Amitriptyline 25mg Tablets Bp
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Amitriptyline 25mg Tablets BP
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 25 mg of Amitriptyline Hydrochloride For excipients see 6.1
3 PHARMACEUTICAL FORM
Coated tablet
Pale Yellow, Circular, deep convex, sugar-coated tablets
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Amitriptyline is an anti-depressant of the tricyclic group. It is indicated for symptoms of a depressive illness especially when sedation is required.
Amitriptyline is also effective in nocturnal enuresis where organic pathology is excluded.
4.2 Posology and method of administration
Route of administration: Oral Adults:
Initial Dose: Usually 50-75mg daily in divided doses, or as a single dose at night. This may be increased, if required, to a total of 150-200mg daily according to clinical response, the additional doses being given in the late afternoon and/or at bedtime. Although the sedative effect is usually achieved rapidly, the antidepressant activity may not be apparent for three or four days and may take up to 30 days to develop adequately.
Maintenance dose: Usually 50 to 100mg daily and the total dosage may be taken as a single dose, preferably in the evening or at bedtime. When satisfactory improvement has been achieved, dosage should be reduced to the lowest amount necessary to maintain control of symptoms. Maintenance therapy should be continued for at least three months in order to reduce the possibility of relapse.
Adolescents and the elderly:
25-50mg daily in divided doses or as a single dose at night. Half the normal maintenance dose may be sufficient to produce a satisfactory clinical response
Children
Not recommended for treatment of depression in children under 16 years of age due to a lack of clinical experience.
For nocturnal enuresis only. The maximum period of treatment (including gradual withdrawal) 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.
Children aged 11-16 years may receive 25 to 50 mg a day.
(7-10 years): A more suitable dosage form should be used for this age group. This product is unsuitable for use in children under 10 years of age.
(Under 7 years): Not recommended for this age group.
4.3 Contraindications
• prior sensitisation to amitriptyline; hypersensitivity to tricyclic antidepressants or to any of the ingredients in the tablets
• history of myocardial infarction, arrhythmias, particularly heart block of any degree congestive heart failure, coronary artery insufficiency
• mania
• severe liver disease
• lactation
• children under 7 years of age
• porphyria
• concomitant use of tricyclic antidepressants with amiodarone or sibutramine
• co-administration with monoamine oxidase inhibitors or have taken them within the last 14 days
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.
Suicidal thoughts and behaviours may also develop during early treatment with antidepressants for other disorders, the same precautions observed when treating patients with depression should therefore be followed when treating patients with other disorders.
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.
General: Amitriptyline should be used with caution in patients with a history of epilepsy, in patients with impaired liver function, blood dyscrasias and because of its atropine-like action, in patients with a history of urinary retention, prostatic hypertrophy, narrow-angle glaucoma or increased intra-ocular pressure. In patients with narrow-angle glaucoma, even average doses may precipitate an attack of glaucoma.
Cardiac arrhythmias and severe hypotension are likely to occur with high dosages or in patients with pre-existing heart disease. There has been a report of fatal dysrhythmia occurring as late as 56 hours after amitriptyline overdose.
If possible, discontinue amitriptyline several days before surgery. But if emergency surgery is unavoidable, the anaesthetist should be informed that the patient is being treated with amitriptyline, because anaesthesia may increase the risk of hypotension and arrhythmias. (see section 4.5)
Hyperpyrexia has been reported when tricyclic anti-depressants are administered with anticholinergic agents or with neuroleptic drugs, particularly during hot weather.
Amitriptyline may impair alertness in some patients and activities made hazardous by diminished alertness (e.g. driving a car) should be avoided.
Elderly patients are particularly liable to experience adverse reactions: especially agitation, confusion and postural hypotension.
Cardiovascular/endocrine disorders: Patients with cardiovascular disorders, hyperthyroid patients and those receiving thyroid medication or anticholinergic agents should be closely supervised and the dosage of all medications carefully adjusted.
Central nervous system disorders: When amitriptyline is used for the depressive component of schizophrenia, psychotic symptoms may be aggravated. In manic-depressives, a shift towards the manic phase may occur. Paranoid delusions, with or without associated hostility, may be aggravated. In such cases, a major tranquilliser should be given concurrently, or the dosage of amitriptyline reduced.
Use in children: Behavioural changes have been observed in children receiving amitriptyline (tricyclics) for the treatment of nocturnal enuresis.
