.
Patients should also be warned that the intake of alcoholic beverages or other drugs may potentiate these effects (see section 4.5).
04.8 Undesirable effects
Side effects are usually mild and transient in nature and generally disappear with continued therapy or possibly reducing the dosage. They are not always related to dose or plasma levels. It is often difficult to distinguish side effects from symptoms of depression such as fatigue, sleep disturbances, agitation, anxiety, constipation and dry mouth.
The onset of severe neurological or psychiatric side effects requires discontinuation of treatment.
Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric or cardiovascular effects. The ability to metabolize and eliminate the drug may in fact be reduced in these patients, with the risk of reaching high plasma concentrations at therapeutic doses.
Side effects are listed by frequency of occurrence, using the following convention:
• very common: ≥1 / 10
• common: ≥1 / 100 e
• uncommon: ≥1 / 10,000 e
• rare: ≥1 / 1000 e
• very rare:
Within the frequency group, undesirable effects are listed in descending order of severity.
Pathologies of the Nervous System
Psychic Effects
Very common: drowsiness, fatigue, feeling of not being able to rest, increased appetite.
common: mental confusion, disorientation, hallucinations (especially in elderly patients or with Parkinson's disease), anxiety, agitation, sleep disturbances, mania, hypomania, aggression, memory lapses, depersonalization, insomnia, nightmares, worsening of depression, difficulty in focus, yawning.
Uncommon: activation of psychotic symptoms.
Neurological effects
Very common: dizziness, tremors, headaches, myoclonus.
common: delirium, speech disorders, paraesthesia, muscle weakness, muscle hypertonia.
Uncommon: convulsions, ataxia.
Very rare: EEG changes, hyperpyrexia.
Anticholinergic effects
Very common: dry mouth, sweating, constipation, visual accommodation disturbances and blurred vision, urination disturbances.
common: hot flashes, mydriasis.
Very rare: glaucoma, urinary retention.
Taste alteration has been reported frequently.
Cardiac pathologies
common: postural hypotension, sinus tachycardia, clinically irrelevant changes in the ECG (eg changes in the TS and T) in patients with a normal cardiological picture, palpitations.
Uncommon: arrhythmias, increased blood pressure.
Very rare: conduction disturbances (eg enlargement of the QRS complex, prolongation of the QTc interval, alterations of the PQ tract, bundle branch block, "torsade de pointes" arrhythmias in particular in patients with hypokalaemia).
Gastrointestinal disorders
Very common: nausea.
common: vomiting, abdominal discomfort, diarrhea, anorexia.
Hepatobiliary disorders
common: increase in transaminase values.
Very rare: hepatitis with or without jaundice.
Disorders of the immune system
Very rare: allergic alveolitis (pneumonia) with or without eosinophilia, systemic anaphylactic / anaphylactoid reactions including hypotension.
Skin and subcutaneous tissue disorders
common: allergic skin reactions (skin rash, urticaria) photosensitivity, itching.
Very rare: edema (local or generalized), local reactions after intravenous injection (thrombophlebitis, lymphangitis, burning sensation, allergic skin reactions), hair loss.
Endocrine pathologies
Very common: weight gain, libido and potency disorders.
common: galactorrhea, breast augmentation.
Very rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Disorders of the blood and lymphatic system
Very rare: leukopenia, agranulocytosis, thrombocytopenia, eosinophilia and purpura.
Ear disorders
Frequent: tinnitus.
Class Effects
Epidemiological studies conducted mainly in patients aged 50 years and over indicate an increased risk of bone fractures in patients taking SSRIs and TCAs.
The mechanism behind this risk is not known.
Discontinuation symptoms
Due to sudden discontinuation of treatment or dose reduction, nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, nervousness, anxiety may occur frequently (see section 4.4).
04.9 Overdose
There have been no reported cases of overdose with injectable Anafranil, therefore the information below refers to cases of overdose with the oral forms.
The signs and symptoms of Anafranil overdose are similar to those reported for other tricyclic antidepressants. The major alterations are found at the cardiac and neurological level. In children, accidental ingestion of Anafranil in any dose should be considered serious and potentially fatal.
Signs and symptoms
Symptoms generally occur within 4 hours of ingestion and reach maximum severity after 24 hours. Due to the slowed absorption (anticholinergic effect), the long half-life and the enterohepatic circulation of the drug, the patient should be considered at risk for 4-6 days.
