Amitriptyline 25mg Film-Coated Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Amitriptyline 25mg Film-Coated Tablets
2. Qualitative and quantitative composition
Amitriptyline hydrochloride 25mg For excipients, see 6.1
3. Pharmaceutical form Film-coated tablet
Amitriptyline 25mg Tablets BP are yellow film coated circular biconvex tablets with A on one face and 25 on the other.
4.1. Therapeutic indications
For the treatment of depressive illness, especially when sedation is required, and of nocturnal enuresis in children.
4.2. Posology and method of administration
Amitriptyline Tablets BP are for oral administration.
Adults:
Initial dose:
Usually 75 mg daily in divided doses (or a single dose at night). This may be increased gradually if necessary to a total of 150 mg a day, with the additional doses being given in the late afternoon and/or at bedtime.
The sedative effect is usually rapidly apparent, while antidepressant activity may be seen within three or four days or may take up to 30 days to develop adequately.
Maintenance dose:
The usual maintenance dosage is 50-100 mg daily. The total dosage may be given in a single dose preferably in the evening or at bedtime. When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms. Maintenance therapy should be continued for three months or longer to lessen chances of relapse.
Elderly:
In general, lower dosages are recommended for these patients, as they are more prone to side effects, especially confusion, agitation and postural hypotension. An initial dosage of 10-25mg three times daily is recommended, which should be increased slowly. A daily dosage of 50mg may be satisfactory in elderly patients who may not tolerate higher dosages. The required dosage may be administered either as divided doses or a single dose preferably in the evening or at bedtime.
Children:
Not recommended for treatment of depression in children under 16 years of age due to lack of clinical experience.
Enuresis:
Children from 6-10 years may receive 10-20 mg a day, while those aged 11-16 years may need 25 mg a day. Treatment should be withdrawn gradually and should not exceed three months (including withdrawal). A full physical examination is recommended before a further course.
4.3. Contra-indications
• Patients who are taking monoamine oxidase inhibitors or who have received them within the last two weeks
• prior sensitisation to amitriptyline
• during the recovery phase after myocardial infarction
• arrhythmias, particularly heart block of any degree
• mania
• severe liver disease
• lactation
• children under six years of age.
4.4. Special warnings and precautions for use
Elderly patients can be particularly sensitive to the side-effects of tricyclic antidepressants and a reduced dose, especially initially, should be employed (see 4.2 Posology and method of administration). Amitriptyline should be used with caution in patients with a history of epilepsy, and in those with impaired liver function, phaeochromocytoma or porphyria.
Due to its atropine-like action, it should be used with caution in patients with a history of urinary retention, prostatic hypertrophy, narrow-angle glaucoma, or increased intra-ocular pressure. Even average doses may precipitate glaucoma in patients with narrow-angle glaucoma. Nocturnal symptoms of gastro-oesophageal reflux may be aggravated if amitriptyline is given in the late evening to patients with hiatus hernia.
Patients with cardiovascular disorders, hyperthyroid patients and those receiving thyroid medication or anticholinergic drugs should be closely monitored and the dosage of all medications carefully adjusted.
Blood sugar concentrations may be altered in diabetic patients.
When used for the depressive component of schizophrenia, amitriptyline may aggravate psychotic symptoms. In manic-depressives, a shift towards the manic phase may occur. Paranoid delusions, with or without associated hostility, may be aggravated. A major tranquilliser should be given concurrently in such cases, or dosage of amitriptyline reduced.
Concurrent administration with ECT may increase the hazards of treatment, and should be limited to patients for whom it is deemed essential.
If possible, amitriptyline should be discontinued several days before surgery.
If emergency surgery is unavoidable, the anaesthetist should be informed that the patient is being treated with amitriptyline, since anaesthesia may increase the risk of hypotension and arrhythmias.
Sudden discontinuation of antidepressant therapy after regular administration for 8 weeks or more may precipitate withdrawal symptoms (see 4.8, Undesirable Effects).
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.
4.5. Interactions with other medicaments and other forms of interaction
Alcohol: Amitriptyline may enhance the response to alcohol and increases the disulfiram (Antabuse) reaction of disulfiram with alcohol. Delirium has been reported in patients taking amitriptyline with disulfiram.
