Amitriptyline Tablets Bp 25mg
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Amitriptyline Tablets BP 25mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Amitriptyline Hydrochloride BP 25.00mg
3 PHARMACEUTICAL FORM
Amitriptyline Tablets BP 25 mg are presented as yellow, film-coated, round normal convex tablets engraved with the company logo on one side and A313 on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Amitriptyline is indicated for the treatment of:
1. Depression (particularly endogenous) especially where sedation is required.
2. Nocturnal enuresis in children where organic pathology has been excluded.
4.2 Posology and method of administration
Recommended doses and dosage schedules:
Depression:
Adults:
Initial dose: 50-75mg daily in divided doses or a single dose at night. If necessary, this may be increased to a total of 150-200mg daily according to clinical response.
The antidepressant activity may be seen within 3-4 days or may even take up to 30 days to provide an adequate response.
Maintenance dose: 50 - 100mg daily.
For maintenance therapy, the total dosage is administered as a single dose preferably in the evening or at bedtime. Following improvement, the dosage should be reduced to the lowest amount required to relieve symptoms. Maintenance therapy should be continued for 3 months or longer to lessen the chance of a 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.
Nocturnal enuresis
Children: 11 - 16 years: 25 - 50mg daily.
7 - 10 years: A more suitable dosage form should be used for this age group. Under 7 years: Not recommended for this age group.
Recommended dosage should not be exceeded. Treatment (including gradual withdrawal) should not exceed 3 months. A further course of treatment should not be started until a full physical examination, including an ECG, has been made.
Method of administration:
For oral administration.
4.3 Contraindications
Concomitant administration with monoamine oxidase inhibitors (MAOIs) or have taken them within the last 14 days ; hypersensitivity to tricyclic antidepressants or to amitriptyline or any of the ingredients in the tablets; during the recovery phase after myocardial infarction; arrhythmias; particularly heartblock of any degree; congestive heart failure, coronary artery insufficiency; mania; severe hepatic dysfunction; lactation; children under 7 years of age.
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.
Caution should be exercised in patients with a history of epilepsy, blood dyscrasias and hepatic dysfunction.
Due to its atropine-like action, care should be taken in patients with a history of urinary retention, prostatic hypertrophy, narrow angle glaucoma or increased intra-ocular pressure. Even average doses may precipitate an attack of glaucoma in patients with narrow-angle glaucoma.
Close supervision is required in patients with cardiovascular disorders, phaeochromocytoma, the elderly, hyperthyroidism and those receiving thyroid medication and anticholinergic agents. The dosage of all medications will need to be carefully adjusted. The elderly are particularly liable to experience adverse reactions, especially agitation, confusion and postural hypotension. Behavioural changes may occur in children receiving amitriptyline for the treatment of nocturnal enuresis.
This product should also be used with caution in patients with porphyria. Tricyclic antidepressants are among a number of drug groups which have shown to be porphyrinogenic. For this reason they have been classified as “unsafe“ for patients with acute porphyrias.
Amitriptyline may also impair alertness in some patients and therefore activities made hazardous by diminished alertness (e.g. driving etc) should be avoided.
Psychosis may be activated in schizophrenic patients and manic-depressive patients may switch to a manic phase. 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. Unless essential, it is inadvisable to combine amitriptyline and electroconvulsive therapy (ECT). Cardiac arrhythmias and severe hypotension are likely to occur with high dosages or in patients with pre-existing heart disease.
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 (see section 4.5). Patients with suicidal tendencies should be carefully supervised.
Abrupt withdrawal of amitriptyline should be avoided if possible.
4.5 Interaction with other medicinal products and other forms of interactions
Other Antidepressants: Monoamine oxidase inhibitors (MAOIs) and selective serotonin re-uptake inhibitors (SSRIs) can potentiate the effects of tricyclic antidepressants such as amitriptyline and hyperpyretic crises, hypertension, CNS excitation, severe convulsions and fatalities have occurred. A minimum of 14 days should elapse between discontinuing an MAOI and starting amitriptyline which should he 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.
Anti-hypertensives: In general, the hypotensive effect is enhanced, but concomitant administration with guanethidine, debrisoquine, betanidine (adrenergic neurone blockers) and possibly clonidine may block anti-hypertensive action of these drugs. There is an increased risk of hypertension on clonidine withdrawal. It is advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.
Sympathomimetic agents: Amitriptyline should not be administered 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.
Alcohol: Amitriptyline may potentiate the response to alcohol, barbiturates and other CNS depressants. See also disulfiram.
