Amirol

Amirol tablets are indicated for:

- the treatment of major depressive disorder in adults

- the treatment of neuropathic pain in adults

- the prophylactic treatment of chronic tension type headache (CTTH) in adults

- the prophylactic treatment of migraine in adults

- the treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, have been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products. This medicinal product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis.

Posology

Not all dosage schemes can be achieved with all the pharmaceutical forms/strengths. The appropriate formulation/strength should be selected for the starting doses and any subsequent dose increments.

Major depressive disorder

Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerability.

Adults

Initially 25 mg 2 times daily (50 mg daily). If necessary, the dose can be increased by 25 mg every other day up to 150 mg daily divided into two doses.

The maintenance dose is the lowest effective dose.

Elderly patients over 65 years of age and patients with cardiovascular disease

Initially 10 mg - 25 mg daily.

The daily dose may be increased up to 100 mg - 150 mg divided into two doses, depending on individual patient response and tolerability.

Doses above 100 mg should be used with caution.

The maintenance dose is the lowest effective dose.

Paediatric population

Amirol should not be used in children and adolescents aged less than 18 years, as long term safety and efficacy have not been established.

Duration of treatment

The antidepressant effect usually sets in after 2 - 4 weeks. Treatment with antidepressants is symptomatic and must therefore be continued for an appropriate length of time usually up to 6 months after recovery in order to prevent relapse.

Neuropathic pain, prophylactic treatment of chronic tension type headache and prophylactic treatment of migraine prophylaxis

Patients should be individually titrated to the dose that provides adequate analgesia with tolerable adverse drug reactions. Generally, the lowest effective dose should be used for the shortest duration required to treat the symptoms.

Adults

Recommended doses are 25 mg - 75 mg daily in the evening. Doses above 100 mg should be used with caution.

The initial dose should be 10 mg - 25 mg in the evening. Doses can be increased with 10 mg - 25 mg every 3 - 7 days as tolerated.

The dose can be taken once daily, or be divided into two doses. A single dose above 75 mg is not recommended.

The analgesic effect is normally seen after 2 - 4 weeks of dosing.

Elderly patients over 65 years of age and patients with cardiovascular disease

A starting dose of 10 mg - 25 mg in the evening is recommended.

Doses above 75 mg should be used with caution.

It is generally recommended to initiate treatment in the lower dose range as recommended for adult. The dose may be increased depending on individual patient response and tolerability.

Paediatric population

Amirol should not be used in children and adolescents aged less than 18 years, as safety and efficacy have not been established.

Duration of treatment

Neuropathic pain

Treatment is symptomatic and should therefore be continued for an appropriate length of time. In many patients, therapy may be needed for several years. Regular reassessment is recommended to confirm that continuation of the treatment remains appropriate for the patient.

Prophylactic treatment of chronic tension type headache and prophylactic treatment of migraine in adults

Treatment must be continued for an appropriate length of time. Regular reassessment is recommended to confirm that continuation of the treatment remains appropriate for the patient.

Nocturnal enuresis

Paediatric population

The recommended doses for:

- children aged 6 to 10 years: 10 mg - 20 mg. A suitable dosage form should be used for this age group.

- children aged 11 years and above: 25 mg - 50 mg daily

The dose should be increased gradually.

Dose to be administered 1-1½ hours before bedtime.

An ECG should be performed prior to initiating therapy with Amirol to exclude long QT syndrome.

The maximum period of treatment course should not exceed 3 months.

If repeated courses of Amirol are needed, a medical review should be conducted every 3 months.

When stopping treatment, Amirol should be withdrawn gradually.

Special populations

Reduced renal function

This medicinal product can be given in usual doses to patients with renal failure.

Reduced liver function

Careful dosing and, if possible, a serum level determination is advisable.

Cytochrome P450 inhibitors of CYP2D6

Depending on individual patient response, a lower dose of Amirol should be considered if a strong CYP2D6 inhibitor (e.g. bupropion, quinidine, fluoxetine, paroxetine) is added to Amirol treatment.