Unless essential it is inadvisable to combine amitriptyline and electroconvulsive therapy (ECT) [see section 4.5 “Interactions”].
Abrupt withdrawal of amitriptyline should be avoided (see section 4.8 “Undesirable Effects, Other reactions”).
Hyponatraemia (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants and should be considered in all patients who develop drowsiness, confusion or convulsions while taking an antidepressant (see section 4.8 “Undesirable Effects, Endocrine”).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Alcohol: Enhances the sedative effect.
Alpha2-adrenoceptor stimulants: Concomitant use of apraclonidine and brimonidine should be avoided.
Other antidepressant drugs: Concomitant use with MAO Is results in CNS excitation and hypertension. The concurrent use of antidepressants having varying modes of action should be made only with due recognition of their possible potentiation and with a thorough knowledge of their respective pharmacologies. Monoamine oxidase inhibitors can potentiate the effects of tricyclic antidepressants such as amitriptyline, and hyperpyretic crises, severe convulsions, and fatalities have occurred. Therefore amitriptyline should not be given with a MAOI and a minimum of 14 days should elapse between discontinuing an MAOI and starting amitriptyline, which should be introduced cautiously and dosage increased gradually. Concomitant use of reboxetine should be with caution. The plasma concentrations of some tricyclics are increased by SSRIs. Fluoxetine markedly inhibits Cytochrome P450 II D6, which is involved in the metabolism of a number of tricyclic antidepressants . Patients should be monitored for increased antidepressant plasma levels and toxicity when fluoxetine is used concurrently. Adjustment of the antidepressant dosage may be necessary.
Antihypertensives: In general, the hypotensive effect is enhanced. Amitriptyline may block the antihypertensive action of adrenergic neurone blockers (e.g. guanethidine, debrisoquine, betanidine), and possibly clonidine. There is an increased risk of hypertension on clonidine withdrawal. It is advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.
Sympathomimetic drugs: Amitriptyline should not be given with sympathomimetic agents such as adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine due to hypertension and arrhythmias. Local anaesthetics with adrenaline appear to be safe. Methylphenidate may inhibit the metabolism of tricyclics and therefore increase the antidepressant action of amitriptyline.
Anticholinergics: Paralytic ileus urinary retention or acute glaucoma may be precipitated, especially in elderly patients. Excessive anticholinergic effects may occur in patients taking tricyclic antidepressants in combination with drugs having an anticholinergic action.
Anxiolytics and hypnotics: Amitriptyline may enhance the response to alcohol, barbiturates, and other CNS depressants. In turn, barbiturates may decrease, and methylphenidate may increase, the antidepressant action of amitriptyline. Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients treated with 1g ethchlorvynol and 75 mg to 150 mg of amitriptyline.
Disulfiram: Concomitant use may inhibit the metabolism of tricyclics. Delirium has been reported in patients taking amitriptyline with disulfiram.
Diuretics: increased risk of postural hypotension.
Ulcer-healing drugs: Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants. Plasma concentrations of amitriptyline are increased by cimetidine (inhibition of metabolism)
Electroconvulsive therapy: Concurrent administration with ECT may increase the hazards of treatment, and should be limited to patients for whom it is deemed essential.
Antivirals: Based on the known metabolism of amitriptyline, the protease inhibitor, ritonavir, may increase the serum levels of amitriptyline. Therefore careful monitoring of therapeutic and adverse effects is recommended when these drugs are administered concomitantly.
Altretamine: Concurrent administration of altretamine and tricyclic antidepressants may cause severe orthostatic hypotension.
Anaesthetics: Concomitant therapy may increase the risk of arrhythmias and hypotension. If surgery is necessary, the anaesthetist should be informed that a patient is being so treated (see section 4.4).
Analgesics: Caution should be exercised when nefopam is administered concurrently with tricyclic antidepressants. There is a possibility of increased side effects with nefopam. Tramadol may increase the risk of CNS toxicity and the potential for tricyclic antidepressants to cause convulsions. The concurrent administration of opioid analgesics with tricyclic antidepressants may lead to increased sedation.
Anti-arrhythmics: There is an increased risk of ventricular arrhythmias with drugs which prolong QT interval, including amiodarone (avoid concomitant use), disopyramide, procainamide, propafenone, quinidine and sotalol.