Barbiturates and methylphenidate: Barbiturates may decrease and methylphenidate (inhibit the metabolism of tricyclics and therefore) may increase, the antidepressant action of amitriptyline. Paralytic ileus, urinary retention or acute glaucoma has been reported in patients (especially in elderly patients) taking tricyclic antidepressants concurrently with drugs with antichlolinergic action. Excessive anticholinergic effects may occur when tricyclic antidepressants are combined with anticholinergic drugs.
Analgesics: possible increase of side-effects with nefopam; tramadol may increase risk of convulsions and CNS toxicity; possible increase of sedative effect with opioid analgesics; risk of ventricular arrhythmias with levacetylmethadol and amitriptyline increased (avoid concomitant use).
Antiepileptics: antagonism with antiepileptics such as valproate causing the convulsive threshold to be lowered; plasma concentrations of some tricyclics (eg by barbiturates, carbamazepine) reduced resulting in reduced antidepressant effect.
Antipsychotics: increased risk of ventricular arrhythmias - avoid concomitant use with pimozide or thioridazine; increased plasma concentrations of tricyclic antidepressants and increased antimuscarinic side- effects with phenothiazines and possibly clozapine.
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: risk of severe postural hypotension.
Anti-arrhythmics: risk of ventricular arrhythmias increased with drugs which prolong QT interval, including amiodarone (avoid concomitant use), disopyramide, procainamide, propafenone and quinidine
Antihistamines: antimuscarinic and sedative effects increased: risk of ventricular arrhythmias increased with terfenadine (avoid concomitant use).
Beta-blockers: risk of ventricular arrhythmias associated with sotalol increased.
Disulfiram: inhibition of metabolism of tricyclics (increased plasma concentrations and increased disulfiram reaction reported with alcohol with amitriptyline). Delirium has been reported in patients taking amitriptyline with disulfiram.
Anaesthetics: increased 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).
Antibacterials: plasma concentrations of some tricyclics are reduced by rifampicin (reduced antidepressant effect). Concomitant use with linezolid may result in CNS excitation and hypertension.
Calcium-channel blockers: possible increase in plasma concentration of amitriptyline with diltiazem and verapamil.
Diuretics: risk of postural hypotension increased.
Muscle relaxants: taken with baclofen, muscle relaxant effect enhanced.
Oral contraceptives (Oestrogens andprogestogens): antidepressant effect antagonised. Side-effects may be increased due to increased plasma concentrations of tricyclics.
Ulcer healing drugs: metabolism inhibited by cimetidine causing plasma concentrations of amitriptyline to increase.
Antidiabetics: Isolated reports describe violent, agitated behaviour (but no adrenergic symptoms) and hypoglycaemia in patients taking insulin with amitriptyline.
Anxiolytics and hypnotics: Concomitant use enhances the sedative effect. Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients treated with 1g ethchlorvynol and 75mg to 150mg of amitriptyline.
Alpha2-adrenoceptor stimulants: Concomitant use of apraclonidine and brimonidine should be avoided.
Dopaminergics: Concomitant use with entacapone should be avoided. CNS toxicity has been reported with selegiline.
Nitrates: Reduced effect of sublingual nitrates (owing to dry mouth).
Sibutramine: Concomitant use is not recommended due to the increased risk of CNS toxicity.
Antifungals: Increased serum concentrations have occurred in patients also taking fluconazole. Serious adverse effects have been reported due to increased anitriptyline plasma concentration.
4.6 Pregnancy and lactation
Amitriptyline and its primary metabolite nortriptyline can readily cross the placental barrier and are excreted in the breast milk. Amitriptyline is detectable in breast milk at high doses. Because of the potential of serious adverse reactions in infants from amitriptyline, a decision should be made whether to discontinue breast feeding or discontinue the drug.
Safety of Amitriptyline during pregnancy and lactation has not been established. Clinical experience of the use of amitriptyline in pregnancy is limited. 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. Animal experiments have shown teratogenic effects on the foetuses at exceptionally high doses.
Amitriptyline is not recommended during pregnancy especially the first and the third trimester unless there are compelling reasons, and in these circumstances, benefits should be weighed against possible hazards to the foetus, child or the mother.
4.7 Effects on ability to drive and use machines
Drowsiness/ impaired alertness is experienced by patients during the start of therapy, patients are therefore advised not to drive or operate 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.
Allergic reactions: Skin rashes, urticaria, photosensitisation, oedema of face and tongue.