Known poor metabolisers of CYP2D6 or CYP2C19

These patients may have higher plasma concentrations of Amirol and its active metabolite nortriptyline. Consider a 50% reduction of the recommended starting dose.

Method of administration

Amirol tablet is for oral use.

The tablets should be swallowed with water.

Discontinuation of treatment

When stopping therapy the drug should be gradually withdrawn during several weeks.

Recent myocardial infarction. Any degree of heart block or disorders of cardiac rhythm and coronary artery insufficiency.

Concomitant treatment with MAOIs (monoamine oxidase inhibitors) is contra-indicated.

Simultaneous administration of Amirol and MAOIs may cause serotonin syndrome (a combination of symptoms, possibly including agitation, confusion, tremor, myoclonus and hyperthermia).

Treatment with Amirol 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 Amirol.

Severe liver disease.

In children under 6 years of age.

Cardiac arrhythmias and severe hypotension are likely to occur with high dosage. They may also occur in patients with pre-existing heart disease taking normal dosage.

QT interval prolongation

Cases of QT interval prolongation and arrhythmia have been reported during the post-marketing period. Caution is advised in patients with significant bradycardia, in patients with uncompensated heart failure, or in patients concurrently taking QT-prolonging drugs. Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) are known to be conditions increasing the proarrhythmic risk.

Anaesthetics given during tri/tetracyclic antidepressant therapy may increase the risk of arrhythmias and hypotension. If possible, discontinue this medicinal product several days before surgery; if emergency surgery is unavoidable, the anaesthetist should be informed that the patient is being so treated.

Great care is necessary if Amirol is administered to hyperthyroid patients or to those receiving thyroid medication, since cardiac arrhythmias may develop.

Elderly patients are particularly susceptible to orthostatic hypotension.

This medical product should be used with caution in patients with convulsive disorders, urinary retention, prostatic hypertrophy, hyperthyroidism, paranoid symptomatology and advanced hepatic or cardiovascular disease, pylorus stenosis and paralytic ileus.

In patients with the rare condition of shallow anterior chamber and narrow chamber angle, attacks of acute glaucoma due to dilation of the pupil may be provoked.

Suicide/suicidal thoughts

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.

In manic-depressives, a shift towards the manic phase may occur; should the patient enter a manic phase Amirol should be discontinued.

As described for other psychotropics, Amirol may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients; in addition, the depressive illness itself may affect patients' glucose balance.

Hyperpyrexia has been reported with tricyclic antidepressants when administered with anticholinergic or with neuroleptic medications, especially in hot weather.

After prolonged administration, abrupt cessation of therapy may produce withdrawal symptoms such as headache, malaise, insomnia and irritability.

Amirol should be used with caution in patients receiving SSRIs.

Nocturnal enuresis

An ECG should be performed prior to initiating therapy with Amirol to exclude long QT syndrome.

Amirol for enuresis should not be combined with an anticholinergic drug.

Suicidal thoughts and behaviours may also develop during early treatment with antidepressants for disorders other than depression; the same precautions observed when treating patients with depression should therefore be followed when treating patients with enuresis.

Paediatric population

Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are not available.

Excipient Warnings

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Amirol is a sedative drug.

Patients who are prescribed psychotropic medication may be expected to have some impairment in general attention and concentration and should be cautioned about their ability to drive or operate machinery. These adverse effects can be potentiated by the concomitant intake of alcohol.

Amirol may induce side effects similar to other tricyclic antidepressants. Some of the below mentioned side effects e.g. headache, tremor, disturbance in attention, constipation and decreased libido may also be symptoms of depression and usually attenuate when the depressive state improves.

In the listing below the following convention is used:

MedDRA system organ class / preferred term;

Very common (> 1/10);

Common (> 1/100, < 1/10);

Uncommon (> 1/1,000, < 1/100);

Rare (> 1/10,000, < 1/1,000);

Very rare (<1/10,000);

Not known (cannot be estimated from the available data).

*Case reports of suicidal thoughts or behaviour were reported during the treatment with or just after conclusion of the treatment with Amirol.