Anaesthetics: Increased risk of hypotension and cardiac arrhythmias during anaesthesia (see 4.4 Special warnings and precautions for use).
Analgesics: increased anticholinergic side-effects with nefopam; increased analgesia with morphine.
Antiarrhythmics: Other drugs which prolong the QT interval, including amiodarone, disopyramide, procainamide and quinidine, should be avoided because of the increased risk ofprolonged QT interval and torsade de pointes.
Antibacterials: plasma concentration reduced by rifampicin (reduced antidepressant effect).
Anticholinergic agents: Excessive anticholinergic effects may occur when tricyclic antidepressants are combined with anticholinergic drugs. Paralytic ileus, urinary retention or acute glaucoma may be precipitated, especially in elderly patients.
Anticoagulants: Amitriptyline may increase or decrease anticoagulant activity - monitor prothrombin time.
Antidepressants: The concurrent use of antidepressants having various mechanisms of action should be undertaken only with due recognition of their possible potentiation and with a thorough knowledge of their pharmacology. Monoamine oxidase inhibitors can potentiate the effects of tricyclic antidepressants such as amitriptyline and hyperpyretic crises, severe convulsions and fatalities have occurred. A minimum of 14 days should elapse between discontinuing an MAOI and starting amitriptyline, which should be introduced cautiously and dosage increased gradually. Fluoxetine markedly inhibits Cyt 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. Caution is also advised with reboxetine.
Antiepileptics: Tricyclic antidepressants may antagonise the anticonvulsant action of antiepileptics (convulsive threshold lowered). Carbamazepine may decrease the antidepressant action of amitriptyline. Sodium valproate can increase amitriptyline plasma levels.
Antifungals: Fluconazole may increase amitriptyline serum concentrations, potentiate QT interval prolongation and increase risk of torsade de pointes.
Antihistamines: Increased CNS depressant effects. Astemizole and terfenadine should be avoided due to increased risk of prolonged QT interval and torsade de pointes.
Anlihypertensives: In general, the hypotensive effect of antihypertensives is enhanced by tricyclic antidepressants, but amitriptyline may block the antihypertensive action of guanethidine, debrisoquine, bethanidine and clonidine. Sudden withdrawal of amitriptyline from a patient stabilized on a postganglionic blocking agent may cause serious hypotension. All antihypertensive therapy should be reviewed following withdrawal of a tricyclic antidepressant as well as during treatment.
Antipsychotics: Increased risk of prolonged QT interval and torsade de pointes with sertindole, pimozide and thioridazine - avoid concomitant use. Plasma concentrations of phenothiazines and amitrpityline may both be increased with concomitant use. Antipsychotics may lower convulsive threshold and increase risk of seizures with amitriptyline.
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 concurrently.
Anxiolytics and hypnotics: Enhanced sedation.
Barbiturates and other CNS depressants. Enhanced response. Barbiturates may decrease the antidepressant action of amitriptyline.
Beta-blockers: Increased risk of prolonged QT interval and torsade de pointes with solalol - avoid concomitant use.
CNS stimulants: Methylphenidate may increase the antidepressant action of amitriptyline.
Diuretics: increased risk of postural hypotension.
Dopaminergics: Selegiline can potentiate effects of tricyclics and hyperpyretic crises, severe convulsions and fatalities have occurred. Tricyclics should not generally be given to patients receiving selegiline, or for at least two weeks after it has been discontinued. At least one week should elapse between withdrawing a tricyclic and starting selegiline.
Nitrates: reduced effect of sublingual nitrates (owing to dry mouth).
Oestrogens and progestogens: Oral contraceptives antagonise antidepressant effect (but side-effects may be increased due to increased plasma concentrations of amitriptyline).
Smoking: May reduce plasma concentration of amitriptyline.
St John’s wort: tricyclic antidepressants should not be used with St John’s wort.
Sympathomimetic agents:
Amitriptyline should not be given with sympathomimetic agents such as adrenaline, isoprenaline, noradrenaline, phenylephrine and, due to enhanced pressor response to these agents (hypertension, cardiac arrhythmias, etc), but local anaesthetics with adrenaline appear to be safe.