Blood and lymphatic system disorders: Blood dyscrasias including bone marrow depression, agranulocytosis, eosinophilia, leucopenia, thrombocytopenia and purpura.
Endocrine disorders: Gynaecomastia, breast enlargement, galactorrhoea, testicular enlargement, libido fluctuations, interference with sexual function, syndrome of inappropriate ADH secretion.
Metabolism and nutrition disorders: Changes in blood sugar concentration. Increased appetite and weight gain may be a drug reaction or due to relief of depression. Hyponatraemia (may be due to inappropriate antidiuretic hormone secretion.
Nervous system disorders: Dizziness, fatigue, headache, drowsiness, weakness, disturbed concentration, disorientation, confusional states, some patients may exhibit nervousness and insomnia, nightmares, delusions, hallucinations, behaviour changes such as hypomania and delirium in susceptible patients, excitement, anxiety, restlessness, peripheral neuropathy, numbness, tingling and paraesthesia of the extremities, inco-ordination, ataxia, tremors, convulsions (epileptiform seizures), altered ECG, extrapyramidal effects including speech difficulties, 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, sour or metallic taste, hyperpyrexia (fever), blurred vision, accommodation disturbance, increased intra-ocular pressure, mydriasis, constipation_occasionally leading to_paralytic ileus, urinary retention, urinary tract dilatation.
Cardiovascular disorders: Orthostatic/postural hypotension, hypertension, palpitations, tachycardia, myocardial infarction, heart block and stroke. Amitriptyline may affect the myocardium adversely resulting in conduction defects and arrhythmias hence increased risk of sudden death in patients with cardiac disease. Arrhythmias and severe hypotension are likely to occur with high doses or overdosage.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, epigastric distress, anorexia, dysgeusia, stomatitis, parotid swelling, black tongue and gastric irritation.
Hepato-biliary disorders: Rarely hepatitis (including altered liver function and jaundice).
Skin and subcutaneous tissue disorders: Increased perspiration and alopecia.
Renal and urinary disorders: Urinary frequency.
Abrupt withdrawal after prolonged administration has caused nausea, headache and malaise. Gradual withdrawal has been associated with transient symptoms such as dream and sleep disturbances, irritability and restlessness during the first two weeks of dosage reduction. These are not thought to be signs associated with addiction.
Mania or hypomania have been reported rarely within 2-7 days of stopping therapy with tricyclic antidepressants.
Side-effects in enuresis: As dosages used in enuresis are low compared to 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 treatment of enuresis.
Class effects
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.
4.9 Overdose symptoms, emergency procedures, antidotes
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).
High dosage (or during recovery) may cause transient visual hallucinations, temporary confusion and disturbed concentration, Overdosage may result in drowsiness, hypothermia, sinus tachycardia and arrhythmic abnormalities such as bundle branch block, conduction defects, congestive heart failure, hot dry skin, dry mouth and tongue, dilated pupils, urinary retention and ileus, progressing to ataxia, nystagmus, divergent squint, convulsions, severe hypotension, stupor and coma and respiratory depression. Other symptoms may include agitation, hyperactive reflexes (with extensor plantar reflexes), muscle rigidity, vomiting, hyperpyrexia, or any of the other side effects listed previously.
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.
Hypothermia and rhabdomyolysis may occur in patients who have been unconscious. Occasionally skin blisters 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.
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.
The stomach should be emptied as quickly as possible by emesis, followed by aspiration and gastric lavage. The use of activated charcoal as an adjunct to gastric lavage has been recommended during the first 24 - 48 hours, at a dosage of 20 - 30g every 4 to 6 hours.
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.
Observe for at least 6 hours after ingestion. Monitor BP, pulse and cardiac rhythm. Repeat ECGs should be performed to detect any cardiac abnormalities and if detected, then cardiac function should be monitored. Patients who remain asymptomatic and have a normal ECG by 6 hours are unlikely to develop late complications.
An open airway, adequate fluid balance and body temperature should be regulated. Check arterial blood gases and correct any hypoxia. If hypercapnia is present assisted ventilation is indicated
Check urea and electrolytes and monitor urine output. Check serum creatine kinase in patients who have been unconscious.
Intravenous physostigmine salicylate, 1 - 3mg has been reported to reverse the symptoms of tricyclic antidepressant poisoning. As physostigmine is rapidly metabolised, repeated administration is required especially if life-threatening signs such as arrhythmias, convulsions and deep coma recur or persist following initial dose.Physostigmine is toxic and not recommended for routine use.