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 of suspected adverse reactions

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 Yellow Card Scheme at Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow card in the google play or Apple App store.

Symptoms

Anticholinergic symptoms: Mydriasis, tachycardia, urinary retention, dry mucous membranes, reduced bowel motility. Convulsions. Fever. Sudden occurrence of CNS depression. Lowered consciousness progressing into coma. Respiratory depression.

Cardiac symptoms: Arrhythmias (ventricular tachyarrhythmias, torsade de pointes, ventricular fibrillation). The ECG characteristically show prolonged PR interval, widening of the QRS-complex, QT prolongation, T-wave flattening or inversion, ST segment depression, and varying degrees of heart block progressing to cardiac standstill. Widening of the QRS-complex usually correlates well with the severity of the toxicity following acute overdoses. Heart failure, hypotension, cardiogenic shock. Metabolic acidosis, hypokalemia.

Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose will be potentiated by simultaneous ingestion of alcohol and other psychotropic.

There is considerably individual variability in response to overdose. Children are especially susceptible to cardiotoxicity and seizures.

During awakening possibly again confusion, agitation and hallucinations and ataxia.

Treatment

1. Admission to hospital (intensive care unit) if required. Treatment is symptomatic and supportive.

2. Assess and treat ABC's (airway, breathing and circulation) as appropriate. Secure an IV access. Close monitoring even in apparently uncomplicated cases.

3. Examine for clinical features. Check urea and electrolytes—look for low potassium and monitor urine output. Check arterial blood gases—look for acidosis. Perform electrocardiograph—look for QRS>0.16 seconds

4. Do not give flumazenil to reverse benzodiazepine toxicity in mixed overdoses.

5. Consider gastric lavage only if within one hour of a potentially fatal overdose.

6. Give 50 g of charcoal if within one hour of ingestion.

7. Patency of the airway is maintained by intubation, where required. Treatment in respirator is advised to prevent a possible respiratory arrest. Continuous ECG-monitoring of cardiac function for 3-5 days. Treatment of the following will be decided on a case by case basis:

- Circulatory failure

8. Unrest and convulsions may be treated with diazepam.

9. Patients who display signs of toxicity should be monitored for a minimum of 12 hours.

10. Monitor for rhabdomyolysis if the patient has been unconscious for a considerable time.

11. Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Deaths by deliberate or accidental overdosage have occurred with this class of medicament.

For further information or treatment in children discuss with your local poisons information service in the UK NPIS 0844 892 0111.

Pharmacotherapeutic group: Antidepressants - Non-selective monoamine reuptake inhibitor (tricyclic antidepressant)

ATC code: N 06 AA 09

Mechanism of action

Amirol is a tricyclic antidepressant and an analgesic. It has marked anticholinergic and sedative properties. It prevents the re-uptake, and hence the inactivation of noradrenaline and serotonin at nerve terminals. Reuptake prevention of these monoamine neurotransmitters potentiate their action in the brain. This appears to be associated with the antidepressant activity.

The mechanism of action also includes ion-channel blocking effects on sodium, potassium and NMDA channel at both central and spinal cord level. The noradrenaline, sodium and the NMDA effects are mechanisms known to be involved in the maintenance of neuropathic pain, chronic tension type headache prophylaxis and migraine prophylaxis. The pain-reducing effect of Amirol is not linked to its anti-depressive properties.

Tricyclic antidepressants possess affinity for muscarinic and histamine H1 receptors to varying degrees.

Clinical efficacy and safety

The efficacy and safety of Amirol has been demonstrated in treatments of the following indications in adults:

- Major Depressive Disorder

- Neuropathic pain

- Chronic tension type headache prophylaxis

- Migraine prophylaxis

The efficacy and safety of Amirol has been demonstrated for treatments of nocturnal enuresis in children aged 6 years and above.

The antidepressant and analgesic effects usually set in after 2-4 weeks; the sedative action is not delayed.

