Tofranil®
Imipramine hydrochloride tablets 10mg & 25mg
Qualitative and quantitative composition
The active ingredient is N- (γ-dimethylaminopropyl)-iminodibenzyl hydrochloride (= imipramine hydrochloride).
One coated tablet contains 10 mg or 25 mg imipramine hydrochloride.
Pharmaceutical form
10mg tablets- reddish brown, triangular, sugar coated, marked CG, FT on reverse
25mg tablets- reddish brown, round, sugar coated, marked CG, CZ on reverse
Clinical particulars
Therapeutic indications
All forms of depression, including endogenous, organic and psychogenic forms, and depression associated with personality disorders or chronic alcoholism.
Nocturnal enuresis (only in patients aged 5 or older, and only if organic causes have been excluded).
Dosage and method of administration
During treatment with Tofranil, patients must be kept under close surveillance with respect to the efficacy and tolerability of the medication.
The dosage and method of administration should be adapted to the individual patient's condition. The aim is to achieve an optimum effect while keeping doses as low as possible and increasing them cautiously, particularly in elderly patients or adolescents, who generally show a stronger response to Tofranil than patients of the intermediate age group.
Depression and depressive syndromes
Outpatients:Start treatment with 25 mg 1-3 times daily. Raise the daily dosage gradually to 150-200 mg. This dosage should be reached by the end of the first week and maintained to until a clear improvement is seen. The maintenance dose, which must be individually determined by cautiously reducing the dosage, is usually 50-100 mg daily.
Hospitalised patients: Start treatment with 25 mg 3 times daily. Raise the dosage by 25 mg daily until a dose of 200 mg has been reached, and keep to this dose until the patient's condition has improved. In severe cases the dose may be increased to 100 mg 3 times daily. Once a clear improvement has set in, the maintenance dose should be determined according to the patient's individual requirements (generally 100 mg daily).
Elderly patients: Start treatment with 1 tablet of 10 mg daily. Gradually raise the dosage to 30-50 mg daily (optimum level), which should be reached after about 10 days and then maintained until the end of treatment.
Children: Start treatment with 1 tablet of 10 mg daily. Over a period of 10 days increase the daily dosage to 2 tablets in children aged 5-8, to 20-50 mg in those aged 9-14, and to 50-80 mg in patients aged over 14 years. In order to guard against possible cardiotoxic effects in children, a daily dosage of 2.5 mg/kg should not be exceeded.
Nocturnal enuresis (only in children aged 5 years or older)
The recommended dose is 1.7 mg/kg/day. Initial daily dose in children aged 5-8 years: 2-3 tablets of 10 mg; in children aged 9-12: 1-2 tablets of 25 mg; in older children: 1-3 tablets of 25 mg. The higher doses are for patients who do not respond fully to treatment within one week. The tablets should be given in a single dose after the evening meal, but children who wet their beds early in the night should be given part of the dose beforehand (at 4 p.m.). Once the desired response has been achieved, treatment should be continued (for 1-3 months) and the dose gradually reduced to the maintenance dose.
No experience is available in children under 5 years of age.
Contraindications
Hypersensitivity to imipramine and any of the excipients, or cross-sensitivity to tricyclic antidepressants of the dibenzazepine group.
Tofranil should not be given in combination, or within 14 days before or after treatment, with a MAO inhibitor (see "Interactions"). Concomitant treatment with selective, reversible MAO-A inhibitors, such as moclobemide, is also contraindicated.
Recent myocardial infarction.
Special warnings and special precautions for use
Warnings
Tricyclic antidepressants are known to lower the convulsion threshold, and Tofranil should, therefore be used with extreme caution in patients with epilepsy and other predisposing factors, e.g. brain damage of varying aetiology, concomitant use of neuroleptics, withdrawal from alcohol or drugs with anticonvulsive properties (e.g. benzodiazepines). The occurrence of seizures seems to be dose-dependent. The recommended total daily dose of Tofranil should therefore not be exceeded.
