Tofranil

Tofranil^®
Tricyclic Anti-depressant

PRESCRIPTION ONLY

Composition
Each sugar coated tablet contains: imipramine hydrochloride 25 mg.

Properties
Pharmacodynamics
Characteristic of imipramine is a multivalent pharmacological spectrum of action, which includes alpha-adrenolytic, antihistamine, anticholinergic, and 5-HT-receptor blocking properties. However, the therapeutic activity of imipramine is believed to be based above all on its ability to inhibit the neuronal re-uptake of noradrenaline (NA) and serotonin (5-HT). Imipramine belongs to the category of so-called "mixed" re-uptake blockers, i.e, it inhibits the re-uptake of NA and 5-HT to approximately the same extent.

Pharmacokinetics
Absorption
Imipramine is absorbed quickly following oral administration. The intake of food has no affect on its absorption and bioavailability. During its first passage through the liver, orally administered imipramine becomes partly converted to desmethylimipramine, a metabolite which likewise exhibits anti depressive activity. Consequently, following parenteral administration the initial concentration of this metabolite is lower.

Plasma concentration
During oral administration of 50 mg 3 times daily for 10 days, the mean steady-state plasma concentrations of imipramine and desmethylimipramine were 33 - 85 ng/ml and 43 - 109 ng/ml respectively. Owing to lower clearance in the plasma, resulting in increased systemic availability, elder patients require lower doses of imipramine than patients in intermediate age groups.
Protein binding: mean 86%
Distribution volume: mean 21 l/kg
Plasma half-life: mean approx. 20 hours

Excretion
Approx. 80% is excreted in the urine and approx. 20% in the faeces, chiefly in the form of inactive metabolites. The quantity of unchanged imipramine and of the active metabolite desmethylimipramine excreted in the urine amounts to 5% and 6%, respectively; only small quantities are excreted in the faeces.

Therapeutics information
Indications
Depressive states of varying aetiology and symptomatology, including masked forms:
Endogenous depression (unipolar, bipolar, involutional depression); Somatogenic depression (organic, symptomatic); Psychogenic depression (neurotic, reactive and exhaustion depression associated with personality disorders); Depressive mood disorders of a reactive, neurotic or psychopathic nature, including their somatic equivalents, also in children; Depressive syndromes in the pre-senium and senium, associated possibly with hypochondriasis, as well as compulsive weeping and lack of emotional control; Depressive syndromes due to arteriosclerosis, cerebrovascular accidents, Parkinson's disease, chronic somatic diseases, chronic painful conditions, and alcoholism.
Further indications: panic attacks, pavor nocturnus, nocturnal enuresis (from the age of 6 years onwards and provided the possibility of organic causes has first been excluded), chronic painful conditions.

Dosage and method of administration
The dosage and method of administration should be determined individually and adapted to the patient's condition.
In principle, every effort must be made to achieve an optimum effect while keeping the doses as low as possible and increasing the dosage cautiously, particularly when treating elderly patients or adolescents, who generally show a more marked response to Tofranil^® than patients belonging to intermediate age groups. During treatment with Tofranil^® patients must be kept under close surveillance with respect to the efficacy and tolerability of the medication.

Depressions and depressive syndromes
Oral treatment on an ambulant basis
Initiate treatment with 25 mg 1 - 3 times daily. Raise the daily dosage step wise to 150 - 200 mg. This dosage should be reached by the end of the first week and adhered to until a clear-cut improvement has occurred. The subsequent maintenance dose, which must be individually determined by cautiously reducing the dosage, usually amounts to 50 - 100 mg daily.

Treatment in hospital with coated tablets
Initiate treatment with 25 mg t.i.d. Raise the daily dosage step-wise by 25 mg, until a dose of 200 mg has been reached, and adhere to this dose until the depressive condition has improved. In severe cases the doses may be increased to 100 mg t.i.d. Once a distinct improvement has set in, the subsequent daily maintenance dose should be determined according to the patient's individual requirements (generally 100 mg). 250 to 300 mg daily may be given if there is no response after two weeks.

Panic attacks
Initially 10 mg daily, possibly in combination with a benzodiazepine (see "Warnings"). Depending on how the medication it tolerated, raise the dosage until the desired response is obtained, while at the same time gradually withdrawing the benzodiazepine. The _ daily dosage required varies greatly from patient to patient and lies between 75 and 150 mg. If necessary it can be increased to 200 mg. It is recommended that the treatment should not be discontinued before 6 months have elapsed and that during this time maintenance dose should be slowly reduced.

Chronic painful conditions
The dosage must be individualized (25 - 300 mg daily). A daily dosage of 25 - 75 mg is generally sufficient.

