Imipramine Tablets Bp 10mg
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Imipramine Tablets BP 10mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Imipramine Hydrochloride BP 10.00mg
3 PHARMACEUTICAL FORM
Orange coloured, sugar coated, deep convex tablets
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
1. Treatment of depressive illness
2. Treatment of nocturnal enuresis in children
4.2 Posology and method of administration
Recommended doses and dosage schedules:
Adults:
1 x 25mg up to three times daily, increasing stepwise to 150-200mg. This should be reached by the end of the first week and maintained until definite improvement has occurred. The subsequent maintenance dose should be individually determined by gradually reducing the dosage, usually to about 50100mg daily. In patients in hospital, i.e. severe cases, the dose may be increased to 100mg three times daily until a distinct improvement is seen. Again the subsequent maintenance dose should be determined individually by reducing the dosage, usually to about 100mg daily.
Children:
In the treatment of nocturnal enuresis only. The tablets should be administered just before bedtime.
6-7 years (weight 20-25kg or 44-55lbs): 25mg daily 8-11years (weight 25-35kg or 55-77lbs): 25 - 50mg daily Over 11 years (weight 35-54kg or 77-119lbs): 50 - 75mg daily
A daily dosage of 2.5mg/kg should not be exceeded in children, nor should it exceed 75mg daily. The maximum period of treatment should not exceed three months including gradual withdrawal. If relapse should occur, treatment should not be re-instituted until a full physical examination has been carried out.
Children under 6 years: Not recommended
Elderly:
Patients over 60 years may respond to lower doses of imipramine than those recommended above. Treatment should be initiated with 10mg daily, gradually increasing to 30-50mg daily. The optimum dose should be reached after about 10 days and then continued until the end of treatment.
Route of administration: oral
4.3 Contraindications
Known hypersensitivity to imipramine, any of the excipients or crosssensitivity to other tricyclic antidepressants of the dibenzazepine group. Recent myocardial infarction, any degree of heart block or other cardiac arrhythmias, mania, porphyria, severe liver disease. Narrow angle glaucoma. Infants and children under 6 years old. Retention of urine. Patients receiving monoamine oxidase inhibitors or within 3 weeks of cessation of therapy. Concomitant treatment with selective, reversible MAO-A inhibitors such as moclobemide, is also contra-indicated.
Patients with rare hereditary problems of galactose or fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
4.4 Special warnings and precautions for use
Suicide/suicidal thoughts or clinical worsening.
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 few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Blood sugar concentrations may be altered in diabetic patients. Imipramine should not be administered for at least three weeks after withdrawing treatment with a monoamine oxidase inhibitor.
Caution is indicated in the treatment of hyperthyroidism or during treatment with thyroid preparations, since aggravation of unwanted cardiac effects may occur.
Before starting treatment it is advisable to check the patients’ blood pressure because patients with hypotension or a labile circulation may react to the drug with a fall in blood pressure.
Caution should be exercised when administering imipramine to patients receiving steroid hormones and those with tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom the drug may provoke hypertensive crises.
Concomitant treatment of imipramine and electroconvulsive therapy should only be resorted to under careful supervision.
Avoid if possible in patients with symptoms of bladder neck obstruction e.g. prostatic hypertrophy.
Tricyclic antidepressants potentiate the central nervous depressant action of alcohol.
Anaesthetics given during tri/tetracyclic antidepressant therapy may increase the risk of arrhythmias and hypotension. If surgery is necessary, the anaesthetist should be informed that a patient is being so treated.
Lengthy treatment with tricyclic antidepressants can lead to an increased incidence of dental caries. Regular dental check-ups are therefore advisable during long-term treatment.
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 cyclic affective disorders receiving treatment with a tricyclic antidepressant. In such cases it may be necessary to reduce the dosage of Imipramine hydrochloride or to withdraw it and administer an antipsychotic agent. After such episodes have subsided, low dose therapy with Imipramine hydrochloride may be resumed if required.
In predisposed and elderly patients, imipramine may, particularly at night, provoke pharmacogenic (delirious) psychoses, which disappear without treatment within a few days of withdrawing the drug. Agitation, confusion and postural hypotension may occur.
