SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Allegron Tablets 10 mg Nortriptyline 10 mg Tablets

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Tablets each containing Nortriptyline Hydrochloride EP equivalent to 10mg nortriptyline base tablets are white, unscored and have a diameter of 5.5mm. They are marked 'KING’.

3. PHARMACEUTICAL FORM

Tablet

4. CLINICAL PARTICULARS

4.1 Therapeutic 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.

4.2 Posology and method of administration

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 P45011D6. 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
8-11	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.

4.3 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.

4.4 Special warnings and precautions for use

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, imtability 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.

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).

4.5 Interactions with other medicinal products and other forms of interaction

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.

4.6 Pregnancy and lactation

Usage in pregnancy: The safety of nortriptyline for use during pregnancy has not been established, nor is there evidence from animal studies that it is free from hazard; therefore the drug should not be administered to pregnant patients or women of childbearing age unless the potential benefits clearly outweigh any potential risk.

Usage in nursing mothers: See ‘Contra-indications’.

4.7 Effects on ability to drive and use machines

Nortriptyline may impair the mental and/or physical abilities required for the performance of hazardous tasks, such as operating machinery or driving a car; therefore the patient should be warned accordingly.

4.8 Undesirable effects

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 after treatment discontinuation (see section 4.4).

Neurological: Numbness, tingling, paraesthesia of extremities; incoordination, 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.

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.

4.9 Overdose

Signs and symptoms: 50mg of a tricyclic antidepressant can be an overdose in a child. Of patients who are alive at presentation, mortality of 0-15% has been reported. Symptoms may begin within several hours and may include blurred vision, confusion, restlessness, dizziness, hypothermia, hyperthermia, agitation, vomiting, hyperactive reflexes, dilated pupils, fever, rapid heart rate, decreased bowel sounds, dry mouth, inability to void, myoclonic jerks, seizures, respiratory depression, myoglobinuric renal failure, nystagmus, ataxia, dysarthria, choreoathetosis, coma, hypotension and cardiac arrhythmias. Cardiac conduction may be slowed, with prolongation of QRS complex and QT intervals, right bundle branch and AV block, ventricular tachyarrhythmias (including Torsade de pointes and fibrillation) and death. Prolongation of QRS duration to more than l00msec is predictive of more severe toxicity. The absence of sinus tachycardia does not ensure a benign course. Hypotension may be caused by vasodilatation, central and peripheral alpha-adrenergic blockade and cardiac depression. In a healthy young person, prolonged resuscitation may be effective; one patient survived 5 hours of cardiac massage.

Treatment: Symptomatic and supportive therapy is recommended. Activated charcoal may be more effective than emesis or lavage to reduce absorption.

Ventricular arrhythmias, especially when accompanied by lengthened QRS intervals, may respond to alkalinisation by hyperventilation or administration of sodium bicarbonate. Serum electrolytes should be monitored and managed. Refractory arrhythmias may respond to propranolol, bretylium or lignocaine. Quinidine and procainamide usually should not be used because they may exacerbate arrhythmias and conduction already slowed by the overdose.

Seizures may respond to diazepam. Phenytoin may treat seizures and cardiac rhythm disturbances. Physostigmine may antagonise atrial tachycardia, gut immotility, myoclonic jerks and somnolence. The effects of physostigmine may be short-lived.

Diuresis and dialysis have little effect. Haemoperfusion is unproven. Monitoring should continue, at least until the QRS duration is normal.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Nortriptyline is a tricyclic antidepressant with actions and uses similar to those of Amitriplyline. It is the principal active metabolite of Amitriplyline.

In the treatment of depression Nortriptyline is given by mouth as the hydrochloride in doses equivalent to Nortriptyline 10mg 3 or 4 times daily initially, gradually increased to 25mg 4 times daily as necessary. A suggested initial dose for adolescents and the elderly is 10mg thrice daily.

Inappropriately high plasma concentrations of Nortriptyline have been associated with deterioration in antidepressant response. Since Nortriptyline has prolonged half-life, once daily dosage regimens are also suitable, usually given at night.

5.2 Pharmacokinetic properties

Parts of metabolism of Nortriptyline include hydroxylation (possibly to active metabolites). N-oxidation and conjugation with glucuronic acid. Nortriptyline is widely distributed throughout the body and is extensively bound to plasma and tissue protein. Plasma concentrations of Nortriptyline vary very widely between individuals and no simple correlation with therapeutic response has been established.

Preclinical safety data

There are no preclinical data of relevance to the prescriber.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Maize Starch, Magnesium Stearate, Lactose Monohydrate, Calcium Phosphate, Purified Water.

Coat: Glycerol, Methylhydroxpropyl Cellulose.

6.2    Incompatibilities

None stated.

6.3    Shelf life

36 months.

6.4    Special precautions for storage

No special requirements.

6.5    Nature and contents of container

High density polyethylene bottles containing 100 and 500 tablets. UPVC blister strips with aluminium foil backing containing 25 tablets.

6.6    Instructions for use/handling

Not applicable.

7 MARKETING AUTHORISATION HOLDER

King Pharmaceuticals Ltd Donegal Street Ballybofey County Donegal

8.    MARKETING AUTHORISATION NUMBER

PL 14385/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/06/2010

10 DATE OF REVISION OF THE TEXT

19/11/2010