The following signs and symptoms may be encountered:
Central nervous system: drowsiness, stupor, coma, ataxia, inability to rest, agitation, hyperreflexia, muscle stiffness, choreoathetoid movements, convulsions. In addition, symptoms attributable to serotonin syndrome (e.g. hyperpyrexia, myoclonus, delirium and coma) have been observed.
Cardiovascular system: arrhythmia, tachycardia, QTc interval prolongation and arrhythmias including "torsade de pointes", conduction disturbances, heart failure, hypotension, shock, in very rare cases cardiac arrest.
Respiratory depression, cyanosis, vomiting, mydriasis, sweating, oliguria or anuria, fever.
Treatment
There is no specific antidote, so treatment is essentially symptomatic and supportive.
Even the mere suspicion of poisoning with tricyclic antidepressants, especially in children, requires immediate hospitalization and careful surveillance for at least 72 hours.
If the patient is conscious, induce vomiting or perform a gastric lavage as soon as possible. If the patient is unconscious, do not induce vomiting and intubate the trachea before proceeding with gastric lavage. These measures should also be taken 12 or more hours after the overdose has occurred, since the anticholinergic properties of the drug can delay gastric emptying. Administration of activated charcoal may be helpful in reducing drug absorption.
Symptoms must be treated with modern methods of intensive care; continuous monitoring of cardiac function, blood gases, electrolytes should be envisaged. Emergency measures such as anticonvulsant therapy, artificial respiration and resuscitation should be taken if necessary. Administration of physostigmine should be avoided, as cases of severe bradycardia, asystole and seizures have been reported. Peritoneal dialysis and hemodialysis are of no benefit as plasma concentrations of clomipramine are low.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Therapeutic drug category: tricyclic antidepressant. Norepinephrine and (preferentially) serotonin reuptake inhibitor.
ATC code: N06A A04.
The antidepressant properties of Anafranil are probably due to its ability to inhibit the neuronal reuptake of noradrenaline (NA) and serotonin (5-HT) released into the synaptic space; however, inhibition of 5-HT reuptake appears to be the predominant component of its activity.
The broad pharmacological spectrum of Anafranil includes α1-adrenolytic, anticholinergic, antihistamine and antiserotonergic (blockade of 5-HT receptors) properties.
Anafranil acts on the depressive syndrome in its entirety, including particular aspects such as psychomotor slowdown, depressed mood and anxiety. The clinical response usually occurs after 2-3 weeks of treatment.
Anafranil also exerts a specific effect, distinct from the antidepressant one, in obsessive-compulsive syndromes. In chronic painful states whether or not dependent on somatic causes, the drug probably acts by facilitating serotonergic and noradrenergic nerve transmission.
05.2 Pharmacokinetic properties
Absorption
Orally administered clomipramine is completely absorbed from the gastrointestinal tract.
After oral administration, the bioavailability of unchanged clomipramine is reduced by 50% by hepatic first pass metabolism, which transforms it into the active metabolite N-desmethylclomipramine. Food intake does not significantly alter the bioavailability of clomipramine: a slight delay in the onset of absorption and therefore a delay in reaching the plasma peak is possible. The absorption of coated tablets and prolonged-release tablets is equivalent. .
During oral administration of constant daily doses of Anafranil, steady-state plasma concentrations show great patient-to-patient variability. The 75 mg daily dose, divided into 3 doses of 25 mg or one 75 mg prolonged-release tablet once daily, produces steady-state concentrations ranging from 20 to 175 ng / mL.
Steady-state concentrations of the active metabolite desmethylclomipramine follow a similar pattern; however, they have values 40-85% higher than those of clomipramine at a dose of 75 mg per day.
After repeated intravenous or intramuscular administration of 50-150 mg daily of Anafranil, steady-state plasma concentrations are achieved in the second week of treatment. These range from
Distribution
Clomipramine is 97.6% bound to plasma proteins.
The apparent volume of distribution is approximately 12-17 L / kg body weight.
Concentrations in CSF are approximately 2% of those in plasma.
Clomipramine is found in breast milk in concentrations similar to those in plasma.
Biotransformation
The major metabolic pathway of clomipramine is demethylation to the active metabolite N-desmethylclomipramine. N-desmethylclomipramine can be formed from various P450 enzymes, mainly CYP3A4, CYP2C19 and CYP1A2. Clomipramine and N-desmethylclomipramine are hydroxylated to form 8-hydroxyclomipramine or 8-hydroxy-N-desmethylclomipramine. The activity of 8-hydroxy metabolites has not been 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 mainly excreted as glucuronides in the urine. The elimination of the active components, clomipramine and N-desmethylclomipramine, through the formation of 2- and 8-hydroxyclomipramine is catalyzed by CYP2D6.