Geriatrics
Initiate treatment with 10 mg daily. Gradually raise the dosage to an optimum level of 30 - 50 mg daily, which should be reached after about 10 days and then adhered to until the end of treatment.

Paediatrics
Initiate treatment with 10 mg daily. Over a period of 10 days increase the daily dosage to 20 mg in children aged 5 - 8, to 20 - 50 mg in those aged 9 -14, and to 50 - 80 mg in patients ages over 14 years.
Nocturnal enuresis
(only in children aged 5 years or older): initial daily dose in children aged 5 - 8 years: 20 - 30 mg; in children aged 9 - 12: 1 - 2 tablets of 25 mg; in older children: 1 - 3 tablets of 25 mg.
The higher doses apply to those cases which do not respond fully to treatment with in one week. The tablets should be given in a single dose after the evening meal, although children who wet their beds early in the night should be given part of the dose before hand (at 4 p.m.). Once the desired response has been achieved the treatment should be continued (for 1 - 3 months) reducing the dose stepwise to the maintenance dose.

Contraindications
Known hypersensitivity to tricyclic antidepressants of the dibenzazepine group. Tofranil^® must not be given in the acute stage of myocardial infarction.

Adverse reactions 
Anticholinergic effects
Frequently dryness of the mouth, constipation, sweating, hot flushes, disorders of visual accommodation and blurred vision. Occasionally disturbances of micturition. Isolated cases of mydriasis, glaucoma and paralytic ileus. Central nervous system

Psychic effects
Occasionally fatigue, drowsiness, sleep disturbances, increased anxiety, feelings of unrest and agitation, swings from depression to hypomania or mania, symptoms of delirium, such as confusion accompanied by disorientation and hallucinations (particularly in geriatric patients and those suffering from Parkinson's disease), activation of psychotic symptoms. In isolated cases aggressiveness.

Neurological effects
Frequently fine tremor. Occasionally paraesthesiae (numbness, tingling sensation, symptoms suggestive of peripheral neuropathy), headache, dizziness. Rarely epileptic seizures. Isolated cases of EEG changes, myoclonus, weakness, extrapyramidal symptoms, ataxia, speech disorders.

Cardiovascular system
Frequently sinus tachycardia and clinically irrelevant ECG changes (T and ST segment) in patients of normal cardiac status, postural hypotension. Occasionally arrhythmias, conduction disorders (widening of QRS complex and PR interval, bundle-branch block), palpitations. Isolated cases of increased blood pressure, cardiac decompensation, peripheral vasospastic reactions.

Respiratory tract
Isolated cases of allergic alveolitis (pneumonia) with or without eosinophilia.

Gastrointestinal tract
Occasional nausea, vomiting, anorexia. Rarely elevated transaminases. Isolated cases of stomatitis, tongue lesions, abdominal disorders, hepatitis with or without jaundice.

Skin
Occasionally alergic skin reactions (skin rash, urticaria). Isolated cases of pruritus, petechiae, photosensitivity, oedema (local or generalized), loss of hair.
Endocrine system and metabolism. Frequently weight gain. Occasionally disturbances of libido and potency. Isolated cases of enlarged mammary glands, galactorrhoea, SIADH (syndrome of inappropriate antidiuretic hormone secretion), increase or decrease in blood sugar weight loss.

Blood
Isolated cases of eosinophilia, agranulocytosis, purpura and thrombocytopenia.

Miscellaneous
Although not indicative of addiction, occasionally withdrawal symptoms following abrupt discontinuation of treatment: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, and anxiety. Isolated cases in tinnitus, drug fever.

Warnings
Combined treatment with Tofranil^® and a MAO inhibitor should, wherever possible, be avoided. It should be employed only in selected patients suffering from refractory depression and only in a hospital setting. In all such cases treatment with Tofranil^®, in an individually adapted dosage, should be started before - or at least simultaneously with - the MAO inhibitor, in order to avoid potentially serious interactions, such as hyperactivity, hypertensive crises, hyperpyrexia, spasticity, convulsions, coma.
Caution is called for when employing Tofranil^® in:
Patients with cardiovascular insufficiency, atrioventricular block (grades I to III), and arrhythmias; patients with narrow-angle glaucoma; patients with disorders of micturition due to an impeded flow of urine (e.g. in diseases of the prostate); patients with a low convulsion threshold (e.g. due to brain dam age of varying aetiology, epilepsy, alcoholism); patients with severe hepatic or renal disease; patients with tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom the drug may provoke hypertensive crisis.
Concomitant treatment with Tofranil^® and electro-convulsive therapy should only be resorted to under careful supervision,
Many patients with panic disorder experience intensified anxiety symptoms at the start of the treatment with antidepressants. This paradoxical initial increase in anxiety is most pronounced during the first few days of treatment and generally subsides within two weeks.