Calcium-channel blockers: Diltiazem and verapamil may possibly increase the plasma concentration of amitriptyline.
Antibacterials: Plasma concentrations of some tricyclics are reduced by rifampicin (reduces antidepressant effect). Concomitant use with linezolid may result in CNS excitation and hypertension.
Rifampicin: The plasma concentration of some tricyclic antidepressants may be reduced by rifampicin.
Antiepileptics: Concomitant use of antiepileptics may lower the convulsive threshold Tricyclic antidepressants may precipitate seizures in susceptible patients and the dosage of antiepileptics may need to be adjusted. The plasma concentration of some tricyclic antidepressants may be reduced (eg., by barbiturates, carbamazepine) by antiepileptics resulting in reduced antidepressant effect.
Antifungals: Increased serum concentrations have occurred in patients also taking fluconazole. Serious adverse effects have been reported due to increased amitriptyline plasma concentration.
Antihistamines: Increased anticholinergic and sedative effects. Concomitant use of terfenadine should be avoided due the increased risk of ventricular arrhythmias.
Antipsychotics: There is an increased risk of ventricular arrhythmias if thioridazine or pimozide are taken concomitantly with tricyclic antidepressants. Concurrent administration with phenothiazines and possibly clozapine may lead to increased plasma concentrations of tricyclic antidepressants and increased antimuscarinic side effects Dopaminergics: The concomitant use of entacapone with tricyclic antidepressants is not recommended. Severe CNS toxicity has been reported in patients with the combination of tricyclic antidepressants and selegiline.
Muscle relaxants: The use of baclofen and tricyclic antidepressants may result in the potentiation of the effect of baclofen, resulting in pronounced muscular hypotenia.
Nitrates: The effectiveness of sublingual and buccal tablet preparations may be reduced by drugs that cause dry mouth since dissolution may be delayed.
Oral contraceptives: Oral contraceptives (Oestrogens and progestogens) antagonise the antidepressant effect of tricyclic antidepressants but may increase the side effects due to increased plasma concentrations of tricyclics.
Sibutramine: Concomitant use is not recommended due to the increased risk of CNS toxicity
St John's Wort: St John's Wort may decrease plasma levels of amitriptyline.
4.6 Pregnancy and lactation
The safety of amitriptyline during pregnancy and lactation has not been established. Do not use during pregnancy, especially during the first and last trimesters, unless there are compelling reasons and the hazards to the foetus, child or mother must be evaluated when considering the possible benefits of amitriptyline therapy during pregnancy. There is limited evidence of safety of the drug in human pregnancy; although it has been in wide use for many years without apparent ill-consequence. There is evidence of harmful effects in pregnancy in animals, when given in exceptionally high doses. Withdrawal symptoms, including respiratory depression and agitation have been reported in neonates whose mothers had taken tricyclic antidepressants during the last trimester of pregnancy. Urinary retention in the neonate has also been associated with maternal use of amitriptyline.
Amitriptyline is detectable in breast milk at high doses. Because of the potential for serious adverse reactions in infants from amitriptyline, a decision should be made whether to discontinue breast-feeding or discontinue the drug.
4.7 Effects on ability to drive and use machines
Amitriptyline may initially impair alertness. Patients should be warned of the possible hazard when driving or operating machinery.
4.8 Undesirable effects
In general, amitriptyline is well tolerated. Not all of the side-effects listed below have been reported with amitriptyline but are included due to the similar pharmacology of other tricyclics. Antidepressant effects of amitriptyline may not become apparent for the first 2-4 weeks of therapy so patients should be closely monitored during this period.
Cardiovascular reactions: Hypotension, syncope, postural hypotension, hypertension, tachycardia, palpitations, myocardial infarction, arrhythmias, heart block, stroke, non-specific ECG changes and changes in AV conduction. Arrhythmias and severe hypotension are likely to occur with high dosage or overdosage.
Nervous system and neuromuscular disorders: Dizziness, fatigue, headache, drowsiness, weakness, disorientation, confusional states, disturbed concentration, disorientation, delusions, hallucinations, hypomania, excitement, anxiety, restlessness, drowsiness, insomnia, nightmares, numbness, tingling and paraesthesia of the extremities, peripheral neuropathy, incoordination, ataxia, tremors, coma, convulsions, alteration of the EEG, extrapyramidal symptoms, including abnormal involuntary movements and tardive dyskinesia, dysarthria, tinnitus. Cases of suicidal ideation and suicidal behaviours have been reported during amitriptyline therapy or early after treatment discontinuation (see section 4.4). Anticholinergic effects include: dry mouth, blurred vision, mydriasis, disturbance of accommodation, increased intra-ocular pressure, constipation, paralytic ileus, hyperpyrexia.