Thyroid hormone: can accelerate the antidepressant response of tricyclic antidepressants but may precipitate cardiac arrhythmias.
Ulcer-healing agents: Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants.
4.6. Pregnancy and lactation
The safety of amitriptyline for use during pregnancy and lactation has not been established. Amitriptyline is not recommended during pregnancy, especially during the first and third trimesters, unless there are compelling reasons, and in these patients the benefits should be weighed against possible hazards to the foetus, child or mother. Clinical experience of the use of amitriptyline in pregnancy has been limited. Animal studies have shown harmful effects at 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. There have been reports of cardiac problems, irritability, respiratory distress, muscle spasms, seizures, and urinary retention in infants whose mothers received tricyclic antidepressants immediately prior to delivery.
Amitriptyline is detectable in breast milk. It should be avoided while breastfeeding due to the potential for serious adverse reactions in the infant.
4.7. Effects on ability to drive and use machines
Amitriptyline may impair alertness in some patients and activities made hazardous by diminished alertness should be avoided.
4.8 Undesirable effects
In general, amitriptyline is well tolerated. The side effects stated below include those of the tricyclic group of antidepressants in general. Not all of them have been reported with amitriptyline, some are included due to similar pharmacology of the group members. As the antidepressant effects of amitriptyline may not become apparent for the first 2-4 weeks of therapy, patients should be closely monitored during this period.
Anticholinergic: Blurred vision, accommodation disturbance, increased intraocular pressure, mydriasis, constipation, paralytic ileus, urinary retention, hyperpyrexia, dry mouth, delirium (particularly in the elderly).
Allergic: Skin rash, urticaria, photosensitisation, oedema of face and tongue.
Cardiovascular: Postural hypotension and dizziness, syncope, hypertension, palpitations, tachycardia, myocardial infarction, heart block, sudden cardiac death. Dose-related ECG changes (generally without consequence). Arrhythmias including, rarely, QT prolongation and torsade de pointes, and severe hypotension are likely to occur with high doses or overdosage.
Endocrine: Gynaecomastia, breast enlargement, galactorrhoea, testicular swelling, syndrome of inappropriate ADH secretion.
Gastro-intestinal: Nausea, vomiting, diarrhoea, epigastric distress, anorexia, dysgeusia, stomatitis.
Haematological: Bone marrow depression including agranulocytosis, eosinophilia, leucopenia, thrombocytopenia and purpura.
Hepatobiliary: Rarely hepatitis (including altered liver function, cholestasis and jaundice) and hepatic necrosis.
Metabolism and nutrition: Elevation or lowering of blood sugar levels. Hyponatraemia (with drowsiness, confusion, or convulsions) may be associated with inappropriate secretion of antidiuretic hormone and may be more prevalent in the elderly. Increased appetite and weight gain may be a drug reaction or due to relief of depression.
Neurological: Drowsiness, disturbed concentration, disorientation, confusional states, insomnia, nightmares, peripheral neuropathy, numbness, tingling and paraesthesia of the extremities, inco-ordination, ataxia, tremors, convulsions, extra-pyramidal symptoms and tinnitus. Rarely, speech disorders, which are more likely to occur with higher doses, or neuroleptic malignant syndrome.
Psychiatric: Agitation, nervousness, excitement, anxiety, restlessness, delusions, hallucinations, hypomania, mania. Cases of suicidal ideation and suicidal behaviours have been reported during Amitriptyline therapy or early after treatment discontinuation (see section 4.4).
Reproductive: Changes in libido, interference with sexual function (e.g. impotence, delayed ejaculation, anorgasmia or delayed orgasm in women).
Urinary: Urinary frequency,
Other reactions: Weakness, fatigue, headache, increased perspiration, alopecia.
Withdrawal symptoms:
The symptoms associated with withdrawal of tricyclic antidepressants include gastrointestinal disturbances; generalised somatic symptoms such as malaise,
chills, headache and increased perspiration; anxiety and agitation; sleep disturbances (insomnia and vivid dreams); parkinsonism or akasthisia; hypomania or mania; cardiac arrhythmias. Withdrawal symptoms seem to be more common and more severe in children.
