Active ingredients: Imipramine (Imipramine hydrochloride)
TOFRANIL 10 mg coated tablets
TOFRANIL 25 mg coated tablets
Why is Tofranil used? What is it for?
Pharmacotherapeutic group
Antidepressant - Non-selective monoamine reuptake inhibitor.
Therapeutic indications
Adults: depressive phase of manic-depressive psychosis. Reactive depression. Masked depression. Neurotic depression. Depression in the course of schizophrenic psychosis. Involving Depressions. Severe depression in the course of neurological diseases or other organic affections.
Contraindications When Tofranil should not be used
- Hypersensitivity to the active substance or to any of the excipients.
- Cross-hypersensitivity to other tricyclic antidepressants belonging to the dibenzazepine group.
- Treatment at the same time or in the two weeks before or after with a monoamine oxidase inhibitor (MAOI) drug (see "Interactions").
- 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.
- Known or suspected pregnancy.
- Feeding time.
- Individuals under the age of 18.
Precautions for use What you need to know before taking Tofranil
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.
SUICIDARY IDEATION / BEHAVIOR
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 clinical experience in general that the risk of suicide may increase in the early stages of improvement.
Other psychiatric conditions for which Tofranil is prescribed may also be associated with an increased risk of suicidal behavior. Additionally, 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 " Discontinuation of treatment "in this section).
In order to reduce the risk of overdose, prescriptions of Tofranil should be for the minimum quantities of tablets useful for good patient management.
Other psychiatric effects
Many patients with panic attacks have reported heightened anxiety at the start of treatment with Tofranil (see "Dose, method and time of administration"); 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 Tofranil and administer antipsychotic drugs. control these episodes, if necessary, low dose treatment with Tofranil 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 Tofranil should be administered with caution in patients with cardiovascular disease, 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 electrocardiography is recommended.
At over-therapeutic doses of Tofranil, there have been isolated cases of QTc interval prolongation and very rare cases of ventricular tachycardia and sudden death, mainly related to overdose, but also in some cases of concomitant therapies which in themselves may lead to at a prolonged QTc interval (e.g., thioridazine).
Before starting treatment, it is recommended to check blood pressure, as a drop in blood pressure may occur in patients with postural hypotension or circulatory dysfunction.
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 (eg 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, Tofranil 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 liver or kidney dysfunction and tumors of the adrenal glands (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 Tofranil 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.
White blood cell count
Although there have been only isolated cases of alteration in the number of white blood cells following treatment with Tofranil, 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
Prior to local or general anesthesia, the anesthetist should be informed that the patient is being treated with Tofranil (see "Interactions").
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 "Undesirable Effects" for a description of the risks of discontinuing Tofranil therapy).
Interactions Which drugs or foods can modify the effect of Tofranil
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
- Monoamine oxidase inhibitors: tricyclic antidepressants should not be combined with MAOIs due to the possibility of serious side effects (hyperthermia, convulsions, hypertensive crisis, myoclonus, agitation, delirium, coma). The same caution should be observed when administering a MAOI after previous treatment with Tofranil. In either case, Tofranil or the MAOI drug should initially be 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): Co-administration may cause additive effects on the serotonergic system. Fluoxetine and fluvoxamine can also cause increased plasma concentrations of imipramine resulting in undesirable effects.
- CNS depressants: 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. The 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 a different mechanism of action to patients who require antihypertensive treatment. (e.g. diuretics, vasodilators or β-blockers).
- Anticoagulants: Tricyclic antidepressants, by inhibiting the hepatic metabolism of coumarin drugs, may increase the anticoagulant effect. Therefore, careful monitoring of plasma prothrombin levels is recommended.
- Anticholinergic drugs: attention must be paid to the use of parasympatholytic drugs (eg phenothiazines, drugs used in the treatment of Parkinson's disease, antihistamines, atropine, biperidene) as tricyclic antidepressants can enhance their effects on the eye, on the Central Nervous System , intestine and bladder.
- Sympathomimetic drugs: during treatment, sympathomimetic drugs (e.g. adrenaline, noradrenaline, isoprenaline, ephedrine, phenylephrine) should not be administered during treatment, the effects of which, especially those on the heart and circulation, can be significantly accentuated. The association between imipramine and L-dopa facilitates the onset of hypotension and cardiac arrhythmias. The patient must also avoid the use of nasal decongestants and products used in the treatment of asthma and pollinosis, containing sympathomimetic substances.
- Quinidine: Tricyclic antidepressants should not be used in combination with quinidine-type antiarrhythmics.
- Hepatic enzyme inducers: Drugs that activate the hepatic mono-oxygenase enzyme system (e.g. carbamazepine, barbiturates, phenytoin, nicotine, oral contraceptives) can accelerate the metabolism of imipramine and thus lower its plasma concentrations, thus reducing its efficacy. Furthermore, the serum concentrations of phenytoin and carbamazepine may increase, resulting in the onset of undesirable effects. It may be necessary to adjust the dosage of these drugs while various phenothiazines, haloperidol and cimetidine can delay their elimination by increasing their blood concentration. The binding of imipramine to plasma proteins can be reduced by competition from phenytoin, phenylbutazone, acetylsalicylic acid, scopolamine and phenothiazines.