Abrupt withdrawal should be avoided because of possible adverse reactions (see section 4.8).
Hyponatraemia (usually in the elderly) has been associated with all types of antidepressants and should be considered in all patients who develop symptoms such as drowsiness, confusion or convulsions.
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 imipramine and administer drugs to control the mania. After such episodes have subsided, low-dose therapy with imipramine may be resumed if required.
Behavioural changes may occur in children receiving imipramine for treatment of nocturnal enuresis.
Tricyclic antidepressants are known to lower the convulsion threshold and Imipramine Hydrochloride 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). It appears that the occurrence of seizures is dose dependent.
Caution is called for when giving tricyclic antidepressants to patients with severe renal disease.
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.
Although changes in the white blood cell count have been reported with imipramine 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.
Because of its anticholinergic properties, imipramine should be used with caution in patients with a history of increased intra- ocular pressure, narrow angle glaucoma, or urinary retention (e.g. diseases of the prostate).
Caution is called for in patients with chronic constipation. Tricyclic antidepressants may cause paralytic ileus, particularly in the elderly and bedridden patients.
Decreased lacrimation and accumulation of mucoid secretions due to anticholinergic properties of tricyclic antidepressants may cause damage to the corneal epithelium in patients with contact lenses.
Imipramine may cause anxiety, feelings of unrest, and hyperexcitation in agitated patients and patients with accompanying schizophrenic symptoms.
Before general or local anaesthesia, the anaesthetist should be aware that the patient has been receiving imipramine. Anaesthetics given during tri/tetracyclic antidepressant therapy may increase the risk of arrhythmias and hypotension
Periodic monitoring of hepatic enzyme levels is recommended in patients with liver disease.
Monitoring of cardiac function is indicated in elderly patients.
4.5 Interaction with other medicinal products and other forms of interaction
Adrenergic neurone blockers: In common with other tricyclic antidepressants, imipramine antagonises the effects of the antihypertensives, bethanidine, reserpine, clonidine, alpha-methylodopa, debrisoquine and gaunethidine. Patients requiring co-medication for hypertension should therefore be given antihypertensives of a different type (e.g. diuretics, vasodilators, or beta blockers).
Diuretics: Concurrent use of a tricyclic antidepressant and a diuretic may increase the risk of postural hypotension.
Alpha2-adrenoceptor stimulants: concomitant use of apraclonidine or Brimonidine should be avoided.
Sympathomimetic drugs: Imipramine may potentiate the effects of the vasoconstrictors adrenaline (epinephrine) and noradrenaline (norepinephrine), ephedrine, isoprenaline, phenylephrine, phenylpropanolamine (e.g. as contained in local anaesthetic preparations and nasal decongestants).
CNS depressants: Imipramine potentiates the effects of central depressant drugs (e.g. barbiturates, benzodiazepines or general anaesthetics) and alcohol and increases the “antabuse reaction” of disulfiram with alcohol.
It also reduces the effect of oral contraceptives, the side-effects of which may be increased.
MAO inhibitors: Imipramine hydrochloride should not be administered for at least 3 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 Imipramine hydrochloride. In both instances Imipramine hydrochloride or the MAO inhibitors 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 inhibitor such as moclobemide, but the 3 week wash-out period must be observed if the MAO inhibitor is given after a tricyclic antidepressant has been used. Monoamine oxidase inhibitors interact with imipramine causing CNS excitement and hypertension.
Anaesthetics given during therapy with imipramine may increase the risk of arrhythmias and hypotension.
Cimetidine, methylphenidate, causes raised blood plasma concentrations of imipramine. Imipramine may lead to elevated serum concentrations of phenytoin when used concurrently.
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. When tricyclic antidepressants are given in combination with anticholinergic or antipsychotics with an anticholinergic action, hyperexcitation states or delirium may occur, as well as attacks of glaucoma.
Calcium channel blockers: Blood levels of imipramine may be increased by calcium channel blockers such as diltiazem and verapamil.