Renal and urinary disorders: urinary retention, urinary tract dilatation, urinary frequency
Immune system disorders: Skin rash, urticaria, photosensitisation, oedema of face and tongue.
Blood and lymphatic system disorders: Bone-marrow depression including agranulocytosis, leucopenia, eosinophilia, purpura, thrombocytopenia.
Hepato-biliary disorders: Rarely hepatitis (including altered liver function and jaundice).
Skin and subcutaneous tissue disorders: Increased perspiration and alopecia. Oedema,
Gastrointestinal disorders: Nausea, epigastric distress, vomiting, anorexia, stomatitis, unpleasant taste, dysgeusia, diarrhoea, parotid swelling, black tongue.
Endocrine disorders: Testicular swelling, gynaecomastia; breast enlargement, galactorrhoea, increased or decreased libido, impotence, interference with sexual function, syndrome of inappropriate ADH (antidiuretic hormone) secretion.
Metabolism and nutrition disorders: Elevation or lowering of blood sugar levels. Increased appetite and weight gain may be a drug reaction or due to relief of depression.
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.
Abrupt withdrawal after prolonged administration has caused nausea, headache and malaise. Reports have associated gradual withdrawal with transient symptoms including irritability, restlessness, as well as dream and sleep disturbances during the first two weeks of dosage reduction. These symptoms are not indicative of addiction.
Adverse reactions such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers had taken tricyclic anti-depressants in the last trimester of pregnancy.
Mania or hypomania has been reported rarely within 2-7 days of stopping chronic therapy with tricyclic antidepressants.
Side effects in 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. Behavioural changes have been observed in children receiving tricyclics for treatment of enuresis.
Side effects - causal relationship unknown :
The following additional side-effects have been reported; however, a causal relationship to therapy with amitriptyline has not been established: lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor).
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
There is no specific antidote for tricyclic antidepressant poisoning. Patients should be hospitalised and treatment should be symptomatic and based on cardiac (including ECG monitoring) and respiratory support.
Symptoms
Toxicity is due to a combination of anticholinergic (antimuscarinic, atropine-like) effects at autonomic nerve endings and in the brain, cardiac sodium channel blockade and a1 adrenergic receptor blockade. In addition, tricyclic antidepressants block presynaptic uptake of amines and the cardiac delayed rectifier potassium channel (Ikr).
Features commonly include: sinus tachycardia, hot dry skin, dry mouth and tongue, dilated pupils, urinary retention and ileus, progressing to ataxia, nystagmus, divergent squint and drowsiness which may lead to deep coma and respiratory depression. Increased tone and hyperreflexia may be present with extensor plantar reflexes. In deep coma all reflexes (including brain-stem reflexes) may be abolished. Convulsions occur in >5% of cases and may herald haemodynamic compromise.
ECG features include prolongation of the PR, QRS and QT intervals, non-specific ST segment and T wave changes and atrioventricular block.
Metabolic acidosis may be present. Hypotension may occur and may be severe.
Hypothermia and rhabdomyolysis may occur in patients who have been unconscious. Occasionally skin blisters may occur.
During recovery confusion, agitation and visual hallucinations may occur.
Features of serotonin toxicity may occur. These include CNS effects (including agitation or coma), autonomic instability (including hyperpyrexia), and neuromuscular excitability (including clonus and raised serum creatine kinase)
This syndrome is more likely to occur if the patient has been exposed to two or more drugs that increase the effect of serotonin in serotonergic synapses (by increasing release, reducing reuptake or metabolism, or stimulating serotonin receptors), either as an acute overdose or if taken regularly, for example - SSRIs, MAOIs, tricyclic antidepressants, venlafaxine, tramadol, triptans, linezolid and St John's Wort; stimulant drugs of abuse (e.g. MDMA (ecstasy), amphetamines, cocaine, cathinone derivatives (mephedrone, etc)).
The cardiovascular and CNS effects in overdose will be potentiated by simultaneous ingestion of alcohol, cardiovascular agents and other psychotropic drugs
Management
Do not give flumazenil to reverse benzodiazepine toxicity in mixed overdoses.