- Cimetidine, methylphenidate: as these drugs increase the plasma concentration of tricyclic antidepressants, the dosage of the latter should be reduced in case of concomitant administration.
- Estrogen: it has been found that the simultaneous administration of estrogen can cause in some cases a paradoxical effect of reducing the efficacy and at the same time increasing the toxicity of Tofranil.
Warnings It is important to know that:
It is recommended not to drink alcoholic beverages while taking Tofranil.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN.
Special warnings
This medicine contains sucrose and lactose; patients suffering from intolerance to some sugars should consult their doctor before taking the medicine.
Pregnancy
Ask your doctor or pharmacist for advice before taking any medicine. The medicine must not be used in known and suspected pregnancy.
Feeding time
Since imipramine and its metabolite desmethylimipramine pass into breast milk in small amounts, treatment with Tofranil should be gradually discontinued in breastfeeding women, or patients should be advised to discontinue breastfeeding.
Effects on ability to drive and use machines
The use of Tofranil can cause the appearance of blurred vision, drowsiness and other disorders of the Central Nervous System (see "Undesirable effects"). Therefore Tofranil impairs the ability to drive vehicles, use machines or perform jobs that require perfect alertness .
In addition, the intake of alcoholic beverages or other drugs may potentiate these effects (see "Interactions").
Dosage and method of use How to use Tofranil: Dosage
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 the lowest effective doses, and then increased gradually and cautiously, especially in elderly patients or adolescents, since these two categories of patients generally show a more marked response to Tofranil than patients of intermediate age.
The tablets should be swallowed whole, without chewing.
Adults
Depressions and depressive syndromes
- Hospitalized adults: start with 25 mg 3 times daily and progressively increase by 25 mg daily to 200 mg / day, dosage which should be maintained until clear clinical improvement is seen. In severe cases, 300 mg / day can be administered in 3 divided doses. The maintenance dose, to be determined from time to time for each individual patient, is usually 100 mg / day.
- Adults on outpatient treatment: start with 25 mg 1-3 times a day and gradually increase up to 150-200 mg / day, to be reached over a week; this dosage will be maintained until there is a clear clinical improvement The maintenance dose, to be determined case by case by gradually reducing the dosage, is usually 50-100 mg per day.
- Elderly: at the beginning of treatment, administer 10 mg per day to be gradually increased until reaching, over a period of 10 days, the optimal dose of 30-50 mg per day, to be maintained until the end of treatment.
Overdose What to do if you have taken too much Tofranil
The signs and symptoms of overdose with Tofranil are similar to those reported for other tricyclic antidepressants. The major alterations are found at the cardiac and neurological level. In children, accidental intake of Tofranil in any dose should be considered serious and potentially fatal.
Signs and symptoms
The first symptoms usually occur within 4 hours of ingestion of the drug and reach maximum severity after 24 hours. Due to the slowed absorption (exacerbation of the anticholinergic effects due to overdose), the long half-life and enterohepatic recirculation of the drug, the patient it must be considered in danger for 4-6 days.
The following signs and symptoms may be encountered:
- Cardiovascular system: conduction disturbances, heart failure, arrhythmias, tachycardia, hypotension, shock, in very rare cases cardiac arrest.
- Central nervous system: drowsiness, stupor, coma, ataxia, restlessness, agitation; hyperreflexia, muscle stiffness with choreoathetoid movements, convulsions.
- Other: mydriasis, sweating, vomiting, respiratory depression, cyanosis, fever, oliguria or anuria. There have been isolated reports of QT interval prolongation, "torsades de pointes" and death following overdose.
Treatment
There is no specific antidote, so treatment is essentially symptomatic and supportive. Even the suspicion of an overdose with Tofranil, especially in children, requires immediate hospitalization and maintenance under close supervision for at least 72 hours.
If the patient is conscious, induce vomiting or perform 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 hours or more after the overdose has occurred, since the anticholinergic properties of the drug can delay gastric emptying. Administration of activated charcoal can be helpful in reducing drug absorption.
Symptoms should be treated with modern methods of intensive care, with continuous monitoring of heart function, blood gases, electrolytes. If necessary, emergency measures such as anticonvulsant therapy, artificial respiration, installation of a temporary cardiac pacemaker, infusion of solutions to increase plasma volume, intravenous drip infusion of dopamine or dobutamine, resuscitation should be taken. 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 Tofranil are low.
In case of accidental ingestion / intake of an excessive dose of Tofranil, notify your doctor immediately or go to the nearest hospital.
Side Effects What are the side effects of Tofranil
Like all medicines, Tofranil can cause side effects, although not everybody gets them.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. Undesirable effects are usually mild and transient in nature, not always related to dose or plasma levels, and generally lessen with continued therapy or possibly dose reduction. It is often difficult to distinguish unwanted effects from symptoms of depression such as fatigue, sleep disturbances, agitation, anxiety, constipation and dry mouth. The appearance of severe neurological or psychic undesirable effects requires discontinuation of treatment.