Elimination
Clomipramine and desmethylclomipramine are eliminated from plasma with a half-life of 21 hours (range: 12-36 hours) and 36 hours, respectively.
After intramuscular or intravenous administration the plasma half-life was 25 hours (range 20-40 hours) and 18 hours, respectively.
About 2/3 of a single dose of clomipramine is excreted as water-soluble conjugates in the urine and about 1/3 in the faeces. The amount of unchanged clomipramine and desmethylclomipramine excreted in the urine amounts to about 2% and 0, respectively. 5% of the administered dose.
Special patient populations
In elderly patients, plasma concentrations of clomipramine are higher than in younger patients, as they have lower plasma clearance.
No data are available regarding the pharmacokinetics of clomipramine in cases of renal or hepatic insufficiency.
05.3 Preclinical safety data
Anafranil does not appear to have, from the available experimental data, any mutagenic, carcinogenic or teratogenic effect.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
ANAFRANIL 10 mg coated tablets
Lactose; glycerine; cornstarch; talc; magnesium stearate; sucrose; jelly; hypromellose; copovidone; titanium dioxide; microcrystalline cellulose; yellow iron oxide; polyethylene glycol-8000; povidone.
ANAFRANIL 25 mg coated tablets
Anhydrous colloidal silica; lactose; stearic acid; glycerine; cornstarch; talc; magnesium stearate; yellow iron oxide; titanium dioxide; copovidone; hypromellose; microcrystalline cellulose; polyethylene glycol-8000; povidone; sucrose.
ANAFRANIL 75 mg prolonged release tablets
Anhydrous colloidal silica; dibasic calcium phosphate; calcium stearate; 30% polyacrylate dispersion; hypromellose; red iron oxide; glyceryl polyethylene glycol oxystearate; talc; titanium dioxide.
ANAFRANIL 25 mg / 2 ml solution for injection
Glycerine; water for injections.
06.2 Incompatibility
Clomipramine is incompatible with diclofenac; therefore, do not mix injectable solutions of the two drugs.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
ANAFRANIL 10 mg and 25 mg coated tablets
Store at a temperature not exceeding 25 ° C, in the original package to protect the medicine from moisture.
ANAFRANIL 25 mg / 2 ml solution for injection
Store at a temperature not exceeding 25 ° C, in the original package in order to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package
ANAFRANIL 10 mg coated tablets: box of 50 tablets coated in PVC blister; PVC / PCTFE.
ANAFRANIL 25 mg coated tablets: box of 20 tablets coated in PVC blister; PVC / PCTFE, PVC / PE / PVDC.
ANAFRANIL 75 mg prolonged-release tablets: box of 20 divisible tablets in PVC blister; PVC / PCTFE, PVC / PE / PVDC.
ANAFRANIL 25 mg / 2 ml solution for injection: box of 5 amber type I glass ampoules.
06.6 Instructions for use and handling
ANAFRANIL 25 mg / 2 ml solution for injection
Opening of the vials with predetermined breaking: take the vial with the colored point facing upwards and break it with a sharp movement.
07.0 MARKETING AUTHORIZATION HOLDER
DEFIANTE FARMACÊUTICA SA - Rua dos Ferreiros, 260 - Funchal, Madeira (Portugal)
Dealer for Italy:
BIOFUTURA PHARMA S.p.A. - Via Pontina km 30,400 - 00040 Pomezia (Rome)
08.0 MARKETING AUTHORIZATION NUMBER
ANAFRANIL 10 mg coated tablets - 50 tablets - AIC n. 021643022
ANAFRANIL 25 mg coated tablets - 20 tablets - AIC n. 021643010
ANAFRANIL 75 mg prolonged release tablets - 20 tablets - AIC n. 021643046
ANAFRANIL 25 mg / 2 ml solution for injection - 5 ampoules - AIC n. 021643034
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
ANAFRANIL 10 mg coated tablets
First authorization: 15.07.1972 / Renewal: 01.06.2010
ANAFRANIL 25 mg coated tablets
First authorization: 09.03.1970 / Renewal: 01.06.2010
ANAFRANIL 75 mg prolonged release tablets
First authorization: 09.03.1991 / Renewal: 01.06.2010
ANAFRANIL 25 mg / 2 ml solution for injection
First authorization: 09.03.1970 / Renewal: 01.06.2010
10.0 DATE OF REVISION OF THE TEXT
August 2010
