Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation: Accord-UK Ltd (Trading style: Accord), Whiddon Valley, Barnstaple, Devon, EX32 8NS
Improvement in depression may not occur during the first two to four weeks of treatment and hence patients should be closely monitored during this period.
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.
As tricyclic antidepressants are known to lower the convulsion threshold, imipramine should 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). Occurrence of seizures appears to be dose-dependent.
Concomitant treatment with imipramine and electroconvulsive therapy should only be resorted to under careful supervision.
Caution is required when giving tricyclic antidepressants to patients with severe renal disease.
Caution is required when giving tricyclic antidepressants to patients with tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), as hypertensive crises may be provoked.
Many patients with panic disorders experience intensified anxiety symptoms at the start of 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.
Caution is required in patients with hyperthyroidism or during concomitant treatment with thyroid preparations as aggravation of unwanted cardiac effects may occur.
Before starting treatment it is advisable to check the patient’s blood pressure because those 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. (See section 4.8).
Periodic monitoring of hepatic enzyme levels is recommended in patients with liver disease.
Monitoring of cardiac function is indicated in elderly patients.
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 required in patients with chronic constipation. Tricyclic antidepressants may cause paralytic ileus, particularly in elderly and bedridden patients.
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 (see section 4.5).
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.
Imipramine may cause anxiety, feelings of unrest and hyperexcitation in agitated patients and patients with accompanying schizophrenic symptoms.
Activation of psychosis has been observed occasionally 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 or to withdraw it and administer an antipsychotic agent. After such episodes have subsided, low dose therapy with imipramine 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).
Behavioural disturbances may occur in children receiving treatment with imipramine for the treatment of nocturnal enuresis.
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.
MAO inhibitors (MAOIs): Imipramine should not be administered for at least three 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). This also applies when giving a MAO inhibitor after previous treatment with imipramine. In both instances imipramine 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 inhibitor such as moclobemide, but the three week wash-out period must be observed if the MAO 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 the plasma concentrations of imipramine, with corresponding adverse effects, resulting in increased plasma levels of tricyclic antidepressants, a lowered convulsion threshold and seizures.
CNS depressants: Tricyclic antidepressants may also potentiate the CNS depressant effects of alcohol and central depressant drugs (e.g. barbiturates, benzodiazepines or general anaesthetics). (See section 4.4).
Alprazolam and disulfiram: It may be necessary to reduce the dosage of imipramine if it is administered concomitantly with alprazolam or disulfiram.
Neuroleptics: Concomitant use 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: Imipramine may diminish or abolish the antihypertensive effects of guanethidine, debrisoquine, bethanidine, reserpine, α-methyldopa and clonidine. Patients requiring co-medication for hypertension should therefore be given antihypertensives of a different type (e.g. vasodilators).
Beta-blockers: Blood concentrations of imipramine may be increased by drugs such as labetalol and propranolol. The clinical importance of these interactions is uncertain.
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.
Anticoagulants: Tricyclic antidepressants may potentiate the anti-coagulant effect of coumarin drugs by inhibiting hepatic metabolism of 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: Imipramine may potentiate the cardiovascular effects of adrenaline (epinephrine), ephedrine, isoprenaline, noradrenaline (norepinephrine), phenylephrine and phenylpropanolamine (e.g. as contained in local anaesthetic preparations and nasal decongestants).
Quinidine: Tricyclic antidepressants should not be employed in combination with anti-arrhythmic 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 the plasma levels of imipramine whose dosage should therefore be reduced.
Oestrogens: There is evidence that oestrogens can sometimes paradoxically reduce the effects of imipramine yet at the same time cause imipramine toxicity.
Antiviral agents: Drugs such as ritonavir have been reported to increase plasma concentrations of antidepressant drugs.
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 sub-lingual 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.
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.
There is no evidence of the safety of the drug in human pregnancy. There have been isolated reports of a possible connection between the use of tricyclic antidepressants and adverse effects (developmental disorders) on the foetus. Treatment with imipramine should be avoided during pregnancy, unless the anticipated benefits justify the potential risk to the foetus.