Particular caution is called for in patients with cardiovascular disorders, especially those with cardiovascular insufficiency, conduction disorders, (e.g. atrioventricular block grades I to III), or arrhythmias. Monitoring of cardiac function and the ECG is indicated in such patients, as well as in elderly patients.
Because of 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. diseases of the prostate).
Caution is called for when giving tricyclic antidepressants to patients with severe hepatic or renal disease and tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom they may provoke hypertensive crises.
Many patients with panic disorder experience more marked anxiety at the start of the treatment with tricyclic antidepressants (see "Dosage"). This paradoxical initial increase in anxiety is most pronounced during the first few days of treatment and generally subsides within two weeks.
Activation of psychosis has occasionally been observed in schizophrenic patients receiving tricyclic antidepressants.
Hypomanic or manic episodes have also been reported during a depressive phase in patients with bipolar affective disorders receiving treatment with a tricyclic antidepressant. In such cases it may be necessary to reduce the dosage of Tofranil or to withdraw it and administer an antipsychotic agent. After such episodes have subsided, low dose therapy with Tofranil may be resumed if required.
Precautions
Risk of suicide is inherent to severe depression and may persist until significant remission occurs. At the beginning of treatment, combined therapy with benzodiazepines or neuroleptics may be indicated (see "Warnings" and "Interactions").
Before starting treatment with Tofranil it is advisable to check blood pressure, because patients with postural hypotension or a labile circulation may experience a fall in blood pressure.
Caution is indicated in patients with hyperthyroidism or patients receiving thyroid preparations, owing to the possibility of unwanted cardiac effects.
Periodic monitoring of hepatic enzyme levels is recommended in patients with liver disease.
Periodic monitoring of patients with known renal impairment is recommended.
Although changes in the white blood cell count have been reported with Tofranil only in isolated cases, periodic blood cell counts and monitoring for symptoms such as fever and sore throat are called for, particularly during the first few months of therapy and during prolonged treatment.
Like related tricyclic antidepressants, Tofranil should be given with electroconvulsive therapy only under careful supervision.
In predisposed and elderly patients, tricyclic antidepressants may provoke pharmacogenic (delirious) psychoses, particularly at night. These disappear within a few days of withdrawing the drug.
Caution is called for in patients with chronic constipation. Tricyclic antidepressants may cause paralytic ileus, particularly in elderly and in bedridden patients.
Before general or local anaesthesia, the anaesthetist should be aware that the patient has been receiving Tofranil (see "Interactions").
An increase in dental caries has been reported during long-term treatment with tricyclic antidepressants. Regular dental check-ups are therefore advisable during long-term treatment.
Decreased lacrimation and accumulation of mucoid secretions due to the anticholinergic properties of tricyclic antidepressants may cause damage to the corneal epithelium in patients with contact lenses.
Abrupt withdrawal should be avoided because of possible adverse reactions (see "Adverse effects").
Interactions with other medicinal products and other forms of interaction
MAO inhibitors
Do not give Tofranil for at least 2 weeks after discontinuation of treatment with MAO inhibitors (there is a risk of severe symptoms such as hypertensive crisis, hyperpyrexia, myoclonus, agitation, seizures, delirium, and coma). The same applies when giving a MAO inhibitor after previous treatment with Tofranil. In both instances Tofranil or the MAO inhibitor should initially be given in small, gradually increasing doses and its effects monitored.
There is evidence to suggest that tricyclic antidepressants may be given as little as 24 hours after a reversible MAO-A inhibitor such as moclobemide, but the two-week wash-out period must be observed if the MAO-A inhibitor is given after a tricyclic antidepressant has been used.
Selective serotonin reuptake inhibitors (SSRIs)
Co-medication may lead to additive effects on the serotonergic system. Fluoxetine and fluvoxamine may also increase plasma concentrations of imipramine, with corresponding adverse effects.