1. Ensure a clear airway and adequate ventilation. Check arterial blood gases and correct any hypoxia. If hypercapnia is present assisted ventilation is indicated.
2. The benefit of gastric decontamination is uncertain. Consider activated charcoal by mouth or naso-gastric tube if the patient presents within 1 hour of ingestion of more than 5mg/kg, provided the airway can be protected.
A second dose of charcoal should be considered after 1 -2 hours in patients with features of toxicity who are able to swallow, or who have been intubated.
3. After cardiac arrest, prolonged resuscitation may be successful and should be continued for at least 1 hour.
4. Observe for at least 6 hours after ingestion. Monitor BP, pulse and cardiac rhythm. Repeat ECGs should be performed. Patients who remain asymptomatic and have a normal ECG by 6 hours are unlikely to develop late complications.
5. Check urea and electrolytes and monitor urine output. Check serum creatine kinase in patients who have been unconscious.
6. If metabolic acidosis persists despite correction of hypoxia and adequate fluid resuscitation consider correction with intravenous sodium bicarbonate. Rapid correction is particularly important if there is prolongation of the QRS or QT intervals.
7. Control convulsions with intravenous diazepam or lorazpam. Give oxygen and correct acid base and metabolic disturbances. Phenytoin is contraindicated in tricyclic overdosage (because in common with TCAs it blocks sodium channels and may increase the risk of cardiac arrhythmias).
8. Correct hypotension by raising the foot of the bed. In severe cases administration of colloid to expand the intravascular volume is required (central venous pressure monitoring may be required). Alkalinisation with sodium bicarbonate may correct hypotension.
9. Agitated adults can be sedated with oral or IV diazepam. If ineffective consider oral or parenteral haloperidol.
10. Glucagon 10mg IV bolus may be given if patients are severely hypotensive.
11. If the patient is hypothermic, rewarm slowly using conventional means.
12. Monitor for rhabdomyolysis if the patient has been unconscious for a considerable time.
13. Forced diuresis, haemodialysis and haemoperfusion are of no value due to the large volume of distribution of tricyclic antidepressants.
14. Other measures as indicated by the patient's clinical condition.
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 tricyclic antidepressants.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Non-selective monoamine reuptake inhibitors ATC code: N06AA09
Amitriptyline is a tricyclic antidepressant. It has marked antimuscarinic and sedative properties, and prevents the re-uptake (and hence the inactivation) of noradrenaline and serotonin at nerve terminals. Its mode of action in depression is not fully understood. Amitriptyline is used in the treatment of depression, particularly endogenous depression.
5.2 Pharmacokinetic properties
Amitriptyline is readily absorbed from the gastro-intestinal tract, peak plasma concentration occurring within about 6 hours of oral administration. Amitriptyline is extensively demethylated in the liver to its primary active metabolite, nortriptyline. Paths of metabolism of both amitriptyline and nortriptyline include hydroxylation (possibly to active metabolites) and N-oxidation. Amitriptyline is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form. Amitriptyline and nortriptyline are widely distributed throughout the body and are extensively bound to plasma and tissue protein. Amitriptyline has been estimated to have a half life ranging from 9 to 25 hours, which may be considerably extended in overdosage.
5.3 Preclinical safety data
There are no pre-clinical data of relavance to the prescriber which are additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate, povidone, magnesium stearate, stearic acid, maize starch.
Sugar-coat excipients: polyvinylacetate phthalate, stearic acid, talc, calcium carbonate, acacia, titanium dioxide, sucrose, povidone, quinoline yellow aluminium lake, sunset yellow aluminium lake, sodium benzoate, shellac, yellow carnauba wax, white beeswax.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C. Store in the original container. Keep the container tightly closed.
6.5 Nature and contents of container
Polypropylene tablet containers with low density polyethylene caps. Packing material: High density polyethylene film.
Pack size: 50, 100, 250 and 500 tablets.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
BRISTOL LABORATORIES,
UNIT 3, CANALSIDE,
NORTHBRIDGE ROAD,
BERKHAMSTED HP4 1EG,
UNITED KINGDOM
8 MARKETING AUTHORISATION NUMBER(S)
PL 17907/0342
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/03/2011
10 DATE OF REVISION OF THE TEXT
16/09/2014