Nitrates: Reduced salivary secretion may lessen the effectiveness of sublingual nitrate preparations.
Dopaminergic agents: CNS toxicity may be enhanced when tricyclic antidepressants are used in conjunction with dopaminergic drugs such as selegiline and entacapone. Centrally acting appetite suppressants: Concomitant use is not recommended due to the increased risk of CNS toxicity.
Antineoplastic drugs: concomitant use of altretamine should be avoided due to the risk of severe postural hypotension.
Substances which activate the hepatic mono-oxygenase enzyme system (carbamazepine, barbiturates, nicotine, phenytoin, and oral contraceptives) may lower the plasma concentration of tricyclic antidepressants and so reduce their antidepressant effect.
Selective serotonin reuptake inhibitors: 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, resulting in increased plasma levels of tricyclic antidepressants, a lowered convulsion threshold and seizures.
Alprazolam and disulfiram: It may be necessary to reduce the dosage of imipramine if it is administered concomitantly with alprazolam or disulfiram.
Neuroleptics: Co-medication may result in increased plasma levels of tricyclic antidepressants, a lowered convulsion threshold and seizures. Combination with thioridazine may produce severe cardiac arrhythmias.
Anticoagulants: Tricyclic antidepressants may potentiate the anti-coagulant effect of coumarin drugs by inhibiting hepatic metabolism of these anticoagulants. Careful monitoring of plasma prothrombin is therefore advised.
Oestrogens: There is evidence that oestrogens can sometimes paradoxically reduce the effects of imipramine yet at the same time cause imipramine toxicity.
Quinidine: Tricyclic antidepressants should not be employed in combination with anti-arrhythmic agents of the quinidine type.
Tricyclic antidepressants may also interact with the following drug classes:
Analgesics: Possible increase in risk of side effects (nefopam), convulsions (tramadol), sedation (opioid analgesics) or ventricular arrhythmias.
Anti-arrhythmics: Increased risk of ventricular arrhythmias with drugs, which prolong the QT interval.
Muscle relaxants: Enhanced muscle relaxant effect of baclofen.
4.6 Fertility, pregnancy and lactation Pregnancy
The use of imipramine in pregnancy has not been established and should be avoided unless there are compelling reasons to the contrary. There have been isolated reports of a possible connection between the use of tricyclic antidepressants and adverse effects (developmental disorders) on the foetus.
Neonates whose mothers had taken imipramine up till delivery have developed dyspnoea, lethargy, colic, irritability, hypotension or hypertension, tremor or spasms, during the first few hours or days. Imipramine should - if this is at all justifiable - be withdrawn at least 7 weeks before the calculated date of confinement.
Lactation
The active substance of imipramine and its metabolite desmethylimipramine pass into the breast milk in small quantities. It should not be administered to nursing mothers unless considered essential when the mother should be advised to cease breast feeding.
4.7 Effects on ability to drive and use machines
Patients receiving Imipramine Hydrochloride should be warned that blurred vision, Drowsiness and mild sedation and other CNS symptoms may occur (see section 4.8). If affected, do not drive or operate machinery or do anything which may require alertness or quick actions.
Patients should also be warned that alcohol or other drugs may potentiate these effects, (see section 4.5).
4.8 Undesirable effects
If severe neurological or psychiatric reactions occur, Imipramine hydrochloride should be withdrawn. Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric, or cardiovascular effects. Their ability to metabolise and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at therapeutic doses.
The following frequency estimates are used: very common (>1/10), common (>1/100 to <1/10), Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <1/1,000).
Blood and lymphatic system disorders:
Rare: agranulocytosis, bone marrow depression including leucopenia, eosinophilia, purpura, thrombocytopenia. It is advisable to perform blood counts during treatment with tritetracyclic antidepressants, especially if the patient develops fever, sore throat or other signs of infection. (See section 4.4).
Immune system disorders:
Rare: allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions including hypotension.
Endocrine disorders:
Rare: SIADH (syndrome of inappropriate antidiuretic hormone secretion). Metabolism and nutrition disorders:
Rare Hyponatraemia, usually in the elderly, has been associated with all types of antidepressants (see section 4.4).
