IMIPRAMINE 10 MG TABLETS - summary of medicine characteristics

Summary of medicine characteristics - IMIPRAMINE 10 MG TABLETS

SUMMARY OF PRODUCT CHARACTERISTICS1 NAME OF THE MEDICINAL PRODUCT

Imipramine 10 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Imipramine Hydrochloride 10 mg.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Coated tablet.

Biconvex orange sugar coated tablets.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of depressive illness in adults.

For the treatment of nocturnal enuresis in children.

4.2 Posology and method of administration

For oral administration.

Adults:

In depressive illness, initially 75 mg daily given in divided doses and increased gradually to 150–200 mg daily. This dose to be reached by the end of the first week of treatment. Once improvement has occurred a maintenance dose should be calculated, on an individual basis and the dose gradually reduced (normally to approx. 50 – 100 mg daily).

For hospitalized patients the dose can be increased to 100 mg three times daily, until significant improvement occurs. Again a maintenance dose should then be calculated, on an individual basis and the dose reduced (normally to approx. 100 mg daily).

Elderly:

Patients over 60 years of age may be responsive to lower doses than those detailed above. Initially 10 mg daily and gradually increasing the dose to 30 –50 mg daily. This dose should be reached approximately 10 days after starting treatment and continued for the length of treatment.

Children:

In the treatment of nocturnal enuresis only:

Do not use in children under 6 years of age.

6–7 years (weight 20–25 kg or 44–55 lbs): 25 mg at bedtime.

8–11 years (weight 25–35 kg or 55–77 lbs): 25 – 50 mg at bedtime.

11 years and over (weight 35–45 kg or 77–119 lbs): 50 – 75 mg at bedtime.

Do not exceed a daily dose of 2.5 mg/kg. Treatment should not exceed three months and the dose should be gradually withdrawn. Should a relapse occur, no further treatment with imipramine should be started until a full physical examination has been made.

4.3 Contraindications

Patients with heart block or other cardiac arrhythmias, mania, severe liver disease, narrow angle glaucoma, urine retention or recent myocardial infarction.

Hypersensitivity to imipramine or any of the other tablet ingredients.

Cross-sensitivity to other tricyclic antidepressants of the dibenzazepine group.

Do not give to infants/children under 6 years of age.

Concurrent use in patients receiving or within 3 weeks of stopping treatment with MAO inhibitors.

Concomitant treatment with selective, reversible MAO-A inhibitors such as moclobemide.

4.4 Special warnings and precautions for useSuicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of 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 anti-depressants 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.

Tricyclic antidepressants are known to lower the seizure threshold, therefore use imipramine with caution in those with epilepsy and other predisposing factors such as patients withdrawing from alcohol or drugs with anticonvulsive properties (eg benzodiazepines), whilst taking neuroleptics or those with brain damage. (It would appear occurrence of seizures is dose dependant).

Treatment with imipramine whilst undergoing electro-convulsive therapy should only be resorted to under careful supervision.

Caution required in patients with: severe renal disease, tumours of the adrenal medulla (may provoke hypertensive crisis), patients with hyperthyroidism or during concomitant treatment with thyroid preparations (may aggravate unwanted cardiac effects), patients with acute porphyria or patients with chronic constipation.

Tricyclic antidepressants may cause paralytic ileus (especially in elderly or bedridden patients).

Due to the anticholinergic properties of the tricyclic antidepressants: Caution is required in those with a history of increased intra-ocular pressure, narrow angle glaucoma or urinary retention.

May cause damage to the corneal epithelium in patients with contact lenses (due to decreased lacrimation and accumulation of mucoid secretions).

Increased anxiety symptoms in patients with panic disorders has occured when taking antidepressants during the first few days of treatment but normally subsides within 2 weeks.

