NORTRIPTYLINE

Posology Adults:

The usual adult dose is 25mg three or four times daily. Dosage should begin at a low level (50mg once daily or 25mg 2-3 times daily). If necessary, dose could be gradually increased in 25mg increments no more rapidly than every other day to be added to the morning dose.

When doses above 100mg daily are administered, monitoring of plasma levels of nortriptyline should be considered 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.

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. The maintenance dose should be the same as the optimal therapeutic dose. 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. Elderly: 30 to 50mg/day in divided doses. Dosage should begin at a low level (10 – 20 mg daily) and be increased as required to the maximum dose of 50mg.

If it is considered necessary to use higher dosing in an elderly patient an ECG should be checked and plasma levels of nortriptyline should be monitored. 4).

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. 5 interactions with other Medicinal products and other forms of Interaction”) Renal failure does not affect the kinetics of nortriptyline.

Duration of treatment:

The antidepressive effect usually sets in after 2-4 weeks. Treatment with antidepressants is symptomatic and should therefore be continued for a sufficient period of time, usually 6 months or longer to prevent recurrence.

Discontinuation:

Treatment should be discontinued gradually, otherwise withdrawal symptoms as headache, sleep disturbances, irritability and malaise could develop. These symptoms are not indicative of addiction Method of administration For oral administration

and Section

Paediatric population Use in children and adolescents under the age of 18 Nortriptyline should not be used in the treatment of depression in children and adolescents under the age of 18 years. Studies in depression of this age group did not show a beneficial effect for class of tricyclic antidepressants.

Studies with other classes of antidepressants (SSRI’s and SNRI’s) have shown risk of suicidality, self- harm and hostility to be related to these compounds. This risk cannot be excluded with nortriptyline. In addition, nortriptyline is associated with a risk of cardiovascular adverse events in all age groups.

) 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 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.

Withdrawal symptoms, including insomnia, irritability, nausea, headache 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.

Caution should be exercised when treating patients with advanced liver disease. Patients with cardiovascular disease or hypotension 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. Arrhythmias and hypotension can occur in patients without prior risk, especially when high doses are prescribed. Therefore patients who receive high doses should be followed up for arrhythmias and hypotension Great care is necessary if nortriptyline is administered to hyperthyroid patients or to those receiving thyroid medication, since cardiac arrhythmias may develop.

Unmasking of Brugada syndrome has been reported in patients treated with nortriptyline. Brugada syndrome is a rare hereditary disease of the cardiac sodium channel with characteristic ECG changes (ST segment elevation and T wave abnormalities in the right precordial leads), which may lead to cardiac arrest and/or sudden death.

Nortriptyline should generally be avoided in patients with Brugada syndrome or those suspected of having Brugada syndrome. 9). g. 5). g. includes buprenorphine/naloxone) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

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, other anti-cholinergic reactions and postural hypotension. Troublesome hostility in a patient may be aroused by the use of nortriptyline.

If possible, the use of nortriptyline should be avoided in patients with narrow angle glaucoma, raised intra-ocular pressure or symptoms suggestive of urinary retention or 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, […]

1 • Recent myocardial infarction, any degree of heart block or other cardiac arrhythmias • Severe liver disease • Mania • Nortriptyline is contraindicated for the nursing mother. 5.