Standard measures should be conducted to manage circulatory shock and metabolic acidosis. 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. Cardiac arrhythmias may be treated with neostigmine, pyridostigmine or propranolol. Cardiac failure may require digitalis. After cardiac arrest, prolonged resuscitation may be successful and should be continued for at least 1 hour. Close monitoring of cardiac function for not less than five days is advisable. Convulsions should be treated with paraldehyde, intravenous diazepam or lorazepam or an inhalation anaesthetic; barbiturates should not be used because amitriptyline increases their CNS-depressant action. 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).
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. Dialysis is of no value because of low plasma concentrations of amitriptyline.
Agitated adults can be sedated with oral or IV diazepam. If ineffective consider oral or parenteral haloperidol.
Glucagon 10mg IV bolus may be given if patients are severely hypotensive.
If the patient is hypothermic, rewarm slowly using conventional means.
Monitor for rhabdomyolysis if the patient has been unconscious for a considerable time.
Forced diuresis, haemodialysis and haemoperfusion are of no value due to the large volume of distribution of tricyclic antidepressants.
Other measures as indicated by the patient's clinical condition.
For further information or treatment in children discuss with your local poisons information service: in the UK NPIS - 0844 892 0111, in Ireland NPIC (01) 809 2566.
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Amitriptyline is a tricyclic anti-depressant. It has marked anticholinergic and sedative properties. Mechanism of action appears to be due to increased synaptic concentration of norepinephrine and/or serotonin in the CNS by blocking their re-uptake by the pre-synaptic neuronal membrane.
Amitriptyline appears to be more potent in blocking serotonin whereas nortriptyline inhibit re-uptake of both norepinephrine and serotonin equally. It also has a slight post synaptic dopamine blocking effect and prominent peripheral and central antimuscarinic effects due to its potent and high binding affinity for histamine H - receptor plus possible quinidine-like myocardial depressant effect due to blockade of amine re-uptake with resultant high norepinephrine concentration in cardiac tissue.
5.2 Pharmacokinetic properties
Amitriptyline is readily absorbed from the gastro-intestinal tract, peak plasma concentration occurring within about 6 hours.
Amitriptyline slows gastro-intestinal transit time, absorption can therefore be delayed, particularly in overdosage. It is extensively demethylated in the liver to its primary active metabolite, nortriptyline. Amitriptyline and nortriptyline are further metabolised by hydroxylation, n-oxidation and conjugation with glucuronic acid.
Amitriptyline and nortriptyline are widely distributed throughout the body and bound to plasma and tissue protein. Estimated half-life of amitriptyline range from 9-25 hours. Plasma concentration of amitriptyline and nortriptyline vary widely between individuals.
Amitriptyline and nortriptyline cross the placental barrier and are excreted in the breast milk.
Amitriptyline is excreted in the urine mainly in the form of its metabolites, either free or in conjugated form.
5.3 Preclinical safety data
There are no pre-clinical data of relevance 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 BP
Povidone BP Magnesium Stearate BP Maize Starch BP
Film-Coating Materials
Opaspray Yellow M-IF-6006B HSE
Hydroxypropyl methylcellulose (E464) HSE (Methocel E5 Premium) Hydroxypropyl methylcellulose HSE (Methocel E15 Premium)
6.2. Incompatibilities
Concomitant administration of monoamine oxidase inhibitors (MAOIs).
6.3. Shelf Life
- 3 years for product packed in opaque plastic containers.
- 2 years for product packed in blister packs.
6.4. Special Precautions for Storage
Keep out of the reach of children. Protect from light and moisture.
6.5. Nature and Contents of Container
(a) opaque plastic containers composed of polypropylene tubes and polyethylene made tamper-evident closures, for all pack sizes (28, 42, 50, 56, 84, 100, 112, 250, 500 and 1,000 tablets).
(b) High Density Polypropylene (HDPP) or High Density Polyethylene (HDPE) opaque plastic containers with tamper evident or child resistant closure composed of High Density Polyethylene (HDPE) for all pack sizes (28, 42, 50, 56, 84, 100, 112, 250, 500 and 1,000 tablets).
Packing inclusion standard polyether foam or polyethylene or polypropylene made filler.
(c) Blister packs composed of aluminium foil and opaque PVC in pack size of 28, 42, 56, 84 and 112.
6.6. Instruction for Use/Handling
No special instructions for use/handling.
7 MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
Units 3 and 4, Quidhampton Business Units
Polhampton Lane
Overton
Hampshire
RG25 3ED
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 20416/0007
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15 November 2003
10 DATE OF REVISION OF THE TEXT
19/09/2011