Psychiatric Disorders:
Behavioural changes in children may occur and confusion in the elderly have been reported.
Common: fatigue, drowsiness, restlessness, delirium, confusion, disorientation and hallucination (particularly in geriatric patients and those suffering from Parkinson's disease), increased anxiety, agitation, sleep disturbances, swings from depression to hypomania or mania.
Uncommon: activation of psychotic symptoms.
Rare: aggressiveness.
Paranoid delusion may be exacerbated during treatment with tricyclic antidepressants. These are more frequently seen in elderly patients or those on high doses.
Cases of suicidal ideation and suicidal behaviours have been reported during Imipramine therapy or early after treatment discontinuation (see section 4.4).
Nervous system disorders:
Very common: tremor.
Common: paraesthesiae, headache, dizziness.
Uncommon: epileptic seizures/convulsions.
Rare: EEG changes, myoclonus, weakness, extrapyramidal symptoms, ataxia, speech disorder, drug fever.
Syncope has also been reported.
Eye disorders:
Very common: blurred vision, disorders of visual accommodation.
Rare: glaucoma, mydriasis.
Ear and labyrinth disorders:
Rare: Tinnitus.
Cardiac disorders:
Very common: sinus tachycardia and clinically irrelevant ECG changes (T and ST changes) in patients of normal cardiac status, postural hypotension.
Common: arrhythmias and heart block follow the use of imipramine and may be the cause of sudden death in patients with cardiac disease, conduction disorders (widening of QRS complex and PR interval, bundle-branch block), palpitations.
Rare: increased blood pressure, cardiac decompensation, peripheral vasospastic reactions.
Other cardiovascular effects include tachycardia and syncope.
Cardiac arrhythmias and severe hypotension are likely to occur with high dosage or in deliberate overdosage. They may also occur in patients with preexisting heart disease taking normal dosage.
Vascular disorders:
Very common: hot flushes
Gastro-Intestinal disorders:
Very common: constipation, dry mouth.
Common: nausea, vomiting, anorexia.
Rare: stomatitis, tongue lesions, abdominal disorders, black tongue and paralytic ileus have been reported.
Hepatobiliary disorders:
Common: elevated transaminases.
Uncommon: impaired liver function.
Rare: hepatitis with or without jaundice.
Skin and subcutaneous tissue disorders:
Very common: sweating.
Common: allergic skin reactions (skin rash, urticaria).
Rare: oedema (local or generalised), photosensitivity, hyperpigmentation, pruritus, petechiae, hair loss.
Renal and urinary disorders:
Common: disturbances of micturition, urinary retention.
Reproductive system and breast disorders:
Common: interference with sexual function.
Rare: enlarged mammary glands, galactorrhoea.
General disorders and administration site conditions:
Although not indicative of addiction, withdrawal symptoms following abrupt discontinuation of treatment: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness and anxiety, excessive perspiration.
Respiratory depression, agitation and withdrawal symptoms have been reported in neonates whose mothers received imipramine during the last trimester of pregnancy.
Investigations:
Very common: weight gain.
Rare: blood sugar and weight changes.
Class effects:
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.
4.9 Overdose
The signs and symptoms of overdose with imipramine 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: The first signs and symptoms of poisoning with tricyclic antidepressants generally take the form of severe anticholinergic reactions, which set in about half/two hours after the drug has been taken, Symptoms generally appear within 4 hours of ingestion and reach a 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 may be encountered:
Central nervous system:
Drowsiness, stupor, coma, ataxia, restlessness, agitation, enhanced reflexes, muscular rigidity, athethoid and chloreiform movements, convulsions.
Cardiovascular system:
Hypotension, tachycardia, arrhythmia, conduction disorders, heart failure, in very rare cases cardiac arrest.
In addition, respiratory depression, cyanosis, shock, vomiting, fever, hydriasis, sweating and oliguria or anuria may occur.