Blood pressure should be checked prior to treatment (a fall in blood pressure may occur upon administration of the drug in patients with a labile circulation or hypotension). Periodic blood cell counts should be performed and monitoring for symptoms such as fever and sore throat, particularly during the first few months of treatment (due to a small number of reported cases of changes in white blood cell counts). Monitoring of hepatic enzyme levels periodically in those with liver disease is advised. Cardiac function should be monitored in the elderly. Regular dental check-ups are advised during longterm treatment due to the possibility of dental caries (increase reported during long-term treatment with tricyclics).

An anaesthetist should be aware that the patient is taking imipramine as local or general anaesthetics given during treatment with tricyclic anti-depressants may increase the risk of arrhythmias or hypotension.

Anxiety, restlessness and hyperexcitation may occur in agitated patients or those with accompanying schizophrenic symptoms.

Tricyclic anti-depressants have occasionally activated psychosis in schizophrenic patients and hypomanic/manic episodes during a depressive phase, in patients with cyclic affective disorders. It may be necessary for the dose to be reduced or the drug withdrawn and an antipsychotic drug administered. Low dose treatment with imipramine may begin, if required, once these episodes have subsided.

Imipramine may cause delirious psychoses (especially at night) in elderly or predisposed patients, this disappears within a few days upon withdrawal of the drug. Agitation, confusion and postural hypotension may occur.

Abrupt withdrawal of this drug should be avoided (see 4.8 side-effects).

Behavioural changes in children may occur.

Patients with rare hereditary problems of fructose or galactose intolerance, the LAPP lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine as it contains lactose and sucrose.

This medicine contains sunset yellow (E110) which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Adrenergic neurone blockers: In common with other tricyclic antidepressants imipramine antagonises the antihypertensive effects of betanidine, guanethidine, a-methyldopa, reserpine and clonidine. Antihypertensives of a different type should be given.

Sympathomimetic drugs: Imipramine may potentiate the cardiovascular effects of adrenaline, noradrenaline, ephedrine, isoprenaline, phenylephrine and phenylpropanolamine.

CNS depressants: Tricylic antidepressants may potentiate the effects of alcohol and other central depressant drugs.

Oestrogens: Can sometimes paradoxically cause effects of imipramine to be reduced and yet also cause imipramine toxicity.

Cimetidine and methylphenidate: May increase plasma concentrations of tricyclic antidepressants, therefore the dose of imipramine should be reduced.

Liver enzyme inducers: Drugs which activate the hepatic mono-oxygenase enzyme system (such as barbiturates, phenytoin, carbamazepine, nicotine and oral contraceptives) may accelerate metabolism and lower plasma concentrations of imipramine. Phenytoin and carbamazepine plasma levels may increase with corresponding adverse effects. Dosage of these drugs may need to be altered.

Quinidine: Anti-arrhythmic drugs of the quinidine type should not be used alongside tricyclic antidepressants.

MAO inhibitors: Do not give imipramine for at least 3 weeks after stopping treatment with a MAO inhibitor. MAO inhibitors should also not be given after treatment with imipramine (risk of severe symptoms such as agitation, coma, delirium, hypertensive crisis, hyperpyrexia, myoclonus, seizures). Imipramine or the MAO inhibitor should then be given in small doses and increased slowly. (Evidence suggests tricyclic antidepressants may be given as little as 24 hours after a reversible MAO inhibitor such as moclobemide, however 3 weeks must elapse if the MAO inhibitor is given after taking a tricyclic antidepressant).

Selective serotonin reuptake inhibitor: Taken concomitantly with imipramine may cause additive effects on the serotonergic system. Fluvoxetine and fluvoxamine may also increase plasma concentrations of imipramine with corresponding adverse effects.

Disulfiram or alprazolam: The dose of imipramine may need to be reduced.

Neuroleptics: May cause an increase in plasma concentrations of tricyclic antidepressants, a lowered convulsion threshold and seizures. Taking with thioridazine may cause severe cardiac arrhythmias.

Anticoagulants: The anticoagulant effect of coumarin drugs may be potentiated by tricyclic antidepressant by inhibiting their hepatic metabolism. Monitoring of plasma prothrombin is therefore advised.