CNS depressants
Tricyclic antidepressants may potentiate the effects of alcohol and other central depressant substances (e.g. barbiturates, benzodiazepines, or general anaesthetics).
NeurolepticsCo-medication may result in increased plasma levels of tricyclic antidepressants, a lowered convulsion threshold, and seizures. Combination with thioridazine may produce severe cardiac arrhythmias.
Adrenergic neurone blockers
Tofranil may diminish or abolish the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine, and alpha-methyldopa. Patients requiring co-medication for hypertension should therefore be given antihypertensives of a different type (e.g. diuretics, vasodilators, or beta-blockers).
Anticoagulants
Tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs by inhibiting hepatic metabolism of these anticoagulants. Careful monitoring of plasma prothrombin is therefore advised.
Anticholinergic agents
Tricyclic antidepressants may potentiate the effects of these drugs (e.g. phenothiazine, antiparkinsonian agents, antihistamines, atropine, biperiden) on the eye, central nervous system, bowel, and bladder.
Sympathomimetic drugs
Tofranil may potentiate the cardiovascular effects of adrenaline, noradrenaline, isoprenaline, ephedrine, and phenylephrine (e.g. local anaesthetics).
Quinidine
Tricyclic antidepressants should not be employed in combination with antiarrhythmic agents of the quinidine type.
Liver-enzyme inducers
Drugs which activate the hepatic mono-oxygenase enzyme system (e.g. barbiturates, carbamazepine, phenytoin, nicotine, and oral contraceptives) may accelerate the metabolism and lower plasma concentrations of imipramine, resulting in decreased efficacy. Plasma levels of phenytoin and carbamazepine may increase, with corresponding adverse effects. It may be necessary to adjust the dosage of these drugs.
Cimetidine, methylphenidate
These drugs may increase plasma concentrations of tricyclic antidepressants, whose dosage should therefore be reduced.
Estrogens
There is evidence that estrogens can sometimes paradoxically reduce the effects of Tofranil yet at the same time cause Tofranil toxicity.
Pregnancy and lactation (Australian Category C)
Since there have been isolated reports of a possible connection between the use of tricyclic antidepressants and adverse effects (developmental disorders) on the fetus, treatment with Tofranil should be avoided during pregnancy, unless the anticipated benefits justify the potential risk to the fetus.
Neonates whose mothers had taken tricyclic antidepressants until delivery showed drug withdrawal symptoms, such as dyspnoea, lethargy, colic, irritability, hypotension or hypertension, and tremor or spasms, during the first few hours or days. To avoid such symptoms, Tofranil should if possible be gradually withdrawn at least 7 weeks before the calculated date of confinement.
Since imipramine and its metabolite desmethylimipramine pass into the breast milk in small quantities, Tofranil should be gradually withdrawn or the mother be advised to cease breast-feeding.
Effects on ability to drive and use machines
Patients receiving Tofranil should be warned that blurred vision, drowsiness and other CNS symptoms (see "Adverse Effects") may occur, in which case they should not drive, operate machinery, or do anything else requiring alertness. Patients should also be warned that alcohol or other drugs may potentiate these effects (see "Interactions").
Adverse effects
Unwanted effects are usually mild and transient, disappearing under continued treatment or with a reduction in the dosage. They do not always correlate with plasma drug levels or dose. It is often difficult to distinguish certain adverse effects from symptoms of depression such as fatigue, sleep disturbances, agitation, anxiety, constipation, and dry mouth.
If severe neurological or psychic reactions occur, Tofranil should be withdrawn.
Elderly patients are particularly susceptible to anticholinergic, neurological, psychic, and cardiovascular effects. Their ability to metabolise and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at therapeutic doses.
Frequency estimate: frequent > 10%, occasional > 1-10%, rare > 0.001-1%, isolated cases < 0.001%.