Usage in children
The effectiveness of the drug in children for conditions other than nocturnal enuresis has not been established.
The safety and effectiveness of the drug as temporary adjunctive therapy for nocturnal enuresis in children less than 6 years of age has not been established.
The safety of the drug for long term, chronic use as adjunctive therapy for nocturnal enuresis in children 6 years of age or older has not been established; consideration should be given to instituting a drug-free period following an adequate therapeutic trial with a favorable response. A dose of 2.5 mg/kg/day should not be exceeded in childhood,

Precautions
Tofranil^® should be employed with caution in patients with cardiovascular disorders, especially those who have a history of conductions disorders (see "Warnings"), as well as in elderly patients. Monitoring of cardiovascular function and ECG is called for in such cases. In order to guard against possible cardiotoxic effects, a daily dosage of 2.5 mg/kg body weight should not be exceeded in children. Before initiating treatment it is advisable to check the patient's blood pressure, because individuals with hypotension or a labile circulation may react to the drug with a fall in blood pressure.
Caution is indicated in patients with hyperthyroidism or in the case of concomitant treatment with thyroid preparations, since aggravation of unwanted cardiac effects can generally be expected to occur owing to the anticholinergic action. The blood count should also be monitored during treatment with Tofranil^® (especially if the patient develops fever, sore throat, or other symptoms such as are associated with influenza infections), since isolated cases of agranulocytosis have been associated with the use of tricyclic antidepressants.
It is also advisable to monitor hepatic and renal function during longterm therapy with Tofranil^®, Lengthy treatment with tricyclic antidepressant can lead to an increased incidence of dental caries. Owing to its activating effect, Tofranil^® may cause anxiety, feelings of unrest, and hyperexcitation in agitated patients and patients with accompanying schizophrenic symptoms. In predisposed and elderly patients, Tofranil^® may, particularly at night, provoke pharmacogenic (delirious) psychoses, which disappear without treatment within a few days of withdrawing the drug. A swing from depression to hypomania or mania is possible in patients with bipolar affective disorders. In such cases it may be necessary to withdraw Tofranil^® and administer drugs to control the mania. After such episodes have subsided, low dose therapy with Tofranil^® may be resumed if required. If there is a risk of suicide, the patient should be kept under very careful surveillance during treatment with Tofranil^®, In these cases initial combined therapy with sedative neuroleptic agents and/or benzodiazepines has yielded good results. Referral to a psychiatric clinic should be considered.
Before surgical interventions, the anaesthetist should be notified that the patient has been receiving Tofranil^®, since little is know about interactions between concomitantly administered tricyclic antidepressants and anaesthetics.

Mutagenicity, carcinogenicity, and reproduction toxicity studies
Imipramine has no mutagenic or carcinogenic potential. Studies in four species (mouse, rat, rabbit and monkey) led to the conclusion that orally administered Tofranil^® has no teratogenic potential. Experiments with high doses of parenterally administered Tofranil^®, which are described in the literature, resulted mainly in severe maternal and embryotoxic effects; they were thus inconclusive with regard to teratogenic effects.

Use during pregnancy and lactation
Experience with Tofranil^® in pregnancy is limited. Since there have been isolated reports of a possible connection between the use of Tofranil^® and adverse effects on the foetus, treatment with Tofranil^® should be avoided during pregnancy, and only considered if the benefits expected justify the potential risk for the foetus.
Neonates whose mothers had taken Tofranil^® up until delivery showed symptoms, such as dyspnoea, lethargy, colic, irritability, hypotension or hypertension, tremor or spasms, during the first few hours or days. To guard against such symptoms, Tofranil^® should - if this is at all justifiable - be withdrawn at least 7 weeks before the calculated date of confinement. The active substance of Tofranil^® and its metabolite desmethylimipramine pass into the breast milk in small quantities. Since nothing is known about the clinical relevance of this finding as regards the infant, babies should be weaned or the medication withdrawn.

Effects on ability to drive or use machines
Tofranil^® occasionally causes fatigue, and, in rare instances, other central nervous symptoms (see "Adverse reactions") which may impair the patient's reactions. Patients must therefore be warned against engaging in activities that require quick reactions, such as driving motor vehicles and operating machines.