Neonates whose mothers had taken imipramine up until delivery have developed dyspnoea, lethargy, colic, irritability, hypotension or hypertension, tremor or spasms, during the first few hours or days. If possible, imipramine should be gradually withdrawn at least 7 weeks before the calculated date of confinement.
As imipramine is excreted in breast milk, it should not be administered to nursing mothers unless considered essential when the mother should be advised to cease breast feeding.
Patients should be warned:
The following frequency estimates are used: frequent >10%, occasional >1-10%, rare >0.001-1%, isolated cases <0.001%.
If severe neurological or psychiatric reactions occur, imipramine 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.
Effects on the central nervous system: fatigue, drowsiness, restlessness, delirium, confusion, disorientation, hallucinations (particularly in geriatric patients and those suffering from Parkinson’s disease), increased anxiety, agitation, sleep disturbances, swings from depression to hypomania or mania have been reported occasionally.
Activation of psychotic symptoms has been reported rarely.
In isolated cases aggressiveness has been reported.
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).
Neurological effects: tremor has been reported frequently.
Paraesthesia, headache and dizziness have been reported occasionally.
Epileptic seizures have been reported rarely.
In isolated cases EEG changes, myoclonus, weakness, extrapyramidal symptoms, ataxia, speech disorders, drug fever has been reported.
Effects on the cardiovascular system: Sinus tachycardia and clinically irrelevant ECG changes (T and ST changes) in patients of normal cardiac status, and postural hypotension have been reported frequently. Cardiac arrhythmias and severe hypotension are likely to occur with high dosage or in deliberate overdosage. They may also occur in patients with pre-existing heart disease taking normal dosage.
Arrhythmias, conduction disorders (widening of QRS complex and PR interval, bundle-branch block), palpitations have been reported occasionally.
Isolated cases of increased blood pressure, cardiac decompensation, peripheral vasospastic reactions have been reported.
Anticholinergic effects: dry mouth, constipation, sweating, disturbances of visual accommodation, blurred vision, hot flushes have been frequently reported.
Disturbances of micturition have been occasionally reported.
Isolated cases of mydriasis, glaucoma and paralytic ileus have been reported.
Effects on the gastro-intestinal tract: Nausea, vomiting, anorexia has been reported occasionally.
Isolated cases of stomatitis, tongue lesions, abdominal disorders have been reported.
Hepatic effects: Elevated transaminases have been reported occasionally.
Impaired liver function has been reported rarely.
Isolated cases of hepatitis with or without jaundice have been reported.
Effects on the skin: Allergic reactions (such as urticaria, skin rash) have been reported occasionally.
Isolated cases of oedema (local or generalised), photosensitivity, pruritus, petechiae, hair loss have been reported.
Effects on the endocrine system and metabolism: weight gain has been reported frequently.
Disturbances in libido and potency have been reported occasionally.
Isolated cases of enlarged mammary glands, galactorrhoea, SIADH (syndrome of inappropriate antidiuretic hormone secretion), increase or decrease in blood sugar, weight loss have been reported.
Hyponatraemia, usually in the elderly, has been associated with all types of antidepressants (see section 4.4).
Hypersensitivity: Isolated cases of allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions including hypotension have been reported.
Effects on the blood: isolated cases of agranulocytosis, bone marrow depression including leucopenia, eosinophilia and thrombocytopenia have been reported. 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)
Effects on the sense organs: tinnitus has been reported.
Miscellaneous effects: although not indicative of addiction, withdrawal symptoms may occur on abrupt cessation of therapy and include nausea, vomiting, abdominal pain, diarrhoea, headache, insomnia, nervousness, anxiety, irritability and excessive perspiration (see section 4.4).
Respiratory depression, agitation and withdrawal symptoms have been reported in neonates whose mothers received imipramine during the last trimester of pregnancy.
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 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; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
None known.
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