Triavil

Uses

Amitriptyline is used for depressive illness, particularly with anxiety and nocturnal enuresis in children.

Perphenazine is a phenothiazine used to treat schizophrenia as well as nausea and vomiting.

For use in the management of the manifestations of psychotic disorders and for the control of severe nausea and vomiting in adults.

Triavil is also used to associated treatment for these conditions: Acute Depression, Anorexia Nervosa (AN), Attention Deficit Hyperactivity Disorder (ADHD), Bulimia Nervosa, Depression, Diabetic Neuropathies, Insomnia, Irritable Bowel Syndrome (IBS), Major Depressive Disorder (MDD), Migraine, Moderate Depression, Neuropathic Pain, Nocturnal Enuresis, Severe Depression, Sleep disorders and disturbances, Tension Headache, Moderate Agitation, Moderate Anxiety, Severe Anxiety, Severe agitationAnxiety, Depression, Schizophrenia, Moderate Agitation, Moderate Anxiety, Moderate Depressed mood, Severe Anxiety, Severe Depressed mood, Severe Nausea and vomiting, Severe agitation

How Triavil works

The mechanism of action of this drug is not fully elucidated. It is suggested that amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain , . These amines are important in regulating mood. The monoamine hypothesis in depression, one of the oldest hypotheses, postulates that deficiencies of serotonin (5-HT) and/or norepinephrine (NE) neurotransmission in the brain lead to depressive effects . This drug counteracts these mechanisms, and this may be the mechanism of amitriptyline in improving depressive symptoms.

Whether its analgesic effects are related to its mood-altering activities or attributable to a different, less obvious pharmacological action (or a combination of both) is unknown .

Binds to the dopamine D1 and dopamine D2 receptors and inhibits their activity. The mechanism of the anti-emetic effect is due predominantly to blockage of the dopamine D2 neurotransmitter receptors in the chemoreceptor trigger zone and vomiting centre. Perphenazine also binds the alpha andrenergic receptor. This receptor's action is mediated by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.

Dosage

Triavil dosage

Depression :

• Adults: Initially 50-70 mg a day in divided dose or as a single dose at night at bed time.
• Elderly and adolescents: 25-50 mg daily in divided doses or as single dose at bed time. Dose can be increased gradually as necessary to a maximum of 150-200 mg. Usual maintenance dose is 50-100 mg daily.

Nocturnal enuresis:

• 6-10 years: 10-20 mg at bed time.
• 11-16 years: 25-50 mg at bed time for up to 3 months and gradually withdrawn.

Side Effects

• Cardiovascular reactions: Hypotension, syncope, postural hypotension, hypertension, tachycardia, palpitations, myocardial infarction, arrythmias, and heart block stroke.
• CNS and neuromuscular: Confusional states, disturbed concentration disorientation, delusions, and hallucinations.
• Anticholinergic: Dry mouth, blurred vision, mydriasis, increased intraoccular pressure, hyperplasia.
• Allergic: Skin rash, urticaria, and photosensitization.
• Haematological: Bone-marrow depression including agranulocytosis, leukopenia, eosinophilia, and thrombocytopenia.
• Gastrointestinal: Nausea, epigastric distress, vomiting anorexia, diarrhoea.
• Endocrine: Testicular swelling, gynaecomastia; breast enlargement, galactorrhoea.
• Other reaction: Dizziness, weakness, fatigue, headache, weight loss

Toxicity

Toxicity Data: Oral TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg .

Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose are further increased by simultaneous ingestion of alcohol and another psychotropic agent . Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma, among others , .

Use in pregnancy

For amitriptyline, only limited clinical data are available regarding its use in pregnancy. Amitriptyline is not recommended during pregnancy unless clearly required and only after careful consideration of both risks and benefits .

Use in breastfeeding

Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % - 1 % of the maternal dose). A risk to the suckling child must be considered. A decision should be made as to whether it is appropriate to discontinue breastfeeding or to discontinue/abstain from the therapy of this medicinal product, considering the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Effects on fertility

Animal studies have shown reproductive toxicity. No data on the effects of amitriptyline on human fertility are available .