Anticholinergic drugs: Tricyclic antidepressants may potentiate the effects of these drugs (eg phenothiazines, anti-parkinsonism drugs, antihistamines, atropine, biperiden) on the eye, CNS, bowel and bladder.

Beta-blockers: Plasma concentration of imipramine increased by labetolol and propranolol.

Calcium channel blockers: Plasma concentration of imipramine increased by diltiazem and verapamil.

Antifungals: Plasma concentration of imipramine possibly increased by terbinafine.

Thyroid hormones: The effects of imipramine are enhanced

4.6 Fertility, pregnancy and lactation

The use of imipramine in pregnancy has not been established but should be avoided unless there are compelling reasons to the contrary as there is a possible connection between the use of tricyclic antidepressants and adverse effects (development disorders) on the foetus. Benefit should therefore outweigh the potential risk to the foetus.

If taken, if possible the drug should be slowly withdrawn at least 7 weeks before the date of confinement due to the adverse effects reported in neonates in those taking imipramine up to term (side-effects reported include tachycardia, colic, dyspnoea, hypotension, irritability, lethargy, tremor or spasms during the first few hours or days).

Imipramine and its metabolite desmethylimipramine pass into the breast milk in small quantities (treatment with imipramine should be gradually withdrawn or the mother advised not to breast feed).

4.7 Effects on ability to drive and use machines

Blurred vision, drowsiness and other CNS symptoms may occur when taking imipramine, patients should be advised not to drive, operate machinery or do anything requiring alertness if affected. Alcohol and other drugs may potentiate these effects, patients should be advised accordingly.

4.8 Undesirable effects

Imipramine should be withdrawn if severe neurological and psychiatric reactions occur.

Elderly patients are particularly sensitive to the anticholinergic, cardiovascular, neurological or psychiatric effects.

The following undesirable effects have been reported with tricyclic antidepressant drugs, not necessarily reported with imipramine (Very common >1/10, common >1/100 – <1/10, rare >1/10,000 – <1/100, very rare <1/10,000):

Blood and the lymphatic system disorders:

Very rarely: agranulocytosis, eosinophilia, leucopenia, purpura and thrombocytopenia.

Endrocrine disorders:

Very common: weight gain.

Common: changes to libido & potency.

Very rarely enlarged mammary glands, galactorrhoea, increase/decrease in blood sugar, SIADH (syndrome of inappropriate antidiuretic hormone secretion) and weight loss.

Metabolism and nutrition disorders:

Not known: hyponatraemia.

Psychiatric effects/disorders:

Common: fatigue, drowsiness, sleep disturbance, increased anxiety, restlessness/agitation, delirium, confusion, swings from depression to hypomania/mania, disorientation and hallucinations (mainly in geriatric patients or those suffering from Parkinson’s disease).

Rarely psychotic symptoms have been activated.

Very rarely aggressiveness.

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: dizziness, headache and paraesthesiae.

Rarely epileptic seizures.

Very rarely ataxia, drug fever, EEG changes, extrapyramidal symptoms, myoclonus, problems with speech and weakness.

Not known: syncope.

Ear and labyrinth disorders:

Tinnitus has been reported.

Cardiac disorders:

Very common: sinus tachycardia and clinically irrelevant ECG changes (T and ST changes) in patients with normal cardiac status, postural hypotension. Common: arrhythmias, conduction disorders and palpitations.

Very rarely increases in blood pressure, cardiac decompensation and peripheral vasospastic reactions.

Gastrointestinal disorders:

Common: anorexia, nausea, vomiting.

Very rarely abdominal disorders, tongue lesions and stomatitis.

Not known: increased appetite and taste disturbances.

Hepato-biliary disorders:

Common: elevated transaminases.

Very rarely hepatitis (with or without jaundice).

Skin and subcutaneous tissue disorders:

Common: allergic skin reactions such as rash and urticaria.