Interactions with other medicaments and other forms of interaction
If Tofranil^® is to be employed following treatment with a MAO inhibitor, it is absolutely essential that an interval of at least 14 days should elapse before starting therapy, because otherwise severe interactions may occur(see "Warnings").
The same precaution should be taken when administering a MAO inhibitor after previous treatment with Tofranil^®. In either, medication with Tofranil^® or with the MAO inhibitor should be initiated cautiously and the dosage slowly raised stepwise until the patient is optimally stabilized. (See "Warnings"). Since tricyclic antidepressants may reduce or abolish the antihypertensive effect of clonidine, guanethidine, bethanidine, reserpine, and methyldopa, antihypertensives with a different mode of action should be used, if necessary (e.g. diuretics, beta-blockers). The cardiovascular effects of sympathomimetics, such as adrenaline, noradrenaline, and amphetamine (as well as of nasal drops and local anaesthetics containing sympathomimetics) may be potentiated by tricyclic antidepressants.
Tricyclic antidepressants may also increase the effects of alcohol and central depressant drugs (e.g. barbiturates, benzodiazepines, or general anaesthetics), as well as that of anticholinergic agents (e.g. atropine, biperiden, levodopa). When tricyclic antidepressants are given in combination with anticholinergic or neuroleptics with an anticholinergic action, hyperexcitation states or delirium may occur, as well as attacks of glaucoma. Tricyclic antidepressants should not be employed in combination with anti-arrhythmic agents of the quinidine type.
Substances which activate the hepatic mono-oxygenase enzyme system (e.g. barbiturates, phenytoin, nicotine) may lower the plasma concentration of tricyclic antidepressants and so reduce their antidepressive effect.
In addition, concomitant administration of imipramine and phenytoin may lead to elevated serum phenytoin concentrations. If necessary, the phenytoin dosage should be adjusted accordingly.
Neuroleptic agents (e.g. phenothiazines) may increase the plasma concentration of imipramine. No such effects are known to occur in combination with diazepam, but it might be necessary to lower the dosage of imipramine if administered concomitantly with alprazolam or disulfiram.
Since cimetidine raised the plasma concentration of imipramine, the dosage of imipramine should be reduced if the two drugs are administered concurrently; by contrast, ranitidine does not alter the kinetics of imipramine.
Methylphenidate may cause the plasma concentration of tricyclics to rise and so intensify their antidepressive effect.
If administered concomitantly with estrogens, the dose of imipramine should be reduced, since steroid hormones inhibit the metabolism of imipramine.

Overdosage
Since children react much more sensitively than adults to acute overdosages of tricyclics, and since fatalities have been reported, every effort should be made to avoid an overdosage (see "Safety note concerning children"), which, if it does occur, should be treated with extreme care.

Signs and symptoms
The first signs and symptoms of poisoning with tricyclic antidepressants generally take the form of severe anticholinergic reactions, which set in about ½ - 2 hours after the drug has been taken.
The severity of poisoning with tricyclic antidepressants may depend on various factors, such as the amount of the drug absorbed, the time elapsing between its ingestion and the start of treatment, and the patient's age.

The following signs and symptoms may be encountered:
Central nervous system: drowsiness, stupor, coma, ataxia, restlessness, agitation, enhanced reflexes, muscular rigidity, athetoid and choreiform movement, convulsions.
Heart: arrhythmia, tachycardia, conduction disorders, heart failure: in very rare cases, cardiac arrest.
In addition, respiratory depression, cyanosis, hypotension, shock, vomiting, fever, mydriasis, sweating, and oliguria or anuria may occur.

Treatment
There is no specific antidote. The use of physostigmine is controversial, since it may increase the risk of epileptic seizures. Where the drug has been taken by mouth, try to induce vomiting: otherwise the stomach must be irrigated. Activated charcoal should be administered.
Severe poisoning with tricyclic drugs requires immediate hospitalization and continuous cardiovascular monitoring for at least 48 hours.
In all patients with ECG abnormalities, cardiac function should:
Even after the ECG tracings have reverted to normal be kept under close observation for at least another 72 hours, because relapses may occur.
The following measures should be taken in cases of overdosage:
In respiratory failure: intubation and artificial respiration.
In severe hypotension: the patient should be placed in an appropriate position and be given a plasma expander, dopamine, or dobutamine by intravenous drop.
Cardiac arrhythmias must be treated according to the requirements of the case.
implantation of a cardiac pacemaker should be considered. Low potassium values and acidosis should be corrected.
In convulsions: diazepam should be given i.v., or another anticonvulsant such as phenobarbitone or paraldehyde (these substances may exacerbate existing respiratory failure, hypotension, or coma).
Dialysis and haemodialysis are of no use.

Storage
Do not store above 30°C, protect from light and moisture. Drugs should be kept out of the reach of children.

Package
Pack of 5 strips of 1 0 sugar coated tablets 25 mg, Reg. No. DKL0030410616Al

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Manufactured by PT Novartis Indonesia, Citeureup, Bogor, Indonesia under license and control of Novartis Pharma AG Basel, Switzerland

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