Elderly patients are particularly sensitive to anticholinergic, neurological, psychic and cardiovascular effects. In fact, in these patients the ability to metabolize and eliminate drugs may be reduced, with the risk of reaching high plasma concentrations at therapeutic doses.
Undesirable effects are listed according to frequency using the following convention: Very common (≥ 1/10); common (≥ 1/100,
Infections and infestations
Very rare: dental caries.
Alterations of the blood and lymphatic system
Very rare: eosinophilia, bone marrow depression with leukopenia, agranulocytosis, thrombocytopenia and purpura. Come on.
Alterations of the immune system
Very rare: anaphylactic reaction.
Alterations of the endocrine system
Very rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Alterations of metabolism and nutrition
Very common: weight gain.
Common: anorexia.
Very rare: changes in blood sugar, weight decrease.
Psychiatric disorders
Common: Euphoria, restlessness, confusion, delirium, hallucinations, anxiety, agitation, mania, hypomania, libido changes, sleep disturbances, disorientation.
Rare: psychotic disorders, suicidal ideation / behavior (see "Precautions for use").
Very rare: aggression.
Alterations of the nervous system
Very common: tremors.
Common: dizziness, headache, sedation, somnolence, paraesthesia.
Rare: convulsions.
Very rare: myoclonus, extrapyramidal disorders, ataxia, speech disorders, EEG abnormalities, stroke.
Eye disorders
Common: blurred vision, visual accommodation disturbances, lacrimation decreased.
Very rare: mydriasis, glaucoma.
Alterations of the auditory and vestibular apparatus
Very rare: tinnitus.
Cardiac alterations
Very common: sinus tachycardia, ECG abnormalities (eg ST and T wave changes).
Common: arrhythmias, palpitations, conduction disturbances (e.g. enlargement of the QRS complex, branch block, alterations of the PQ tract).
Very rare: heart failure, QT interval prolongation, ventricular arrhythmia, ventricular tachycardia, ventricular fibrillation, "torsades de pointes", myocardial infarction, heart failure.
Alterations of the vascular system
Very common: hot flushes, orthostatic hypotension.
Very rare: purpura, petechiae, vasospasm, increased blood pressure.
Alterations of the respiratory system, thorax and mediastinum
Very rare: allergic alveolitis (with or without eosinophilia).
Alterations of the gastrointestinal system
Very common: dry mouth, constipation.
Common: nausea, vomiting, diarrhea.
Very rare: paralytic ileus, stomatitis, abdominal discomfort, tongue ulceration.
Alterations of the hepatobiliary system
Common: abnormal liver function test.
Very rare: hepatitis (with or without jaundice).
Alterations of the skin and subcutaneous tissue
Very common: hyperhidrosis.
Common: allergic dermatitis (rash, urticaria, erythema).
Very rare: pruritus, photosensitivity reactions, alopecia, skin hyperpigmentation.
Renal and urinary disorders
Common: urination disturbances.
Very rare: urinary retention.
Disorders of the reproductive system and breast
Very rare: breast hypertrophy, galactorrhea.
General disorders and changes in the administration site
Common: fatigue.
Very rare: asthenia, edema (localized or generalized), fever, sudden death.
Discontinuation symptoms
The following symptoms commonly appear after abrupt discontinuation or dose reduction: nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, nervousness and anxiety (see "Precautions for use"). Compliance with the instructions in the package leaflet reduces the risk of side effects.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Expiration
See the expiry date printed on the package.
The expiry date refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date shown on the package.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
Composition
One 10 mg coated tablet contains: Active ingredient: 10 mg imipramine hydrochloride.
One 25 mg coated tablet contains: Active ingredient: 25 mg imipramine hydrochloride.
Excipients: glycerol; lactose monohydrate; magnesium stearate; cornstarch; stearic acid; talc; anhydrous colloidal silica; sucrose; microcrystalline cellulose; titanium dioxide; povidone; macrogoli; copovidone; red iron oxide; hypromellose.
Pharmaceutical forms and content
Coated tablets. Box of 60 tablets of 10 mg; box of 50 tablets of 25 mg.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016.The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
TOFRANIL COATED TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
TOFRANIL 10 mg coated tablets
Each coated tablet contains: Active ingredient: imipramine hydrochloride 10 mg
TOFRANIL 25 mg coated tablets
Each coated tablet contains: Active ingredient: imipramine hydrochloride 25 mg.
Excipients with known effects: lactose monohydrate, sucrose
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Coated tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Adults
Depressive phase of manic-depressive psychosis. Reactive depression. Masked depression. Neurotic depression. Depression in the course of schizophrenic psychosis. Involving Depressions. Severe depression in the course of neurological diseases or other organic affections.
04.2 Posology and method of administration
Dosage
The posology and method of administration should be determined individually by the attending physician and adapted to the patient's condition. As a rule, one should try to obtain the optimal effect with minimal effective doses, and then gradually and cautiously increase them, especially in elderly patients, as this category of patients generally shows a more marked response to Tofranil than in intermediate-aged patients.
