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Drug Details

ALLEGRON

• Drug Class Description
  Tricyclic antidepressants (TCADs) .
• Generic Name
  Nortriptyline
• Presentation
  Tablets
• Description
  Tablets containing Nortriptyline Hydrochloride EP equivalent to 10mg nortriptyline base tablets are white, unscored and have a diameter of 5.5mm. Marked 'KING'. Tablets containing Nortriptyline Hydrochloride EP equivalent to 25mg nortriptyline base tablets are orange, scored and have a diameter of 8mm. Marked 'KING'.
• Indications
  Allegron is indicated for the relief of symptoms of depression. It may also be used for the treatment of some cases of nocturnal enuresis.
• Adult Dosage
  

  For oral administration.

  Adults: The usual adult dose is 25mg three or four times daily. Dosage should begin at a low level and be increased as required. Alternatively, the total daily dose may be given once a day. When doses above 100mg daily are administered, plasma levels of nortriptyline should be monitored and maintained in the optimum range of 50 to 150ng/ml. Doses above 150mg per day are not recommended.

  Lower than usual dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients than for hospitalised patients who will be under close supervision. The physician should initiate dosage at a low level and increase it gradually, noting carefully the clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission.

  If a patient develops minor side-effects, the dosage should be reduced. The drug should be discontinued promptly if adverse effects of a serious nature or allergic manifestations occur.

  The elderly: 30 to 50mg/day in divided doses.

  Adolescent patients: 30 to 50mg/day in divided doses.

  Plasma levels: Optimal responses to nortriptyline have been associated with plasma concentrations of 50 to 150ng/ml. Higher concentrations may be associated with more adverse experiences. Plasma concentrations are difficult to measure, and physicians should consult the laboratory professional staff.

  Many antidepressants (tricyclic antidepressants, including nortriptyline, selective serotonin re-uptake inhibitors and others) are metabolised by the hepatic cytochrome P450 isoenzyme P450IID6. Three to ten per cent of the population have reduced isoenzyme activity ('poor metabolisers') and may have higher than expected plasma concentrations at usual doses. The percentage of 'poor metabolisers' in a population is also affected by its ethnic origin.

  Older patients have been reported to have higher plasma concentrations of the active nortriptyline metabolite 10-hydroxynortriptyline. In one case, this was associated with apparent cardiotoxicity, despite the fact that nortriptyline concentrations were within the 'therapeutic range'. Clinical findings should predominate over plasma concentrations as primary determinants of dosage changes.

  Children: (for nocturnal enuresis only).

  Age (years)	Weight		Dose (mg)
  	kg	lb
  6-7	20-25	44-55	10
  8-1	25-35	55-77	10-20
  >11	35-54	77-119	25-35

  The dose should be administered thirty minutes before bedtime.

  The maximum period of treatment should not exceed three months. A further course of treatment should not be started until a full physical examination, including an ECG, has been made.

• Child Dosage
  Enuresis, under 6 years, not recommended; over 6 years, 10 - 35 mg 30 minutes before bedtime. See data sheet.
• Elderly Dosage
  Initially 10 mg three times daily.
• Contra Indications
  

  Hypersensitivity to nortriptyline.

  Recent myocardial infarction, any degree of heart block or other cardiac arrhythmias.

  Severe liver disease.

  Mania.

  Nortriptyline is contra-indicated for the nursing mother and for children under the age of six years.

  Please also refer to 'Drug interactions' section.

• Special Precautions
  

  Warnings: As improvement may not occur during the initial weeks of therapy, patients, especially those posing a high suicidal risk, should be closely monitored during this period.

  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 this 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 tan 25 years old.

  Close supervision of patients and in particular those at high risk should accompany drug therapy in early treatment and following dose changes. Patients (an 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.

  Withdrawal symptoms, including insomnia, irritability and excessive perspiration, may occur on abrupt cessation of therapy.

  The use of nortriptyline in schizophrenic patients may result in an exacerbation of the psychosis or may activate latent schizophrenic symptoms. If administered to overactive or agitated patients, increased anxiety and agitation may occur. In manic-depressive patients, nortriptyline may cause symptoms of the manic phase to emerge.

  Cross sensitivity between nortriptyline and other tricyclic antidepressants is a possibility.

  Patients with cardiovascular disease should be given nortriptyline only under close supervision because of the tendency of the drug to produce sinus tachycardia and to prolong the conduction time. Myocardial infarction, arrhythmia and strokes have occurred. Great care is necessary if nortriptyline is administered to hyperthyroid patients or to those receiving thyroid medication, since cardiac arrhythmias may develop.

  The use of nortriptyline should be avoided, if possible, in patients with a history of epilepsy. If it is used, however, the patients should be observed carefully at the beginning of treatment, for nortriptyline is known to lower the convulsive threshold.