Very rarely oedema (local or generalised), hair loss, photosensitivity, pruritus and petechiae.

Not known: hyperpigmentation.

Hypersensitivity:

Very rarely allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions including hypotension.

Reproductive system and breast disorders: Not known: testicular enlargement.

Anticholinergic effects:

Very commonly (due the anticholinergic action of tricyclic antidepressant drugs) may cause constipation, dry mouth, sweating, hot flushes, blurred vision or disorders of visual accommodation.

Commonly micturition disturbances.

Very rarely glaucoma, mydriasis and paralytic ileus.

Other effects:

Occasionally if treatment is stopped abruptly the patient may suffer from withdrawal symptoms such as abdominal pain, anxiety, diarrhoea, headache, insomnia, nausea, nervousness and vomiting.

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.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

The first signs of overdose with tricyclic antidepressants generally occur within four hours after the drug has been taken (maximum severity reached after 24 hours). The patient may be at risk for up to 4–6 days due to the delayed absorption of the drug in overdose (increased anticholinergic effect), long half life and enterohepatic recycling. Accidental ingestion of any amount in children should be considered as serious and potentially fatal.

Overdose may present the following signs and symptoms (consistent with other tricyclic antidepressants):

Central nervous system: agitation, ataxia, athetoid and chorieform movements, coma, convulsions, drowsiness, enhanced reflexes, muscular rigidity, stupor, restlessness.

Cardiovascular system: arrhythmia, conduction disorders, heart failure, hypotension, tachycardia and in very rare cases cardiac arrest.

Additionally anuria or oliguria, cyanosis, fever, hydrasis, respiratory depression, shock, sweating and vomiting may occur.

Treatment:

There is no specific antidote, essentially symptomatic and supportive treatment is required. Anyone with suspected overdose (especially children) should be admitted to hospital and observed closely for at least 72 hours. If the patient is fully conscious try to induce vomiting (DO NOT induce vomiting in unconscious patients) or otherwise perform gastric lavage. This can be carried out for up to 12 hours or even longer after the overdose (the anti-cholinergic effect of the drug may delay gastric emptying). Activated charcoal can be administered and may help reduce absorption of the drug.

Cardiac function, blood gases and electrolyte levels should be continuously monitored. If necessary patients can receive emergency measures including anticonvulsive therapy, artificial respiration, implantation of a temporary cardiac pacemaker, given a plasma expander, dopamine or dobutamine by intravenous drip and resuscitation.

Physostigmine should not be used in cases of imipramine overdose since it may cause asystole, bradycardia or seizures. Haemodialysis or peritoneal dialysis are ineffective due to the low plasma levels of imipramine.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

N06A A02 – Non-selective monoamine reuptake inhibitors

Imipramine is a tricyclic, antidepressant with actions which include alpha-adrenolytic antihistamine, anticholinergic and 5HT – receptor blocking properties but exhibiting a less marked tendency to cause sedation. Its mode of action in depressive illness is not fully understood but it 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 from the gastrointestinal tract. It is extensively demethylated in the liver to desipramine. Imipramine and desipramine are extensively bound to tissue and plasma protein. Imipramine is excreted in the urine mainly as metabolites in either free or conjugated form. Its half-life varies depending on the individual and the dose, but is commonly in the range of 8–19 hours.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber, which are additional to those already included in other sections of the SmPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose (spray dried)

Talc

Colloidal Anhydrous Silica

Stearic Acid

Sucrose

Titanium Dioxide (E171)

Dispersed Orange 15005 (containing Sunset Yellow Aluminium Lake (E110) & Aluminium Hydroxide Gel).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Tablet containers: Do not store above 25°C. Keep the container tightly closed.

Blisters: Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

High density polypropylene containers with low density polyethylene caps of 28, 100, 250, 500 & 1000 tablets.

Al/PVC/ blisters enclosed in an outer carton, containing 28 or 56 tablets.

Not all packs may be marketed.

6.6 Special precautions for disposal