Hospitalized adults
Start with 25 mg 3 times a day and progressively increase by 25 mg a day up to 200 mg / day, which should be maintained until clear clinical improvement is seen. In severe cases, 300 mg / day can be administered in 3 divided doses. The maintenance dose, to be determined from time to time for each individual patient, is usually 100 mg / day.
Adults in outpatient treatment
Start with 25 mg 1-3 times a day and gradually increase up to 150-200 mg / day, to be reached over a week; this dosage will be maintained until there is a clear clinical improvement. The maintenance dose , to be determined case by case by gradually reducing the dosage, it is usually 50-100 mg per day.
Senior citizens
At the start of treatment, administer 10 mg per day to be gradually increased until the optimal dose of 30-50 mg per day is reached over 10 days, to be maintained until the end of treatment (see section 5.2).
Hepatic and / or renal impairment
Tricyclic antidepressants should be used with caution in patients with advanced hepatic or renal impairment (see section 4.4). The dosage should therefore be reduced (see section 5.2).
Pediatric population
The safety and efficacy of TOFRANIL in children and adolescents have not been established. The use of TOFRANIL in children and adolescents is contraindicated (see section 4.3).
Method of administration
For oral administration only.
The tablets should be swallowed whole, without chewing.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Known hypersensitivity to tricyclic antidepressants belonging to the dibenzazepine group.
Concurrent or within two weeks of treatment with a monoamine oxidase inhibitor (MAOI) (see section 4.5).
Glaucoma (see section 4.4).
Prostatic hypertrophy, pyloric stenosis and other stenosing diseases of the gastrointestinal and genitourinary tract (see section 4.4).
Heart failure. Myocardial rhythm and conduction disturbances (see section 4.4).
Post-infarct recovery period.
Known or suspected pregnancy (see section 4.6).
Breastfeeding (see section 4.6).
Subjects less than 18 years of age (see section 4.2).
Porphyria.
04.4 Special warnings and appropriate precautions for use
Suicide / Suicidal ideation
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events) (see section 4.8). This risk persists until significant remission is achieved. As no improvement may occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. The general clinical experience is that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicide-related events, or who exhibit a significant degree of suicidal ideation prior to initiation of treatment, are known to be at increased risk of suicidal thoughts or suicide attempts, and should be closely monitored during treatment. Treatment: A meta-analysis of clinical trials conducted with antidepressant drugs compared with placebo in the treatment 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 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 for any clinical worsening, suicidal behavior or thoughts, or unusual behavioral changes and seek immediate medical attention if these symptoms occur.
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 " Discontinuation of treatment "in section 4.4).
In order to reduce the risk of overdose, prescriptions of Tofranil should be for the minimum quantities of tablets useful for good patient management.
Other psychiatric effects
Many patients with panic attacks have reported heightened anxiety upon initiation of Tofranil treatment; 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 have been reported during the depressive phase (see section 4.8). In these cases it is necessary to reduce the dosage or discontinue Tofranil and administer antipsychotic drugs. After monitoring these episodes, low dose treatment with Tofranil can be resumed if necessary.
In predisposed patients and in elderly patients, tricyclic antidepressants can cause drug-induced psychosis (delusions), especially at night. These disorders disappear within a few days of stopping the medicine.
The specific improvement in mood often occurs after the improvement of symptoms such as insomnia or anxiety. This should be considered before stopping treatment for ineffectiveness and also when adjusting the effective dosage.
Cardiac and vascular disorders
Tricyclic antidepressants can reduce cardiac conduction, causing delayed intraventricular conduction, atrioventricular block, flat T wave, ST segment elevation, and QT interval prolongation. Tricyclic antidepressants can cause tachycardia.
Treatment with Tofranil should be administered with caution in patients with cardiovascular disease, cardiomyopathy and in elderly patients, given the tachycardic and hypotensive effects of this class of products. Monitoring of cardiac function and electrocardiography is recommended in these patients.
Treatment with Tofranil is contraindicated in patients with heart failure and with cardiac rhythm and conduction disorders (see section 4.3).
At over-therapeutic doses of Tofranil, there have been isolated cases of QTc interval prolongation and very rare cases of ventricular tachycardia and sudden death, mainly related to overdose, but also in some cases of concomitant therapies which in themselves "may" lead to a prolonged QTc interval (eg, thioridazine).
When used with medicines that can cause long QT syndrome / torsades de pointes, Tofranil may increase the risk of long QT syndrome and the development of torsades de pointes. Therefore it should not be used with this type of medicinal product (see section 4.5).
Before starting treatment, it is recommended to check blood pressure, as a drop in blood pressure may occur in patients with postural hypotension or circulatory dysfunction.
