NORTRIPTYLINE

Posology 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 usually at night. 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. 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 50 mg/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.

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.

Cytochrome P450 isoenzyme CYP2D6 and poor metabolisers Many antidepressants (tricyclic antidepressants, including nortriptyline, selective serotonin re- uptake inhibitors and others) are metabolised by the hepatic cytochrome P450 isoenzyme P450IID6 CYP2D6.

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.

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.

In the listing below the following convention is used:

MedDRA system organ class / preferred term 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); very rare (<1/10,000); not known (cannot be estimated from the available data) MedDRA SOC Frequency Preferred Term Blood and lymphatic system disorders Rare Bone marrow depression, agranulocytosis, leucopenia, eosinophilia, thrombocytopenia.

Endocrine disorders Not Known Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Metabolism and nutrition disorders Rare Decreased appetite. Not Known changes of blood sugar Levels Hyponatraemia Psychiatric disorders Very common Aggression Common Confusional state, libido decreased, agitation Uncommon Hypomania, mania, anxiety, insomnia, nightmare Rare Delirium (in elderly patients), hallucination (in schizophrenic patients).

Not Known *Suicidal ideation and suicidal behaviour, Paranoia Nervous system disorders Very common Tremor, dizziness, headache. Common Disturbance in attention, dysgeusia, paresthesia, ataxia. Uncommon Convulsion. Rare akathisia, dyskinesia Not Known Extrapyramidal disorder Eye disorders Very common Accommodation disorder.

Common Mydriasis. Very rare Acute glaucoma Ear and labyrinth disorders Uncommon Tinnitus. Cardiac disorders Very common Palpitations, tachycardia Common Atrioventricular block, bundle branch block. Uncommon Collapse conditions, worsening of cardiac Failure Rare Arrhythmia.

Very rare Cardiomyopathies, torsades de pointes Not Known Hypersensitivity Myocarditis Brugada Syndrome (unmasking) (frequency unknown) Vascular disorders Common Orthostatic hypotension. Uncommon Hypertension Not known Hyperthermia Respiratory, thoracic, and mediastinal disorders Very common Congested nose.

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 behavior 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 behavior 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.

1. Recent myocardial infarction, any degree of heart block or other cardiac arrhythmias and coronary insufficiency. Severe liver disease. Mania. 5). Simultaneous administration of nortriptyline and MAOIs may cause serotonin syndrome (a combination of symptoms, possibly including agitation, confusion, tremor, myoclonus and hyperthermia).

Treatment with nortriptyline may be instituted 14 days after discontinuation of irreversible non- selective MAOIs and minimum one day after discontinuation of the reversible moclobemide. Treatment with MAOIs may be introduced 14 days after discontinuation of nortriptyline.