Treatment:
There is no specific antidote and treatment is essentially symptomatic and supportive. Anyone suspected of received an overdose of imipramine, particularly children, should be admitted to hospital and kept under close surveillance for at least 72 hours. Physostigmine should not be used since it may increase the risk of epileptic seizures, severe bradycardia and asystole. Where the drug has been taken by mouth, try to induce vomiting; otherwise the stomach must be irrigated 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. Activated charcoal should be administered to reduce drug absorption. Severe poisoning with tricyclic drugs requires immediate hospitalisation 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 relapse may occur. Treatment of symptoms is based on modern methods of intensive care, with continuous monitoring of cardiac function, blood gases and electrolytes, and if necessary the following measures should be taken in cases of overdosage or emergency:
• 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 the intravenous drip.
• Cardiac arrhythmias must be treated according to the requirements of the case.
• Insertion of a temporary cardiac pacemaker should be considered.
• Low potassium values and acidosis should be corrected. Convulsions are also a common symptom of overdosage and may be treated with intravenous diazepam.
• Anticonvulsive therapy.
• Resuscitation.
Haemodialysis or peritoneal dialysis are ineffective because of the low plasma
concentrations of imipramine.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Imipramine is a tricyclic antidepressant with actions which include alpha-adrenolytic, antihistamine, anticholinergic and 5 HT-receptor blocking properties but exhibiting a less marked tendency to cause sedation. Its mode of action in depressive illness is not fully understood but is believed to be based mainly on its ability to inhibit the neuronal re-uptake of noradrenaline and 5HT inhibiting their uptake approximately to the same extent.
5.2 Pharmacokinetic properties
Imipramine is absorbed quickly and completely following oral administration.
The intake of 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 likewise exhibits antidepressant activity.
During oral administration of 50mg 3 times daily for 10 days, the mean steady-state plasma concentrations of imipramine and desmethylimipramine were 33-85ng/ml and 43-109ng/ml, respectively. Owing to lower clearance in the plasma, resulting in increased systemic availability, elderly patients require lower doses of imipramine than patients in intermediate age groups. Renal impairment is not expected to have any influence on the kinetics of unchanged imipramine and its desmethyl metabolite, since both are excreted only in small amounts by the kidneys.
The mean plasma half-life of imipramine is approximately 20 hours, mean plasma protein binding 86% and mean distribution volume 21 l/kg. The quantity of unchanged imipramine and active metabolite desmethylimipramine excreted is low, most excretion being as inactive metabolites in urine (approximately 80%) and faeces (approximately 20%).
5.3 Preclinical safety data
Not applicable
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Ingredient:
Lactose BP Povidone BP Isopropyl Alcohol BP Maize Starch BP Magnesium Stearate BP
Coating Materials:
Coating Varnish HSE Talc BP Syrup BP
Standard Coating Cream HSE Opalux 2626A Tan Colour Coat HSE
6.2 Incompatibilities
None
6.3 Shelf life
24 months - blister packs 36 months - amber glass bottles 60 months - opaque plastic containers
6.4 Special precautions for storage
Keep out of the reach of children Protect from heat, light and moisture
6.5 Nature and contents of container
1. Amber glass bottles with screw caps in pack sizes of 50, 100, 250, 500 & 1,000 tablets.
2. Opaque plastic containers (securitainers) with plastic caps in pack sizes of 28, 42, 50, 56, 84, 100, 112, 250, 500 & 1,000 tablets.
3. Opaque plastic containers (HDPP or HDPE) with a tamper-evident or child-resistant, tamper-evident closure (HDPE) with a packing inclusion of standard polyether foam or PE or PP-made filler in pack sizes of 28, 42, 50, 56, 84, 100, 112, 250, 500 & 1,000 tablets.
4. Aluminium/Opaque PVC blister packs containing 28, 42, 56, 84, & 112 tablets.
6.6 Special precautions for disposal
No special instructions for use/handling
7 MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited Unit 3 & 4
Quidhampton Business Units
Polhampton Lane
Overton
Hampshire
RG25 3ED
United Kingdom
8 MARKETING AUTHORISATION NUMBER
PL 20416/0092
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29/01/2004 / 11/03/2009
DATE OF REVISION OF THE TEXT
04/11/2011
10