Serotonin syndrome
Due to the risk of serotonergic toxicity, it is advisable to follow the suggested dosage and if concurrently administering other serotonergic agents, dose increases should be made with caution. In situations where imipramine, selective serotonin reuptake inhibitors (SSRIs) and non-adrenal reuptake inhibitors are used concomitantly with tricyclic antidepressants or other serotenergic drugs, symptoms of serotonin syndrome such as behavioral disturbances (confusion, hypomania, agitation) may occur. ), autonomic nervous system dysfunctions (diarrhea, chills, hyperpyrexia, sweating, changes in blood pressure, nausea, vomiting) and changes in neuromuscular functions (myoclonus, hyperreflexia, tremor, difficulty coordinating movements), delirium and coma (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. In the event of seizures, treatment should be discontinued.
As with other tricyclic antidepressants, concomitant electroconvulsive therapy should only be conducted by particularly experienced personnel.
Anticholinergic effects
Due to its anticholinergic properties, Tofranil should not be used in patients with glaucoma, prostatic hypertrophy, pyloric stenosis and other stenosing affections of the gastrointestinal and genitourinary tract (see section 4.3).
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 (see section 4.5).
In the case of patients with hepatic dysfunction, hepatic function parameters should be monitored periodically (see section 4.2).
Caution is advised when administering Tofranil 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.
Caution should be exercised in elderly patients who are more sensitive to orthostatic hypotension, sedation and possible prostatic hypertrophy.
White blood cell count
Although there have been only isolated cases of alteration in the number of white blood cells and, in rare cases agranulocytosis, following treatment with Tofranil, it is advisable to carry out periodic checks of the blood count and clinical monitoring especially in the presence of symptoms such as fever and sore throat. or other symptoms related to a possible infection.
These checks are particularly indicated during the first months of therapy and during prolonged treatments.
Anesthesia
Prior to local or general anesthesia, the anesthetist should be informed that the patient is being treated with Tofranil (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 the appearance of symptoms such as nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, nervousness and anxiety (see section 4.8).
Pharmacological monitoring
In patients at risk of overdose (elderly patients, patients with concomitant cardiac, hepatic or renal disease), who are resistant to treatment, who have marked adverse effects or those undergoing multi-medication, it may be indicated to evaluate the implementation of monitoring of plasma drug concentrations.
Pediatric population
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, in particular selective serotonin reuptake inhibitors, have shown risk of suicide, self-harm and related hostility. with such drugs This risk may also occur with 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.
Lactose and sucrose
Tofranil coated tablets contain lactose and sucrose.
Patients with rare hereditary problems of galactose intolerance, fructose intolerance, sucrase isomaltase insufficiency, the Lapp lactase deficiency, or glucose / galactose malabsorption syndrome should not take this medicine.
Alcoholic beverages are not recommended during therapy with Tofranil (see section 4.7).
04.5 Interactions with other medicinal products and other forms of interaction
Monoamine oxidase inhibitors : Tricyclic antidepressants should not be combined with MAOIs due to the possibility of serious side effects (hyperthermia, convulsions, hypertensive crisis, myoclonus, agitation, delirium, coma). The same caution should be observed when administering a MAOI after previous treatment with Tofranil. In either case, after an appropriate two-week wash out period between the two medicinal products, Tofranil or the MAOI should be initially administered in low doses, which can then be gradually increased by monitoring for 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 should in any case be observed if the MAO-A inhibitor is administered after treatment with a tricyclic antidepressant (see section 4.3).
Selective Serotonin Reuptake Inhibitors (SSRIs) : concomitant administration may cause additive effects on the serotonergic system. SSRIs such as fluoxetine, paroxetine, sertraline or citalopram are potent inhibitors of CYP2D6. Fluvoxamine is a potent CYP1A2 inhibitor and a medium level inhibitor of CYP2D6.Therefore, the use of SSRIs together with imipramine may result in exposure to increased plasma concentrations of imipramine with related mainly cardiovascular adverse events. Therefore, an adjustment of the imipramine dosage may be necessary.
Other serotonergic medicines : Simultaneous applications can cause additive effects in the serotinergic system. In situations where imipramine and norepinephrine-serotonin reuptake inhibitors (SNRIs) are used concomitantly with tricyclic antidepressants or other serotonergic medicinal products such as lithium, serotonin syndrome may occur (see section 4.4). Special warnings and precautions for use.
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 convulsive seizures. The concomitant administration of thioridazine can induce severe cardiac arrhythmias.
Oral antifungal, terbinafine : Simultaneous administration of imipramine and terbinafine, a potent inhibitor of CYP2D6, may result in increased exposure and accumulation of imipramine and desipramine. Therefore, when given with terbinafine, imipramine may need dose adjustment.
Blockers of adrenergic neurons : tricyclic antidepressants block the synaptic recovery of guanethidine and other hypertensive agents that act centrally with similar mechanisms of action, reducing their therapeutic activity. Therefore it is recommended to administer medicines with different mechanisms of action to patients who require antihypertensive treatment (e.g. diuretics, vasodilators or? -blockers).
Anticoagulants : Tricyclic antidepressants, by inhibiting the hepatic metabolism of coumarin medicinal products, may increase the anticoagulant effect. Careful monitoring of plasma prothrombin levels is therefore recommended.