  The elderly are particularly liable to experience adverse reactions, especially agitation, confusion and postural hypotension.

  Troublesome hostility in a patient may be aroused by the use of nortriptyline.

  Behavioural changes may occur in children receiving therapy for nocturnal enuresis.

  If possible, the use of nortriptyline should be avoided in patients with narrow angle glaucoma or symptoms suggestive of prostatic hypertrophy.

  The possibility of a suicide attempt by a depressed patient remains after the initiation of treatment. This possibility should be considered in relation to the quantity of drug dispensed at any one time.

  When it is essential, nortriptyline may be administered with electroconvulsive therapy, although the hazards may be increased.

  Both elevation and lowering of blood sugar levels have been reported. Significant hypoglycaemia was reported in a Type II diabetic patient maintained on chlorpropamide (250mg/day), after the addition of nortriptyline (125mg/day).

• Interactions
  

  Drug interactions: Under no circumstances should nortriptyline be given concurrently with, or within two weeks of cessation of, therapy with monoamine oxidase inhibitors. Hyperpyretic crises, severe convulsions and fatalities have occurred when similar tricyclic antidepressants were used in such combinations.

  Nortriptyline should not be given with sympathomimetic agents such as adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine and phenylpropanolamine.

  Nortriptyline may decrease the antihypertensive effect of guanethidine, debrisoquine, bethanidine and possibly clonidine. Concurrent administration of reserpine has been shown to produce a 'stimulating' effect in some depressed patients. It would be advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.

  Barbiturates may increase the rate of metabolism of nortriptyline.

  Anaesthetics given during tricyclic antidepressant therapy may increase the risk of arrhythmias and hypotension. If surgery is necessary, the drug should be discontinued, if possible, for several days prior to the procedure, or the anaesthetist should be informed if the patient is still receiving therapy.

  Tricyclic antidepressants may potentiate the CNS depressant effect of alcohol.

  The potentiating effect of excessive consumption of alcohol may lead to increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation.

  Steady-state serum concentrations of the tricyclic antidepressants are reported to fluctuate significantly as cimetidine is either added to or deleted from the drug regimen. Higher than expected steady-state serum concentrations of the tricyclic antidepressant have been observed when therapy is initiated in patients already taking cimetidine. A decrease may occur when cimetidine therapy is discontinued.

  Because nortriptyline's metabolism (like other tricyclic and SSRI antidepressants) involves the hepatic cytochrome P450IID6 isoenzyme system, concomitant therapy with drugs also metabolised by this system may lead to drug interactions. Lower doses than are usually prescribed for either the tricyclic antidepressant or the other drug may therefore be required.

  Greater than two-fold increases in previously stable plasma levels of nortriptyline have occurred when fluoxetine was administered concomitantly. Fluoxetine and its active metabolite, norfluoxetine, have long half-lives (4-16 days for norfluoxetine).

  Concomitant therapy with other drugs that are metabolised by this isoenzyme, including other antidepressants, phenothiazines, carbamazepine, propafenone, flecainide and encainide, or that inhibit this enzyme (eg, quinidine), should be approached with caution.

  Supervision and adjustment of dosage may be required when nortriptyline is used with other anticholinergic drugs.

• Adverse Drug Reactions
  

  Included in the following list are a few adverse reactions that have not been reported with this specific drug. However, the pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when nortriptyline is administered.

  Cardiovascular: Hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke.

  Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia, panic, nightmares; hypomania; exacerbation of psychosis. Cases of suicidal ideation and suicidal behaviours have been reported during nortriptyline therapy or early treatment discontinuation.

  Neurological: Numbness, tingling, paraesthesia of extremities; inco-ordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alteration of EEG patterns; tinnitus.

  Anticholinergic: Dry mouth and, rarely, associated sublingual adenitis or gingivitis; blurred vision, disturbance of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract.

  Allergic: Rash, petechiae, urticaria, itching, photosensitisation (avoid excessive exposure to sunlight); oedema (general or of face and tongue), drug fever, cross-sensitivity with other tricyclic drugs.

  Haematological: Bone-marrow depression, including agranulocytosis; aplastic anaemia; eosinophilia; purpura; thrombocytopenia.

  Gastro-intestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhoea; peculiar taste, stomatitis, abdominal cramps, black tongue, constipation, paralytic ileus.

  Endocrine: Gynaecomastia in the male; breast enlargement and galactorrhoea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; syndrome of inappropriate secretion of antidiuretic hormone.

  Other: Jaundice (simulating obstructive); altered liver function, hepatitis and liver necrosis; weight gain or loss; sweating; flushing; urinary frequency, nocturia; drowsiness, dizziness, weakness, fatigue; headache; parotid swelling; alopecia.

  Withdrawal symptoms: Though these are not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache and malaise.