Absorption

Oral administration of tablets results in maximum serum levels in about 4 hours. (t_max = 3.89±1.87 hours; range 1.93-7.98 hours). After peroral administration of 50 mg the mean C_max = 30.95±9.61 ng/ml; range 10.85-45.70 ng/ml (111.57±34.64 nmol/l; range 39.06-164.52 nmol/l). The mean absolute oral bioavailability is 53% (F_abs = 0.527±0.123; range 0.219-0.756).

Distribution

The apparent volume of distribution (V_d)_β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg).

The plasma protein binding is about 95%.

Amirol and the main metabolite nortriptyline pass across the placental barrier.

In nursing mothers Amirol and nortriptyline are excreted in small amounts with the breast milk. The ratio milk concentration/plasma concentration in women is around 1:1. The estimated daily infant exposure (Amirol + nortriptyline) averages 2% of the corresponding maternal weight related doses of Amirol (in mg/kg).

Biotransformation

In vitro the metabolism of Amirol proceeds mainly by demethylation (CYP2C19, CYP3A4) and hydroxylation (CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved are CYP1A2 and CYP2C9. The metabolism is subject to genetic polymorphism. The main active metabolite is the secondary amine, nortriptyline.

Nortriptyline is a more potent inhibitor of noradrenaline than of serotonin uptake, while Amirol inhibits the uptake of noradrenaline and serotonin equally well. Other metabolites such as cis- and trans-10-hydroxyAmirol and cis- and trans-10-hydroxynortriptyline have the same profile as nortriptyline but is considerably weaker. Demethylnortriptyline and Amirol N oxide are only present in plasma in minute amounts; the latter is almost inactive. All the metabolites are less anticholinergic than Amirol and nortriptyline. In plasma the amount of total 10-hydroxynortriptyline dominates but most of the metabolites are conjugated.

Elimination

The elimination half-life (t_½ β) Amirol after peroral administration is about 25 hours (24.65±6.31 hours; range 16.49-40.36 hours). The mean systemic clearance (Cl_s) is 39.24±10.18 L/h, range 24.53-53.73 L/h.

The excretion proceeds mainly with urine. The renal elimination of unchanged Amirol is insignificant (about 2%).

Steady state plasma levels of Amirol + nortriptyline are reached within a week for most patients, and in steady state the plasma level comprises approximately equal parts of Amirol and nortriptyline around the clock following treatment with conventional tablets 3 times a day.

Elderly patients

Longer half-lives and decreased oral (Cl_o) clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients.

Reduced hepatic function

Hepatic impairment may reduce hepatic extraction resulting in higher plasma levels and caution should be exercised when dosing these patients.

Reduced renal function

Renal failure has no influence on the kinetics.

Polymorphism

The metabolism is subject to genetic polymorphism (CYP2D6 and CYP2C19).

Pharmacokinetic/pharmacodynamic relationship

Plasma concentrations of Amirol and nortriptyline vary very widely between individuals and no simple correlation with therapeutic response has been established.

The therapeutic plasma concentration in major depression is around 80 - 200 ng/ml (≈ 280 - 700 nmol/l) (for Amirol + nortriptyline). Levels above 300-400 ng/ml are associated with increased risk of disturbance in cardiac conduction in terms of prolonged QRS-complex or AV block.

Amirol inhibited ion channels, which are responsible for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations. Therefore, Amirol may increase the risk for cardiac arrhythmia.

The genotoxic potential of Amirol has been investigated in various in vitro and in vivo studies. Although these investigations revealed partially contradictory results, particularly a potential to induce chromosome aberrations cannot be excluded. Long-term carcinogenicity studies have not been performed.

In reproductive studies, teratogenic effects were not observed in mice, rats, or rabbits when Amirol was given orally at doses of 2-40 mg/kg/day (up to 13 times the maximum recommended human Amirol dose of 150 mg/day or 3 mg/kg/day for a 50-kg patient). However, literature data suggested a risk for malformations and delays in ossification of mice, hamsters, rats and rabbits at 9 33 times the maximum recommended dose. There was a possible association with an effect on fertility in rats, namely a lower pregnancy rate. The reason for the effect on fertility is unknown.

None known

No special instructions