Anticholinergic drugs : the use of parasympatholytic drugs (eg phenothiazines, antihistamines, atropine, biperidene or other antiparkinsonian drugs) is required as tricyclic antidepressants can enhance their effects on the eye, central nervous system, intestine and bladder.
Sympathomimetic drugs Sympathomimetic drugs (e.g. adrenaline, noradrenaline, isoprenaline, ephedrine, phenylephrine) should not be administered during treatment, the effects of which, especially those on the heart and circulation, can be significantly accentuated.
The association between imipramine and L-dopa facilitates the onset of hypotension and cardiac arrhythmias.
The patient must also avoid the use of nasal decongestants and products used in the treatment of asthma and pollinosis, containing sympathomimetic substances.
Quinidine : Tricyclic antidepressants should not be used in combination with quinidine antiarrhythmics.
Inducers of liver enzymes : Drugs that activate the hepatic mono-oxygenase enzyme system (e.g. carbamazepine, barbiturates, phenytoin, nicotine, oral contraceptives) can accelerate the metabolism of imipramine and therefore lower its plasma concentrations, thus reducing its efficacy. In addition, the serum concentrations of phenytoin and carbamazepine may increase, resulting in undesirable effects. The dosage of these drugs may need to be adjusted, while various phenothiazines, haloperidol and cimetidine can delay their elimination by increasing their blood concentration. The binding of imipramine to plasma proteins can be reduced by competition from phenytoin, phenylbutazone, acetylsalicylic acid, scopolamine and phenothiazines.
Cimetidine, methylphenidate : as these drugs increase the plasma concentration of tricyclic antidepressants, the dosage of the latter must be reduced in case of concomitant administration.
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 Tofranil.
Drugs that induce a prolongation of the QTc interval : QTc interval prolongation and induction of torsade de pointes tachycardia may be the result of the combined administration of imipramine with a substance capable of prolonging the QTc interval (eg thioridazine, cisapride, cotrimoxazole) (see section 4.4).
Calcium channel blockers : Verapamil and diltiazem may increase the plasma levels of imipramine as a result of interference with the metabolism of imipramine.
Beta blockers : Labetalol and propranolol increase the plasma concentration of imipramine.
Thyroid preparations : possibility of aggravation of cardiac undesirable effects (see section 4.4).
04.6 Pregnancy and breastfeeding
Pregnancy
Women of childbearing potential should use effective contraceptive methods during treatment. Animal studies with reference to the effects on pregnancy and / or embryo / fetus development and / or development during and after birth are insufficient. Based on human data, imipramine is suspected to cause developmental disturbances when administered during pregnancy. As there have been isolated reports of a possible relationship between the use of tricyclic antidepressants and adverse effects on the fetus (developmental disorders) , treatment with Tofranil should be avoided during pregnancy (see section 4.3).
Infants whose mothers had taken Tofranil until delivery had withdrawal symptoms during the early hours of the day such as dyspnoea, lethargy, irritability, colic, hypotension or hypertension, tremors or cramps.
Feeding time
Since imipramine and its metabolite desmethylimipramine pass into breast milk, treatment with Tofranil should be gradually discontinued in breastfeeding women, or patients should be advised to discontinue breastfeeding (see section 4.3).
Fertility
No data available.
04.7 Effects on ability to drive and use machines
Patients taking Tofranil should be warned about the possible occurrence of blurred vision, somnolence, sedation, dizziness and clouding of consciousness 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
Undesirable effects are usually mild and transient in nature, not always related to dose or plasma levels, and generally lessen with continued therapy or possibly dose reduction. It is often difficult to distinguish side effects from symptoms of depression such as fatigue, asthenia, sleep disturbances, restlessness, agitation, anxiety, constipation and dry mouth.
The appearance of severe neurological or psychotic undesirable effects requires discontinuation of treatment.
Elderly patients are particularly sensitive to anticholinergic, neurological, psychic and cardiovascular effects. In fact, in these patients the ability to metabolize and eliminate drugs may be reduced, with the risk of reaching high plasma concentrations at therapeutic doses.
Undesirable effects are listed according to frequency using the following convention: Very common (≥ 1/10); common (≥ 1/100,
Disorders of the blood and lymphatic system
Very rare : eosinophilia, bone marrow depression with leukopenia, agranulocytosis, thrombocytopenia, adenitis.
Disorders of the immune system
Very rare : anaphylactic reactions
Endocrine diseases
Very rare : inappropriate secretion of antidiuretic hormone (SIADH).
Metabolic and nutritional diseases :
Very common : abnormal weight gain
common : nervous anorexia
Very rare : weight loss
Psychic disorders
common : euphoria, restlessness, confusion, delirium, hallucinations, anxiety, agitation, mania, hypomania (see section 4.4), libido disturbances, sleep disturbances, disorientation.
Rare : psychotic disorders.
Very rare : aggression
Not known : suicidal ideation and suicidal behaviors (see section 4.4).
Nervous system disorders
Very common : tremors
common : dizziness, headache, sedation, somnolence, paraesthesia (see section 4.7).