Psychic effects
Occasional: drowsiness, fatigue, restlessness, confusion, delirium, disorientation, hallucinations (particularly in elderly patients and patients with Parkinson's disease), increased anxiety, agitation, sleep disturbances, swing from depression to hypomania or mania.
Rare: activation of psychotic symptoms.
Isolated cases: aggressiveness.
Neurological effects
Frequent: tremor.
Occasional: dizziness, headache, paraesthesias.
Rare: epileptic seizures.
Isolated cases: EEG changes, myoclonus, weakness, extrapyramidal symptoms, ataxia, speech disorders, drug fever.
Anticholinergic effects
Frequent: dry mouth, sweating, constipation, disorders of visual accommodation, blurred vision, hot flushes.
Occasional: disturbances of micturition.
Isolated cases: mydriasis, glaucoma, paralytic ileus.
Cardiovascular system
Frequent: sinus tachycardia, postural hypotension, clinically irrelevant ECG changes (e.g. ST and T changes) in patients of normal cardiac status.
Occasional: arrhythmias, conduction disorders (e.g. widening of QRS complex, PQ changes, bundle-branch block), palpitations.
Isolated cases: increased blood pressure, cardiac decompensation, peripheral vasospastic reactions.
Gastrointestinal tract
Occasional: nausea, vomiting, anorexia.
Isolated cases: stomatitis, tongue lesions, abdominal disorders.
Liver
Occasional: elevated transaminases.
Isolated cases: hepatitis with or without jaundice.
Skin
Occasional: allergic skin reactions (skin rash, urticaria).
Isolated cases: oedema (local or generalised), photosensitivity, pruritus, petechiae, hair loss.
Endocrine system and metabolism
Frequent: weight gain.
Occasional: disturbances of libido and potency.
Isolated cases: galactorrhoea, breast enlargement, SIADH (inappropriate antidiuretic hormone secretion syndrome), increase or decrease in blood sugar, weight loss.
Hypersensitivity
Isolated cases: allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions including hypotension.
Blood
Isolated cases: leucopenia, agranulocytosis, thrombocytopenia, eosinophilia, purpura.
Sense organs
Isolated cases: tinnitus.
Others
The following symptoms occasionally occur after abrupt withdrawal or reduction of the dose: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, and anxiety.
Overdose
The signs and symptoms of overdose with Tofranil are similar to those reported with other tricyclic antidepressants. Cardiac abnormalities and neurological disturbances are the main complications. In children accidental ingestion of any amount should be regarded as serious and potentially fatal.
Signs and symptoms
Symptoms generally appear within 4 hours of ingestion and reach maximum severity after 24 hours. Owing to delayed absorption (increased anticholinergic effect due to overdose), long half-life, and enterohepatic recycling of the drug, the patient may be at risk for up to 4-6 days.
The following signs and symptoms may be seen:
Central nervous system: drowsiness, stupor, coma, ataxia, restlessness, agitation, enhanced reflexes, muscular rigidity and choreoathetoid movements, convulsions.
Cardiovascular system: hypotension, tachycardia, arrhythmias, conduction disorders, shock, heart failure; in very rare cases cardiac arrest.
Others: respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, and oliguria or anuria may also occur.
Treatment
There is no specific antidote, and treatment is essentially symptomatic and supportive.
Anyone suspected of receiving an overdose of Tofranil, particularly children, should be hospitalised and kept under close surveillance for at least 72 hours.
Perform gastric lavage or induce vomiting as soon as possible if the patient is fully conscious. If the patient has impaired consciousness, secure the airway with a cuffed endotracheal tube before beginning lavage, and do not induce vomiting. These measures are recommended for up to 12 hours or even longer after the overdose, since the anticholinergic effect of the drug may delay gastric emptying. Administration of activated charcoal may help to reduce drug absorption.