Mutagenesis and carcinogenesis

The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. Although these investigations showed some contradictory results, a potential of amitriptyline to lead to chromosome abnormalities cannot be excluded. Long-term carcinogenicity studies have not been performed to this date .

Symptoms of overdose include stupor or coma, and children may have convulsive seizures. Signs of arousal may not occur for 48 hours. Oral LD₅₀=318 mg/kg (rat); IPR LD₅₀=64 mg/kg (mouse)

Precaution

Schizophrenic patients may develop increased symptoms of psychosis; patients with paranoid symptomatology may have an exaggeration of such symptoms. Depressed patients, particularly those with known manic-depressive illness, may experience a shift to mania or hypomania. In these circumstances the dose of Amitriptyline may be reduced or a major tranquilizer such as perphenazine may be administered concurrently.

The possibility of suicide in depressed patients remains until significant remission occurs. Potentially suicidal patients should not have access to large quantities of this drug. Prescriptions should be written for the smallest amount feasible.

Concurrent administration of Amitriptyline hydrochloride and electroshock therapy may increase the hazards associated with such therapy. Such treatment should be limited to patients for whom it is essential.

When possible, the drug should be discontinued several days before elective surgery. Both elevation and lowering of blood sugar levels have been reported. Amitriptyline hydrochloride should be used with caution in patients with impaired liver function.

Interaction

Monoamine oxidase inhibitors can potentiate the effects of Amitriptyline.

Anticholinergic agents: Amitriptylin should not be given with symptomatic agents such as adrenaline, epinephrine, isoprenaline, noradrenaline.

CNS depressant: Amitriptyline may enhance the response to alcohol, barbiturates.

Cemitidine: Cemitidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants.

Volume of Distribution

The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg) . It is found widely distributed throughout the body . Amitriptyline and the main metabolite nortriptyline pass across the placental barrier and small amounts are present in breast milk .

Elimination Route

Rapidly absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations are reached 2-12 hours after oral or intramuscular administration . Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences .

Absolute bioavailability is 40% following oral administration.

Half Life

The elimination half-life (t1⁄2 β) amitriptyline after peroral administration is about 25 hours (24.65 ± 6.31 hours; range 16.49-40.36 hours) .

8-12 hours, but ranges up to 20 hours.

Clearance

The mean systemic clearance (Cls) is 39.24 ± 10.18 L/h (range: 24.53-53.73 L/h) . No clear effect of older age on the pharmacokinetics of amitriptyline has been determined, although it is possible that clearance may be decreased .

Elimination Route

Amitriptyline and its metabolites are mainly excreted in the urine. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with approximately 2% of unchanged drug appearing in the urine . 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours . Small amounts are excreted in feces via biliary elimination .

Perphenazine is extensively metabolized in the liver to a number of metabolites by sulfoxidation, hydroxylation, dealkylation, and glucuronidation.

Pregnancy & Breastfeeding use

Pregnancy Category C. Amitriptyline is not recommended during pregnancy, especially during the first and third trimester because the safety of Amitriptyline has not been established yet.

Amitriptyline is detectable in breast milk. Because of the serious adverse reactions in infants from Amitriptyline, a decision should be made whether to continue breast feeding or discontinue the drug

Contraindication

Amitriptyline is contraindicated in myocardial infarction; arrythmias, particularly heartblock of any degree; mania; severe liver disease. Initially sedation may effect the ability to drive or operate machinery. It should be used with caution in patients with a history of epilepsy, glaucoma, urinary retention, prostatic hypertrophy, constipation, cardiac disease, diabetes, pregnancy, hepatic impairment, thyroid disease, increased intraoccular pressure, psychoses (may aggravate mania).

Storage Condition

Keep containers well closed and stored below 25˚ C, protected from light.

Innovators Monograph

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