Rare : convulsions.
Very rare : myoclonus, extrapyramidal disorders, ataxia, speech disorders, stroke in progress.
Not known : dysgeusia.
Ocular pathologies
common : blurred vision, accommodation problems, decreased lacrimation.
Very rare : mydriasis, glaucoma.
Ear and labyrinth disorders
Very rare : tinnitus.
Cardiac pathologies
Very common : sinus tachycardia
common : arrhythmia, palpitations, conduction disturbances (e.g. expansion of the QRS complex, gill block, changes in PQ sections).
Very rare : QT prolongation, cardiovascular failure, ventricular arrhythmia, ventricular tachycardia, ventricular fibrillation, torsades de pointes, myocardial infarction.
Vascular pathologies
Very common : hot flashes, orthostatic hypotension.
Very rare : vasospasm.
Respiratory, thoracic and mediastinal disorders
Very rare : allergic alveolitis (with or without eosinophilia).
Gastrointestinal disorders
Very common : dry mouth, constipation.
common : nausea, vomiting, diarrhea.
Very rare : paralytic ileus, stomatitis, abdominal discomfort, tongue ulceration, dental caries.
Hepatobiliary disorders
Very rare : hepatitis (with or without jaundice).
Disorders of the skin and subcutaneous tissues
Very common : hyperhidrosis.
common : allergic dermatitis, rash, urticaria.
Very rare : itching, purpura, petechiae, photosensitivity reactions, alopecia, skin hyperpigmentation.
Renal and urinary disorders
common : disorders of urination.
Very rare : urinary retention.
Reproductive system and breast disorders
Very rare : breast hypertrophy (gynecomastia), galactorrhea.
General Disorders and Administration Site Conditions
common : exhaustion.
Very rare : asthenia, edema (local or generalized), pyrexia, sudden death.
Diagnostic tests
Very common : abnormal electrocardiogram, (eg ST segment and T wave changes).
common : liver function test abnormal.
Very rare : abnormal blood glucose value, abnormal EEG, prolonged QT electrocardiogram, increased blood pressure.
Symptoms of drug withdrawal
The following symptoms commonly appear after discontinuation or abrupt dose reduction: nausea, vomiting, abdominal pain, diarrhea, chills, sweating, muculoskeletal pain, insomnia, headache, nervousness, irritability, dizziness, malaise and anxiety. It is therefore recommended to gradually reduce the imipramine dose when treatment is no longer required (see section 4.4).
Bone fractures
Epidemiological studies, mainly conducted in patients aged 50 years or older, show an increased risk of bone fractures in patients treated with selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). The mechanism responsible for this risk is unknown.
The following adverse reactions have also been observed with the TCA class of drugs: nervousness, dysarthria, dyskinesia, serotonin syndrome, syncope, dry eyes, cases of impotence, cases of cardiomyopathy.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili
04.9 Overdose
The signs and symptoms of overdose with Tofranil are similar to those reported for other tricyclic antidepressants. The major alterations are found at the cardiac and neurological level. In children, accidental intake of Tofranil in any dose should be considered serious and potentially fatal.
Signs and symptoms
The first symptoms usually occur within 4 hours of ingestion of the drug and reach maximum severity after 24 hours. Due to the slowed absorption (exacerbation of the anticholinergic effects due to overdose), the long half-life and enterohepatic recirculation of the drug, the patient it must be considered in danger for 4-6 days.
The following signs and symptoms may be encountered:
Cardiovascular system : conduction disturbances, heart failure, arrhythmias, tachycardia, hypotension, shock, in very rare cases cardiac arrest.
There have been isolated reports of torsade de pointes QT interval prolongation and death following overdose.
Central nervous system : drowsiness, stupor, coma, ataxia, restlessness, agitation; hyperreflexia, muscle stiffness with choreoathetoid movements, convulsions, clouding of consciousness and serotonin syndrome.
Other : hypothermia, mydriasis, sweating, dry mouth, vomiting, constipation, respiratory depression, cyanosis, fever, oliguria or anuria.
Treatment
There is no specific antidote, so treatment is essentially symptomatic and supportive.
Even the suspicion of an overdose with Tofranil, especially in children, requires immediate hospitalization and maintenance under close supervision for at least 72 hours.
If the patient is conscious, induce vomiting or perform 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 hours or more after the overdose has occurred, since the anticholinergic properties of the drug can delay gastric emptying. Administration of activated charcoal can be helpful in reducing drug absorption.
Symptoms should be treated with standard intensive care methods, with continuous monitoring of heart function, blood gases, electrolytes. If necessary, emergency measures such as anticonvulsant therapy, artificial respiration, installation of a temporary cardiac pacemaker, infusion of solutions designed to increase plasma volume, intravenous drip infusion of dopamine or dobutamine, resuscitation should be undertaken. 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 Tofranil are low.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Psychoanaleptic-Antidepressant- Non-selective inhibitor of monoamine reuptake.
