Amitriptyline10mg Tabs 28s UK

UGX15,000.00

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Name of the medicinal product

AMITRIPTYLINE TABLETS BP 10mg

2. Qualitative and quantitative composition

Each tablet contains 10mg Amitriptyline Hydrochloride.

Excipient with known effect:

Each tablet contains 54.50 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Blue film-coated tablets.

4. Clinical particulars
4.1 Therapeutic indications

Amitriptyline is 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.

4.2 Posology and method of administration

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 100mg – 150mg, divided into two doses, depending on individual patient response and tolerability.

Daily doses above 100mg should be used with caution.

The maintenance dose is the lowest effective dose.

Paediatric population

Amitriptyline should not be used in children and adolescents aged less than 18 years, as long term safety and efficacy have not been established (see section 4.4).

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 in adults

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 25mg – 75mg 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 10mg – 25mg in the evening is recommended. Doses above 75mg should be used with caution.

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

Paediatric population

Amitriptyline should not be used in children and adolescents aged less than 18 years, as long term safety and efficacy have not been established (see section 4.4).

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 the 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 the continuation of the treatment remains appropriate for the patient.

Nocturnal enuresis

Paediatric population

The recommended doses for:

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

• children aged 11 years and above: 25mg – 50mg 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 amitriptyline to exclude long QT syndrome.

Duration of treatment

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

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

When stopping treatment, amitriptyline 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 amitriptyline should be considered if a strong CYP2D6 inhibitor (e.g. bupropion, quinidine, fluoxetine, paroxetine) is added to amitriptyline treatment (see section 4.5).

Known poor metabolisers of CYP2D6 or CYP2C19

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

Method of administration

Amitriptyline is for oral use.

The tablets should be swallowed with water.

Discontinuation of treatment

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

4.3 Contraindications

• Hypersensitivity to the active substance, tricyclic antidepressants or to any of the excipients listed in section 6.1;

• 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 contraindicated (see section 4.5).

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

• Treatment with amitriptyline 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 amitriptyline.

• Severe liver disease.

• Porphyria.

• In children under 6 years of age.

4.4 Special warnings and precautions for use

Amitriptyline should be used with caution in patients with a history of epilepsy, and in those with impaired liver function or phaeochromocytoma.

Blood sugar concentrations may be altered in diabetic patients.

When used for the depressive component of schizophrenia, amitriptyline may aggravate psychotic symptoms.

Cardiac arrhythmias and severe hypotension are likely to occur with high dosage. They may also occur in patients with pre-existing heart disease taking the 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 amitriptyline 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 the 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 a 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 manic phase amitriptyline should be discontinued.

As described for other psychotropics, amitriptyline 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.

Amitriptyline should be used with caution in patients receiving SSRIs (see sections 4.2 and 4.5).

Nocturnal enuresis

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

Amitriptyline 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 (see section 4.2).

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Potential for amitriptyline to affect other medicinal products

Analgesics: increased anticholinergic side-effects with nefopam; increased analgesia with morphine. Increased risk of CNS toxicity when tricyclics are given with tramadol.

Muscle relaxants: Tricyclics enhance muscle relaxant effect of baclofen.

Nitrates: reduced effect of sublingual nitrates (owing to dry mouth).

Contraindicated combinations

MAOIs (non-selective as well as selective A (moclobemide) and B (selegiline)) – the risk of “serotonin syndrome” (see section 4.3).

Combinations that are not recommended

Sympathomimetic agents: Amitriptyline may potentiate the cardiovascular effects of adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine (e.g. as contained in local and general anaesthetics and nasal decongestants).

Adrenergic neurone blockers: Tricyclic antidepressants may counteract the antihypertensive effects of centrally acting antihypertensives such as guanethidine, betanidine, reserpine, clonidine and methyldopa. It is advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants. There is an increased risk of hypertension on clonidine withdrawal.

Anticholinergic agents: Tricyclic antidepressants may potentiate the effects of these drugs on the eye, central nervous system, bowel and bladder; concomitant use of these should be avoided due to an increased risk of paralytic ileus, hyperpyrexia, etc.

Drugs which prolong the QT-interval including antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, some antipsychotics (notably pimozide and sertindole), cisapride, halofantrine, and sotalol, may increase the likelihood of ventricular arrhythmias when taken with tricyclic antidepressants.

Use caution when using amitriptyline and methadone concomitantly due to a potential for additive effects on the QT interval and increased risk of serious cardiovascular effects.