Treatment of symptoms is based on modern methods of intensive care, with continuous monitoring of cardiac function, blood gases, and electrolytes, and if necessary emergency measures such as anticonvulsive therapy, artificial respiration, insertion of a temporary cardiac pacemaker, plasma expander, dopamine or dobutamine administered by intravenous drip, and resuscitation. Since it has been reported that physostigmine may cause severe bradycardia, asystole, and seizures, its use is not recommended in cases of overdosage with Tofranil. Haemodialysis or peritoneal dialysis is ineffective because of the low plasma concentrations of Tofranil.
Pharmacological properties
Pharmacodynamic properties
Pharmacotherapeutic group
Tricyclic antidepressant. Noradrenaline and serotonin reuptake inhibitor.
Mechanism of action
Imipramine has several pharmacological properties, including alpha-adrenolytic, antihistaminic, anticholinergic, and 5-HT-receptor blocking properties. However, the main therapeutic activity is believed to be inhibition of the neuronal reuptake of noradrenaline (NA) and serotonin (5-HT).
Imipramine is a so-called "mixed" re-uptake blocker, i.e. it inhibits the re-uptake of NA and 5-HT to about the same extent.
Pharmacokinetic properties
Absorption
Imipramine hydrochloride is absorbed rapidly and almost completely from the gastrointestinal tract. Food has no effect on its absorption and bioavailability. During its first passage through the liver, orally administered imipramine becomes partly converted to desmethylimipramine, a metabolite which also exhibits antidepressive activity.
Following oral administration of 50 mg three times a day for 10 days, mean steady-state plasma concentrations of imipramine and desmethylimipramine were 33-85 ng/mL and 43-109 ng/mL respectively.
Distribution
About 86% of imipramine binds to plasma proteins. Concentrations of imipramine in the cerebrospinal fluid and the plasma are highly correlated.
The apparent distribution volume is about 21 L/kg bodyweight.
Imipramine and its metabolite desmethylimipramine both pass into the breast milk in concentrations similar to those found in the plasma.
Biotransformation
Imipramine is extensively metabolised in the liver. It is cleared mainly by demethylation and to a lesser extent by hydroxylation. Both metabolic pathways are under genetic control.
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. Urinary excretion of unchanged imipramine and of the active metabolite desmethylimipramine is about 5% and 6%, respectively. Only small quantities are excreted in the faeces.
Characteristics in patients
Owing to reduced metabolic clearance, plasma concentrations of imipramine are higher in elderly patients than in younger patients.
In children the mean clearance and elimination half-life does not differ significantly from adult controls, but the between-patient variability is high.
In patients with severe renal impairment, no change occurs in the renal excretion of imipramine and its biologically active unconjugated metabolites. However, steady-state plasma concentrations of the conjugated metabolites, which are considered to be biologically inactive, are elevated. The clinical significance of this finding is not known.
Preclinical safety data
Imipramine has no mutagenic or carcinogenic potential. Studies in four species (mouse, rat, rabbit, and monkey) led to the conclusion that orally administered imipramine has no teratogenic potential. Experiments with high doses of parenterally administered imipramine resulted mainly in severe maternal toxicity and embryotoxic effects; they were thus inconclusive with regard to teratogenic effects.
Pharmaceutical particulars
List of excipients
Coated tablets of 10 mg and 25 mg: glycerin (85%, PH), lactose, magnesium stearate, maize starch, stearic acid, silica aerogel, hydroxypropyl methylcellulose, vinylpyrrolidone/vinylacetate copolymer, microcrystalline. cellulose, titanium dioxide, red iron oxide, macrogol 8000, polyvidone, sucrose, talc, white printing ink, carnauba wax.
Incompatibilities
None known.
Shelf life
10 mg tablets- 5 years
25 mg tablets- 3 years
Special precautions for storage
Protect from moisture and heat
Store below 30°C
Medicines should be kept out of the reach of children.
Nature and contents of container
50 tablet blister packs
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