ATC code: N06A A02
Mechanism of action
The broad pharmacological spectrum of imipramine includes a-adrenolytic, antihistamine, anticholinergic and antiserotonergic properties (block of 5-HT receptors). The main therapeutic activity is however linked to the inhibition of neuronal re-uptake of noradrenaline (NA) and serotonin (5-HT).
Imipramine belongs to the category of "mixed" re-uptake blockers, ie it inhibits both norepinephrine and serotonin re-uptake equally.
05.2 Pharmacokinetic properties
Absorption
Imipramine hydrochloride is rapidly and almost completely absorbed in the intestinal tract. Food intake does not significantly alter the bioavailability of imipramine.
After oral administration of 50 mg three times daily of imipramine for 10 days, plasma concentrations of imipramine and desmethylimipramine reach the stable medium stage at 33-85 ng / mL and 43-109 ng / mL, respectively.
The bioavailability of imipramine depends on the subject (it ranges from about 25 to 50%). Due to a significant hepatic first pass effect, the bioavailability of imipramine is approximately 50% lower when administered orally compared to the parenteral route of administration.
Distribution
Imipramine is approximately 86% bound to plasma proteins. Concentrations in cerebrospinal fluid are closely related to plasma concentrations.
The mean volume of distribution is approximately 21 L / kg of body weight.
The total plasma clearance of imipramine, calculated after intravenous administration is 1 L / min. The plasma elimination half-life of imipramine depends on the subject and ranges from 9 to 20 hours.
Imipramine crosses the blood brain barrier and passes into breast milk. Imipramine and its metabolite desmethylimipramine are found in human milk in concentrations similar to those in plasma.
Biotransformation
Imipramine undergoes a high first pass effect and is largely metabolised by the liver.
In principle, imipramine is N-demethylated in the N-desmethylimipramine form (desipramine) (active metabolite) by CYP3A4, CYP2C19 and CYP1A2. Imipramine and desipramine undergo hydrolyzation, catalyzed by CYP2D6 to form 2-hydroxymipramine (active metabolite) and 2-hydroxidesipramine (active metabolite).
The major metabolite, desmethylimipramine or desipramine, has a slightly longer half-life than the parent molecule.Hydrolyzation of these two molecules produces other active metabolites. They are inactivated through conjugation with glucuronic acid which results in water-soluble substances which are excreted in the urine or bile.
Elimination
Imipramine is eliminated from the blood with a mean half-life of 19 hours.
About 80% is excreted in the urine and about 20% in the faeces, mainly in the form of inactive metabolites. The amounts of unchanged imipramine and desmethylimipramine excreted in the urine amount to about 5% and 6%, respectively, while only small quantities are found in the stool.
Particular categories of patients
In elderly patients, due to reduced metabolic clearance, plasma concentrations of imipramine are higher than those found in young patients, it is advisable to administer lower doses of imipramine to them than in patients of other age groups (see section 4.2).
In children the mean values of clearance and elimination half-life do not differ significantly from those found in adults, but there is a high variability between individuals.
In patients with severe renal insufficiency there were no changes in renal excretion of imipramine and unconjugated biologically active metabolites, while there were elevated plasma concentrations of conjugated metabolites which are considered biologically inactive. The clinical significance of these data is unknown. (see section 4.2).
05.3 Preclinical safety data
Imipramine is not potentially mutagenic or carcinogenic. Experimental studies in rats, mice, rabbits and monkeys indicated that orally administered imipramine is not potentially teratogenic. In the course of experiments conducted with imipramine administered at high doses and parenterally, severe maternal toxicity and embryotoxicity were found, but without conclusive data on the teratogenic potential.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Glycerol; lactose monohydrate; magnesium stearate; cornstarch; stearic acid; talc; anhydrous colloidal silica; sucrose; microcrystalline cellulose; titanium dioxide; povidone; macrogoli; copovidone; red iron oxide; hypromellose.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
TOFRANIL 10 mg coated tablets
5 years
TOFRANIL 25 mg coated tablets
4 years
06.4 Special precautions for storage
None.
06.5 Nature of the immediate packaging and contents of the package
TOFRANIL 10 mg coated tablets
Non-toxic PVC blister.
Carton containing 60 coated tablets of 10 mg.
TOFRANIL 25 mg coated tablets
PVC / PE / PVDC-Al blisters
Carton containing 50 coated tablets of 25 mg.
06.6 Instructions for use and handling
No special instructions
07.0 MARKETING AUTHORIZATION HOLDER
Amdipharm Limited
3 Burlington Road - Dublin 4 - Temple Chambers Ireland
08.0 MARKETING AUTHORIZATION NUMBER
TOFRANIL 10 mg coated tablets - 60 tablets - A.I.C. n. 014969024
TOFRANIL 25 mg coated tablets - 50 tablets - A.I.C. n. 014969012
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
TOFRANIL 10 mg coated tablets
First authorization: 11.03.1961
Renewal: 01.06.2005
TOFRANIL 25 mg coated tablets
First authorization: 12.03.1959
Renewal: 30.11.2009
10.0 DATE OF REVISION OF THE TEXT
15/10/2016