Caution is also advised for co-administration of amitriptyline and diuretics inducing hypokalaemia (e.g. furosemide)

Thioridazine: Co-administration of amitriptyline and thioridazine (CYP2D6 substrate) should be avoided due to inhibition of thioridazine metabolism and consequently increased risk of cardiac side effects

Tramadol: Concomitant use of tramadol (a CYP2D6 substrate) and tricyclic antidepressants (TCAs), such as amitriptyline increases the risk for seizures and serotonin syndrome. Additionally, this combination can inhibit the metabolism of tramadol to the active metabolite and thereby increasing tramadol concentrations potentially causing opioid toxicity.

Antifungals such as fluconazole and terbinafine increase serum concentrations of tricyclics and accompanying toxicity. Syncope and torsade de pointes have occurred.

Combinations requiring precautions for use

CNS depressants: Amitriptyline may enhance the sedative effects of alcohol, barbiturates and other CNS depressants.

The potential of other medicinal products to affect amitriptyline

Tricyclic antidepressants (TCA) including amitriptyline are primarily metabolised by the hepatic cytochrome P450 isozymes CYP2D6 and CYP2C19, which are polymorphic in the population. Other isozymes involved in the metabolism of amitriptyline are CYP3A4, CYP1A2 and CYP2C9.

CYP2D6 inhibitors: The CYP2D6 isozyme can be inhibited by a variety of drugs, e.g. neuroleptics, serotonin reuptake inhibitors, beta-blockers, and antiarrhythmics. Examples of strong CYP2D6 inhibitors include bupropion, fluoxetine, paroxetine and quinidine. These drugs may produce substantial decreases in TCA metabolism and marked increases in plasma concentrations. Consider monitoring TCA plasma levels, whenever a TCA is to be co-administered with another drug known to be an inhibitor of CYP2D6. Dose adjustment of amitriptyline may be necessary (see section 4.2).

Other Cytochrome P450 inhibitors: Cimetidine, methylphenidate and calcium-channel blockers (e.g. diltiazem and verapamil) may increase plasma levels of tricyclic antidepressants and accompanying toxicity. Antifungals such as fluconazole (CYP2C9 inhibitor) and terbinafine (a CYP2D6 inhibitor) have been observed to increase serum levels of amitriptyline and nortriptyline.

The CYP3A4 and CYP1A2 isozymes metabolise amitriptyline to a lesser extent. However, fluvoxamine (strong CYP1A2 inhibitor) was shown to increase amitriptyline plasma concentrations and this combination should be avoided. Clinically relevant interactions may be expected with concomitant use of amitriptyline and strong CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir.

Tricyclic antidepressants and neuroleptics mutually inhibit the metabolism of each other; this may lead to a lowered convulsion threshold and seizures. It may be necessary to adjust the dosage of these drugs.

Cytochrome P450 inducers: Oral contraceptives, rifampicin, phenytoin, barbiturates, carbamazepine and St. John’s Wort (Hypericum perforatum) may increase the metabolism of tricyclic antidepressants and result in lowered plasma levels of tricyclic antidepressants and reduced antidepressant response.

In the presence of ethanol amitriptyline, free plasma concentrations and nortriptyline concentrations were increased.

Amitriptyline plasma concentration can be increased by sodium valproate and valpromide. Clinical monitoring is therefore recommended.

4.6 Fertility, pregnancy and lactation

Pregnancy

For amitriptyline only limited clinical data are available regarding exposed pregnancies. Animal studies have shown reproductive toxicity (see section 5.3).

Amitriptyline is not recommended during pregnancy unless clearly necessary and only after careful consideration of the risk/benefit.

During chronic use and after administration in the final weeks of pregnancy, neonatal withdrawal symptoms can occur. This may include irritability, hypertonia, tremor, irregular breathing, poor drinking and loud crying and possibly anticholinergic symptoms (urinary retention, constipation).

Breast-feeding

Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % – 1 % of the maternal dose). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from the therapy of this medicinal product taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

Amitriptyline reduced the pregnancy rate in rats (see section 5.3).

No data on the effects of amitriptyline on human fertility are available.

4.7 Effects on ability to drive and use machines

Amitriptyline 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.