Side-effects in enuresis: As dosages used in enuresis are low compared with those used for depression, side-effects are less frequent. The most common are drowsiness and anticholinergic effects. Infrequently, mild sweating and itching have been reported. Behavioural changes have been observed in children receiving tricyclics for treatments of enuresis.
The recommended dosage must not be exceeded.
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.
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
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 drugs.
Overdose effects are mainly due to anticholinergic (atropine-like) effects at autonomic nerve endings and in the brain. There is also a quinidine-like effect on the myocardium.
Peripheral symptoms
Commonly include sinus tachycardia, hot dry skin, dry mouth and tongue, dilated pupils and urinary retention.
The most important ECG feature of toxicity is prolongation of the QRS interval, which indicates a high risk of ventricular tachycardia. In very severe poisoning the ECG may be bizarre. Rarely, prolongation of the PR interval or heart block may occur. QT interval prolongation and torsade de pointes has also been reported.
Central symptoms
Commonly include ataxia, nystagmus 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 may be abolished. A divergent squint may be present.
Hypotension and hypothermia may occur. Fits occur in >5% of cases.
During recovery confusion, agitation and visual hallucinations may occur.
Management
An ECG should be taken and in particular the QRS interval should be assessed since prolongation signifies an increased risk of arrhythmia and convulsions. Give activated charcoal by mouth or naso-gastric tube if more than 4 mg/kg has been ingested within one hour, provided the airway can be protected. A second dose of charcoal should be considered after two hours in patients with central features of toxicity who are able to swallow.
Tachyarrhythmias are best treated by correction of hypoxia and acidosis. Even in the absence of acidosis 50 millimoles of sodium bicarbonate should be given by intravenous infusion to adults with arrhythmias or clinically significant QRS prolongation on the ECG.
Control convulsions with intravenous diazepam or lorazepam. Give oxygen and correct acid base and metabolic disturbances. Phenytoin is contraindicated in tricyclic overdosage, because, like tricyclic antidepressants, it blocks sodium channels and may increase the risk of cardiac arrhythmias. Glucagon has been used to correct myocardial depression and hypotension.
5.1. Pharmacodynamic properties
Amitriptyline is a tricyclic antidepressant. It has marked anticholinergic and sedative properties. It prevents the re-uptake, and hence the inactivation of noradrenaline and serotonin at nerve terminals. Its mode of action in depressive illness is not fully understood.
5.2. Pharmacokinetic properties
Amitriptyline is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring within about 6 hours of oral administration. Since amitriptyline slows gastro-intestinal transit time, absorption may be delayed, particularly in overdosage. Onset of antidepressant activity takes 2-3 weeks.
Amitriptyline is extensively demethylated in the liver to its primary active metabolite, nortriptyline. Amitriptyline and nortriptyline are widely distributed throughout the body and very highly bound to plasma and tissue protein. The estimated half-life of amitriptyline is 9 to 25 hours, which may be considerably extended in overdosage. Plasma concentrations of amitriptyline and nortriptyline vary widely between individuals and no simple correlation with therapeutic response has been established.
5.3. Preclinical safety data
There are no preclinical data of relevance to the prescriber, which are additional to those included in other sections.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet Core:
Calcium hydrogen phosphate dihydrate Sodium starch glycollate Maize starch
Microcrystalline cellulose Magnesium stearate
Film Coating:
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol
Tartrazine aluminium lake (E102) Sunset yellow FCF (E110)
6.2. Incompatibilities
None known.
6.3. Shelf life
Three years.
6.4. Special precautions for storage
Do not store above 25°C.
6.5. Nature and contents of container
100 or 500 tablets in polyethylene or polypropylene tablet containers.
28 tablets in blisters consisting of hard tempered aluminium foil (20 micron) and PVC film (250 micron) in cartons.
6.6. Instructions for use/handling
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd Ash Road North Wrexham Industrial Estate Wrexham LL13 9UF United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0008
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/06/1982
10 DATE OF REVISION OF THE TEXT
15/05/2015