4.8 Undesirable effects

Amitriptyline 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 (> 1/1000, < 1/100);

Rare (> 1/10,000, < 1/1000);

Very Rare (< 1/10,00);

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

MedDRA SOC Frequency Preferred term
Blood and lymphatic system disorders Rare Bone marrow depression including agranulocytosis, eosinophilia, leucopenia, thrombocytopenia
Metabolism and nutrition disorders Rare Decreased appetite
Not known Elevation or lowering of blood sugar levels. Anorexia.
Psychiatric disorders Very common Aggression.
Common Confusional states, libido decrease, agitation.
Uncommon Hypomania, mania, anxiety, insomnia, nightmares,
Rare Delirium (in elderly patients), hallucinations, suicidal thoughts or behaviour*.
Not known Paranoia.
Nervous system disorders Very common Somnolence, tremors, dizziness, headache, drowsiness, speech disorders (dysarthria).
Common Disturbance in attention, dysgeusia, paraesthesia, ataxia.
Uncommon Convulsions.
Very Rare Akathisia, polyneuropathy.
Not known Extrapyramidal disorder.
Eye disorders Very common Accommodation disorder.
Common Mydriasis.
Very rare Acute glaucoma.
Not known Dry eye
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 Arrhythmias.
Very rare Cardiomyopathies, torsades de pointes.
Not known Hypersensitivity myocarditis.
Vascular disorders Very common Orthostatic hypotension.
Uncommon Hypertension.
Not known Hyperthermia.
Respiratory, thoracic, and mediastinal disorders Very common Congested nose.
Very rare Allergic inflammation of the pulmonary alveoli and of the lung tissue, respectively (alveolitis, Löffler’s syndrome).
Gastrointestinal disorders Very common Dry mouth, constipation, nausea.
Uncommon Diarrhoea, vomiting, tongue oedema.
Rare Salivary gland enlargement, ileus paralytic.
Not known Epigastric distress, stomatitis.
Hepatobiliary disorders Rare Jaundice.
Uncommon Hepatic impairment (e.g. cholestatic liver disease).
Not known Hepatitis.
Skin and subcutaneous tissue disorders Very common Hyperhidrosis.
Uncommon Rash, urticaria, face oedema.
Rare Alopecia, photosensitivity reaction.
Not known Pruritis
Renal and urinary disorders Common Micturition disorders.
Uncommon Urinary retention.
Reproductive system and breast disorders Common Erectile dysfunction.
Uncommon Galactorrhoea.
Rare Gynaecomastia.
General disorders and administration site conditions Common Fatigue, feeling thirst.
Rare Pyrexia.
Investigations Very common Weight increased.
Common Electrocardiogram abnormal, electrocardiogram QT prolonged, electrocardiogram QRS complex prolonged, hyponatremia.
Uncommon Intraocular pressure increased.
Rare Weight decreased. Liver function test abnormal, blood alkaline phosphatase increased, transaminases increased.

*Case reports of suicidal thoughts or behaviour were reported during the treatment with or just after the conclusion of the treatment with amitriptyline (see section 4.4).

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 increased risk is unknown.

Side-effects in enuresis

Behavioural changes have been observed in children receiving tricyclics for treatments of enuresis. Dosages used in enuresis are low compared with those used in depression and side-effects are therefore less frequent. The most common are drowsiness and anticholinergic effects. The only other side-effects reported infrequently at these dosages, have been mild sweating and itching. The recommended dosage must not be exceeded.

Withdrawal symptoms:

The symptoms associated with withdrawal of tricyclic antidepressants, particularly after prolonged administration, include gastrointestinal disturbances such as nausea; generalised somatic symptoms such as malaise, chills, headache and increased perspiration; irritability, restlessness, anxiety and agitation; sleep disturbances (insomnia and vivid dreams); parkinsonism or akathisia; hypomania or mania (reported rarely, occurring within 2-7 days of stopping chronic therapy with tricyclic antidepressants); cardiac arrhythmias. These symptoms are not indicative of addiction. Withdrawal symptoms seem to be more common and more severe in children.

Adverse reactions such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers had taken tricyclic antidepressants in the last trimester of pregnancy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product are 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 the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

Anticholinergic symptoms: Mydriasis, tachycardia, urinary retention, dry mucous membranes, reduced bowel motility. Convulsions. Fever. Sudden occurrence of CNS depression. Lowered consciousness progressing into a coma. Respiratory depression. Hyperreflexia may be present with extensor plantar reflexes. Hypothermia may occur.

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 a 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, hyponatraemia.

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 psychotropics. There is considerable individual variability in response to overdose. Children are especially susceptible to cardiotoxicity, seizures and hyponatraemia.

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

1. Admission to a 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 a 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:

– Wide QRS-intervals, cardiac failure and ventricular arrhythmias

– Circulatory failure

– Hypotension

– Hyperthermia

– Convulsions

– Metabolic acidosis.

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.

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